ArticlePDF AvailableLiterature ReviewExploring Dysregulated Signaling Pathways in CancerJanuary 2020Current Pharmaceutical Design 26(4)DOI:10.2174/1381612826666200115095937Authors: Sabah NisarSidra Medicine Sheema HashemSidra Medicine Muzafar A MachaIslamic University of Science and Technology Santosh YadavSidra MedicineShow all 10 authorsHide Download full-text PDFRead full-textDownload full-text PDFRead full-textDownload citation Copy link Link copied Read full-text Download citation Copy link Link copiedCitations (5)References (370)AbstractCancer cell biology takes the advantage of identifying diverse cellular signaling pathways that are disrupted in cancer. Signaling pathways are an important means of communication from exterior of cell to intracellular mediators, as well as intracellular interactions that governs diverse cellular processes. Oncogenic mutations or abnormal expression of signaling components disrupt the regulatory networks that govern cell function, thus enabling tumor cells to undergo dysregulated mitogenesis, to resist apoptosis, and to promote invasion to neighboring tissues. Unraveling of dysregulated signaling pathways may advance the understanding of tumor pathophysiology and lead to improvement of targeted tumor therapy. In this review article, we discussed different signaling pathways and how their dysregulation contributes to the development of tumors. Discover the world s research20+ million members135+ million publications700k+ research projectsJoin for freePublic Full-text 1Content uploaded by Geetanjali SageenaAuthor contentAll content in this area was uploaded by Geetanjali Sageena on Oct 06, 2020 Content may be subject to copyright. Send Orders for Reprints to reprints@benthamscience.net Current Pharmaceutical Design, 2020, 26, 1-18 1 REVIEW ARTICLE 1381-6128/20 $65.00+.00 © 2020 Bentham Science Publishers Exploring Dysregulated Signaling Pathways in Cancer Sabah Nisar1, Sheema Hashem1, Muzafar A. Macha2,3, Santosh K. Yadav1, Sankavi Muralitharan4, Lubna Therachiyil5, Geetanjali Sageena6, Hamda Al-Naemi7, Mohammad Haris1,7 and Ajaz A. Bhat1 1Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar; 2Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, USA; 3Department of Biotechnology, Central University of Kashmir, Ganderbal, Jammu and Kashmir, India; 4Peterborough City Hospital, Cambridgeshire, U.K; 5Translational Research Institute, Academic Health System, Hamad Medical Corporation, Qatar; 6Keshav Mahavidyalaya, University of Delhi, India; 7Laboratory Animal Research Center, Qatar University, Doha, Qatar A R T I C L E H I S T O R Y Received: October 11, 2019 Accepted: November 27, 2019 DOI: 10.2174/1381612826666200115095937!Abstract: Cancer cell biology takes advantage of identifying diverse cellular signaling pathways that are dis-rupted in cancer. Signaling pathways are an important means of communication from the exterior of cell to intra-cellular mediators, as well as intracellular interactions that govern diverse cellular processes. Oncogenic muta-tions or abnormal expression of signaling components disrupt the regulatory networks that govern cell function, thus enabling tumor cells to undergo dysregulated mitogenesis, to resist apoptosis, and to promote invasion to neighboring tissues. Unraveling of dysregulated signaling pathways may advance the understanding of tumor pathophysiology and lead to the improvement of targeted tumor therapy. In this review article, different signaling pathways and how their dysregulation contributes to the development of tumors have been d iscussed. Keywords: Angiogenesis, apoptosis, cell invasion, cell proliferation, drug targets, metastasis, signaling pathways, tumor microenvironment. 1. INTRODUCTION Cancer is a disease affecting millions of people worldwide. Cancer cells have the ability to abnormally divide and grow as a result of alteration or mutation in specific genes. The common sig-naling pathways and processes underlying cancer are now easily understood due to the advanced DNA sequencing over the past few years [1]. The genes and pathways altered, varies across different individuals and different types of tumor. There must be a complete understanding of all these dysregulated cancer pathways in order to identify and broaden therapeutic options [2]. The cell signaling systems that control the fate of the cell are disrupted by oncogenic mutations which contribute towards the malignant behavior of the tumor cells. The development of a malignant tumor depends on the acquired traits of cancer cells, which are known as \"Hallmark s of cancer”. There are ten major hallmarks of cancer: sustained prolif-erative signals, replicating immortality, evad ing growth suppres-sion, resisting cell death, activ ating invasion m etastasis, inducing angiogenesis, tumor-promoting inflammation, avoiding immune destruction, genomic instability mutation, and deregulated cellu-lar energetics [3]. Many studies have shown that solid tumors are highly complex eco-system infiltrated with many immune cells, endothelial cells, cancer-associated fibroblasts (CAFs), endocrine cells entangled in the extracellular matrix (ECM) proteins which together make the Tumor Microenvironment (TME). This TME, by secreting various growth factors, immune-suppressive factors recruit tumor-promoting macrophages, inflammatory cells, cancer-associated fibroblasts [4], help escape immune recognition [5], and provide a permissive environment for tumor progression, metastasis and de-velopment of resistance to therapy [6]. In addition, th e accumula-tion of genetic and epigenetic alterations during the cancer *Address correspondence to this author at the Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar; Tel: +974 40 037 407 ; E-mail: abhat@sidra.org progression results in the clonal selection of cells with more aggres-sive ph enotypes. As the tumor size increases, its core loses access to the oxygen and nutrients th at promote the formation of new blood vessels called angiogenesis as a compensatory mechanism to obtain more oxygen and nutrients, thus allowing cancer cells to enter the blood circulation to establish distant metastasis. Recent high throughput genomic data has identified a trove of mutations that result in the deregulation of many signal transduction pathways promoting cellular characteristics favoring carcinogenesis. In this review, the deregulated pathways imparting proliferative, survival, and invading advantages to various tumors have been comprehen-sively describ ed [7]. 2. SIGNALING PATHWAYS Many signaling pathways are interconnected with each other and form complex networks. The activ ation of these cellular path-ways by various external and internal cues and their integration lead to the execution of various cellular functions controlling cell growth, motility, cell architecture polarity, differentiation, pro-grammed cell death, protein synthesis, etc. [8] (Fig . 1). While these signaling pathways are precisely controlled in normal cells, the deregulation of these pathways results in uncontrolled proliferation and development of cancers. The most common geneti-cally/epigenetically altered signaling pathways in various cancers are discussed below [2]. 2.1. ErbB/EGFR Signaling Pathway The ErbB family, including ErbB-1/EGFR, HER2/neu/ErbB-2, HER3/ErbB-3 and HER4/ErbB-4 is a family of receptor tyrosine kinases that modulate numerous signal transducers and activate many intracellular pathways [9]. While mutations and alternative splicing play an important role in protein function, expression, an d their stability, mutated and truncated EGFR (EGFRvIII) has been shown to play an important role in the development, progression, metastasis and therapeutic resistance of many cancers including 2 Current Pharmaceutical Design, 2020, Vol. 26, No. 00 Nisar et al. head and neck squamous cell carcinoma (HNSCC ). These family members and some of their ligands are often overexpressed, ampli-fied, or mutated in many cancers resulting in constitutive activation of these signaling molecules. The binding of ligands (EGF, heparin binding EGF (HB-EGF), transforming growth factor-α (TGF-α), amphi-regulin, epigen, beta cellulin (BTC), and epiregulin (EPR) to EGFR and binding of neuregulins (NRG-1, NRG-2, NRG-3 and NRG-4) to ErbB3 and ErbB4 receptors except ErbB2 results in their homo/heterodimerization, trans-phosphory-lation of tyrosine residues on cytoplasmic domain and subsequent activation of sev-eral downstream pathways, including PI3K/Akt, STAT, Ras/Raf/ MAPK/ERK, and the PLC-γ signaling pathways. Through these downstream signaling molecules, ErbB signaling pathway regulates cell adhesion, invasion motility, survival and cell cycle progres-sion, inflamm ation, and controls protein synthesis, angiogenesis, cancer stem cell maintenance and chemo-radiation therapy (CRT) resistance [10, 11]. 2.2. P13K/AKT Signaling Pathway PI3K/AKT signaling pathway controls cellular processes, in-cluding proliferation, grow th, survival and cellular m etabolism [7]. Unfortunately, this signaling pathway is the most frequently dys-regulated in cancers and promotes tumor progression and metasta-sis. Various cellular pro cesses considered to be hallmarks of cancer are also regulated by AKT [12]. The underlying pro-tumorigenic effects of AKT involve the BAD phosphorylation thereby prevent-ing cytochrome-c release from mitochondria [13] and inhibit apop-tosis. In addition, it induces phosphorylation and inactivation of FOXO transcription factors to decrease the expression of apoptotic genes. By regulating the expression of Matrix Metalloproteinases (MMPs), AKT also regulates tumor cell migration, invasion and metastasis [14]. Vascular Endothelial Growth Factor (VEGF) by activating Flk1/VEGFR2-PI3K-AKT pathway in endothelial cells promotes angiogenesis and survival during tumor development [15]. Among multiple factors leading to aberrant activation of PI3K/AKT signaling pathway in cancers, genomic alterations in critical genes such as PIK3CA, PIK3R1, AKT, PTEN, TSC1, TSC2, LKB1 and mTOR are among the important ones in addition to constitutive activation of upstream ErbB receptor tyrosine kinases [16, 17]. PIK3CA encoding the catalytic subunit p110α is one of the most mutated oncogene in human cancers including brain, BC, CL, gastric (GC) and endometrial cancers (EmC) [18, 19]. AKT, a serine/threonine kinase is frequently activated in many human primary tumors like carcinomas such as thyroid [20, 21], papillary thyroid [22], small cell lung [23], non-small cell lung [24-27], breast [28-31], gastric [32], pancreatic [33, 34], ovarian [31, 35], prostate [31, 36], renal [37] and endometrial [38] carcinomas including Glioblastoma Multiforme (GBM) [39], various hemato-logical malignancies, and correlates with advanced stag e of the disease and/or poor prognosis [40]. For example, elevated activity of AKT1 has been found in 40% of BC OC, ≥ 50% in PCa and 80% of high-grade carcinomas [31]. While activated AKT2 has been reported in 30-40% of OC and PCs [41, 42], activated AKT3 has been shown in ER-ve BC and androgen- insensitive PCa cell lines [43]. The missense mutations in the PH domain of AKT1 result in its localization to the plasma membrane and associated with its prolonged activation [44]. In addition to mutations, amplifi-cation (20-fold) of AKT1 in GCs [45], increased levels of PIK3CA in OCs [46], and AKT2 in undifferentiated PC, OC and BC [47] were also reported. In corroboration with these studies, phosphory-lated mamm alian target of rapamycin-1 (mTOR) and forkhead box proteins (FOXO), downstream effectors of AKT has been reported in many cancers [48, 49]. Furthermore, mutational inactivation of phosphatase and tensin homolog (PTEN, tumor suppressor gene) in melanoma, PCa, renal, EmC and non-small cell lung cancers Fig. (1). Signaling pathways that control three core cancer functions and commonly dysregulated are cell survival, cell fate, and genome maintenance. HH; Hedgehog, APC; Adenomatous polyposis co li. (A higher resolution / colour version of this figure is available in the electronic copy of the article). Exploring Dysregulated Signaling Pathways in Cancer Current Pharmaceutical Desig n, 2020, Vol. 26, No. 00 3 (NSLC) [19, 50, 51] also result in constitutive activation of AKT. PTEN dephosphorylates the third position of phosphatidylinositol causing inhibition of th e AKT activ ation [52]. 2.3. The RAS/RAF/ERK and MAPK Pathways In addition to PI3K/AKT, ErbB/EGFR signaling pathway also activates RAS/RAF/MEK/ERK and M APK signaling pathway s [53]. While the MAPK pathw ay activates E-26 Transformation-Specific (ETS) family of proteins, ephrin receptor EphA2 [54] and regulates the expression of anti-apoptotic genes [8], RAS/RAF/ MEK/ERK modulates the expression of cell cycle control gen es and EGFR ligands [55] thereby controlling survival and proliferation, respectively. RAS, including H-RAS, K-RAS, and N-RAS belong to a family of small GTPase’s and were the first oncogenes to be identified in human tumors nearly three decades ago [56]. Interest-ingly, RAS proteins are highly mutated in various cancers such as PC, LC, CRC, melanoma, thyroid cancer (TC) and biliary tract carcinoma (BTC). Surprisingly, 90% of PC patients have a muta-tion in KRAS in codon 12 (KRASG12D). While the mutations in H-RAS and N-RAS are rare [57], but melanomas [58, 59] and salivary gland tumors [60, 61] have a high rate of mutations in N-RAS and H-RAS respectively. RAS, by interacting with effector rapidly ac-celerated fib rosarcoma (RAF), activates MAPK and RAF-MEK-ERK signaling pathways [62]. RAF, is a highly conserved family of serine/threonine kinases including A-RAF, B-RAF, and C-RAF. Many studies have shown that inappropriate activation of the RAF proteins results in abnormal cell differentiation and the develop-ment of cancers. Like RAS proteins, RAF particularly BRAF, is highly mutated in many cancers, including melanoma [63], TC [64], CRC [65] and NSCLC [66]. The most prevalent single-base missense mutation in melanomas and TCs includes the substitution of valine for glutamic acid at codon 600 (V600E) [67, 68] that leads to hyperactiv ation of the MAPK pathway [69] and promotes tu-morigenesis [68, 70]. This V600E mutation is reported in ~45% of papillary TC (PTC) and 25% of undifferentiated TCs [67, 68, 71]. Though single base mutations in A-RAF and C-RAF are rare, trun-cated forms of these proteins are reportedly in some can cers at shal-low frequency [72, 73]. 2.4. Notch Signaling Pathway Notch signaling is an essential developmental pathway that plays a crucial role in cell survival, proliferation and differentiation. Also, recent studies highlighted its oncogenic role that promotes the progression and development of several cancers by imparting cell survival and angiogenesis [74, 75] and EMT [76-78]. The notch is a highly conserved pathway in both vertebrates and invertebrates. It is pertinent to mention that the activation of Notch signaling re-quires three proteolytic events. The first cleavage called S1 takes place in the Golgi apparatu s resulting in two peptides called ex-tracellular Notch subunit (ECN) and Notch transmembrane subunit (NTM) [79, 80]. The second cleavage S2 occu rs by tumor necrosis factor-α-converting enzyme (TACE), a disintegrin and metallopro-tease (ADAM) near th e plasma membrane [81] and creates a short-lived and a membrane-bound intermediate. The membrane-bound intermediate is cleaved by an intramembrane protease γ-secretase (third cleavage (S3) and produces a Notch Intracellular Domains (NICD) th at translocate into the nucleus [82, 83]. Notch signaling was first identified as a cancer promoter in lymphoblastic leukem ia (T-ALL). Later studies revealed Notch-1 activating mutations in 50% of all human T-ALLs that occur in extracellular heterodimerization domain and the C-terminal PEST domain [84]. In addition, the oncogenic role of Notch has also been reported in human and murine BCs [85-89]. While the mutational activation of Notch is rarely observed in BC’s, 50% of human BC’s show reduced levels of Notch negative regulator Numb [90]. The underlying mechanisms of Notch-mediated tumorigenesis re-vealed regulation of c-MYC expression [91] and suppression of p53 function [92] in T-ALL, resulting in increased cell cycle progres-sion and increased cell survival with genomic instability. Studies using microarray analysis also revealed co-expression of Notch-1 and c-MYC in BC patient samples [93]. Interestingly, Notch signa-ling also induces cancer stem cell-like properties in BC cells [86, 94]. In addition, upregulated expression of Notch receptors are observed in PC [95, 96], LC [97], LiC [98] and melanomas [99, 100]. All these studies confer to the importance of targeting Notch signaling in BC and T-ALLs. 2.5. JAK-STAT Pathway The Janus kinase/signal transducer and activator of transcrip-tion (JAK-STAT) pathway by responding to the extracellular cues and initiating a gene transcription program plays a significant role in cell proliferation, differentiation, survival [101] and organize the epigenetic landscape of immun e cells. Currently, seven STAT genes, including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6 that have been identified in the humans, are activated by a plethora of cytokines, like interferons (IFNs), ILs, growth factors (GFs) and hormones. Besides overexpression of cytokines of the interleukin-6 (IL-6) family, the canonical ligand for activation of the JAK-STAT pathway, non-canonical pathways such as GPCRs, microRNA s and stabilization of heterochromatin result in deregulation of JAK-STAT signaling pathway [102]. Inter-estingly, JAK independent activation of STAT by EGFR and an-drogen receptor (AR) signaling has also been suggested by recent studies. Hyperactivated in many human cancers, JAK-STAT path-way either independently or in collaboration with other signaling pathways promotes the development and progression of malignan-cies via regulating gene expression program, generating pro-inflammatory microenvironment, inducing epithelial-mesenchymal transition, promoting cancer stem cell self-renewal differentia-tion, and helping to establish the pre-metastatic niches [103]. While the STAT1 (an essential component o f IFN signaling) is downregu-lated in many tumors and performs a tumor suppressor role [104], constitutive activation of STAT3 and STAT5 in addition to trans-formation of normal cells in culture, positively influences many tumor hallmarks including cell survival, proliferation and invasion, making JAK-STAT pathway a favorite target for drug development and cancer therapy [105]. In addition to direct gene regulation, STAT3 also regulates many transcription factors thereby, adds complexity to the transcriptional control. On the contrary, tumor-suppressive functions of STAT3 has been reported in KAS!induced lung carcinogenesis using APC!mutant mice model and its overexpression associated with better prognosis in CRC, leiomyo-sarcoma and nasopharyngeal carcinoma patients [104]. While epi-genetic changes, miRNA- and hormone-regulated TFs promote constitutive STAT5 (STAT5a STAT5b) activation in many can-cer; however, mutation al activation is exclusively found in humans hematologic cancers [106]. Though suggested to be tumor suppres-sor in BC and nasopharyngeal cancers [107, 108], STAT5 by regu-lating the activation of VEGF mediated proliferativ ely and survival TGF-β, PI3K/PTEN HIF1α signaling pathways; anti-apoptotic signals by down-regulation of miRNA15/16 up-regulation of Bcl-2, MCL-1 Bcl-XL; DNA damage by up-regulating RAD51 and cell cycle transition by up-regulating cyclin D1, D2, D3 c-myc play a vital role during carcinogenesis of many solid tumors [104]. Interestingly, 9p24 locus containing the JAK2 gene is ampli-fied in triple-negative BCs (TNBCs) patients treated with neoadju-vant chemotherapy [109] confirming its tumor suppressor role. Overall, activation of each STAT family member seems to be spe-cific to can cer type as pSTAT3 immunostaining is associated with higher lymph node metastases recurrence in melanoma patients, but the inverse is true for pSTAT1 expression. Similarly, pSTAT3 over expression correlates with a higher survival rate of BC pa-tients, but pSTAT5 immunostaining was associated with lower survival of PCa patients [101]. Interestingly, STAT3 plays an im- 4 Current Pharmaceutical Design, 2020, Vol. 26, No. 00 Nisar et al. portant role in the inflammation mediated cachexia, the muscle atrophy and adipose wasting in cancers [110]. 2.6. Hedgehog (Hh) Signaling Pathway The hedgehog pathway (Hh) is also an important developmental pathway and its deregulation or activation is associated with the development of one-third of all the malignant tumors [111, 112]. This constitutively active Hh signaling can be classified into ligand-independent (type I), autocrin e/juxtacrine ligand-dependent (type II) and paracrine or reverse paracrine ligand-dependent (Type IIIa/b) [113]. Type I signaling occurs due to mutational activation in smoothened (SMO)or patched 1 (Ptch1) or inactivation in nega-tive Hh regulator, fused homolog (Sufu) protein s [114]. While the Ptch1 mutation was first identified in patien t Gorlin syndrome [115], later studies identified them in many tumors such as trichoepitheliomas [116], esophageal (ESC) and BlC [117, 118]. In addition, both Ptch1 and Sufu mutations were also observed in rhabdomyosarcoma, a rare muscle tumor [119]. Ptch2 mutations are scantly found in Basal Cell Carcinomas (BCCs), but their percent-age is high in Medulloblastoma (MB) [120]. On the other hand, type II Hh signaling is observed in GC, ESC, PC, [121], CRC [122], OC [123], BC [124], PCa [125], LC [126], melanomas [127], and gliomas [128]. Though high transcript levels of sonic hedgehog (SHh) ligand were found in CRC [129, 130], contradictory observa-tions were also reported [121, 131, 132]. Type III Hh signaling utilizes paracrine or reverses paracrine signaling in which the Ptch1 receptors present either on the tumor or stromal cells bind to the ligands released either by the tumor or stromal cells resu lt in the activation of Hh signaling pathway. Type III pathway in which SHh signaling is activated in stromal cells was reported in PCa, PC an d CRCs. In this connection, PCa cells have been shown to activate Hh signaling in stromal cells in a lig and-dependent or paracrine manner [133]. On the contrary, reverse paracrine signaling in which Hh ligands are secreted from bone marrow cells and activated signaling in the tumors were observed in hematological malignancies such as B-cell lymphoma, leukemia and multiple myeloma [134, 135]. 2.7. Wnt Signaling Pathway The Wnt signaling pathway plays a critical role in embryonic development and tissue homeostasis by regulating proliferation, cell adhesion, migration, structural remodeling, differentiation, fate determination, adipogenesis, aging, etc. Therefore, the deregulation of Wnt signaling has been associated with many human diseases like neurodegeneration and cancers. Wnt signaling pathway is di-vided into canonical, non-canonical Planar Cell Polarity (PCP) and non-canonical Wnt/calcium pathways. In the canonical Wnt path-way, the Wnt ligand binds to the Frizzled receptors, low-density lipoprotein receptor-related protein 5/6 (LRP5/6) and co-receptors for the initiation of intracellular signaling via nuclear translocation of β-catenin. Non-canonical PCP pathway is activated upon binding of Wnt ligands which bind to the Frizzled receptors and recruitment of Dishevelled followed by activation of small GTPases such as Ras homolog gene family member A (RhoA), Ras-related C3 botu-linum toxin substrate (RAC) and cell division control protein 42 (Cdc42) [136]. The PCP pathway is responsible for the activation of target genes that are involved in cell adhesion and migration [137]. On the other hand, the Ca2+-dependent pathway is activated when Wnt ligands bind to Frizzled and alternative receptors receptor-lik e tyrosine kinase (RYK) or retinoic acid receptor-related orphan re-ceptor (ROR) that result in intracellular Ca2+ flux and activation of calmodulin kinase II (CaMK2), Jun kinase (JNK) and protein kinase C (PKC) thereby enhancing cell migration [138, 139]. Deregulation of Wnt/β-catenin signaling has been reported in many human cancers. The overexpression of many Wnt pathway components such as Wnt ligands Wnt1 [140], Wnt2 [141], Wnt2B2 [142] and Wnt3A [143], frizzled receptors Fzd7 [144] and Fzd10 [145] and Dishevelled (Dvl) family members that result in aberrant Wnt/β-catenin signaling pathway has been reported [146, 147]. In addition, loss of negative Wnt regulators due to DNA methylation, epigenetic gene silencing and histone modification contributing to Wnt/β-catenin signaling pathway activation has also been reported. In fact, recent studies showed epigenetic silencing of negative Wnt regulators than mutation s activating Wnt/β-caten in signaling during the early stages of tumor dev elopment [148-150]. While Wnt1, Wnt2, Wnt3A and Wnt5A proteins are overexpressed in GC [151], Wnt1 in BC [140], Wnt2 in CRC [152], Wnt5A in LC [153] and Wnt3A in PCa [143], Wnt5A antagonizes Wnt/β-catenin signaling and inhibits proliferation of hematopoietic cancer cells [154, 155]. Similarly, Wnt7A is epigenetically inactivated in PC [156], and Wnt9A is in CRC and ALL [157]. In addition, downregulation of extracellular Wnt antagonists such as SFRP1, SFRP2, SFRP4, SFRP5, WIF1, DKK1, DKK2 and DKK3 by aberrant promoter methylation leading to the activation of canonical Wnt/β-catenin signaling is one of the examples [148, 158-163]. APC, Axin and dapper antagonist of catenin (DACT) family members are essential components of the β-catenin destruction complex. The epigenetic silencing of APC, Axin and DACT3, a negative modulator of Wnt/β-catenin signaling is a hallmark of CRCs. The transcription of Wnt target genes is negatively regulated by the interaction of SRY-box containing genes SOX7 and SOX17 with the nuclear transcrip-tion complex TCF/LEF [164]. However, the downregulation of SOX17 by promoter methylation contributes to the aberrant Wnt/β-catenin signaling activation in CRC and BCs [164, 165]. Another negative regulator of the Wnt/β-catenin signaling, epithelial adhe-sion molecule E-cadherin (CDH1) is also downregulated by pro-moter methylation [166-168]. 2.8. Nuclear Factor-κB Nuclear Factor-κB (NF-κB) is a transcription factor that con-trols the expression of cy tokines, chemokines, immune and in-flammatory mediators that are crucial for response to stress, growth, development and survival [169-172]. Th e aberrant NF-κB contrib-utes to the development of various disorders including atherosclero-sis, multiple sclero sis, rheumatoid arthritis, inflammatory bowel diseases and development of many tumors [173]. NF-κB is dys-regulated in the majority of human tumors and promotes cell prolif-eration, protects can cer cells from apoptosis, and enhances metasta-sis [174-176]. Many mutations, chromosomal translocations, and deletions disrupt NF-κB and IκB (inhibitors of NF-κB) [177, 178] genes resulting in constitutive activation of these signaling path-ways and cancer development [176]. Many studies reported in-creased activity of NF-κB as evidenced by elevated NF-κB-DNA binding in BC, [179, 180], CRC, and stromal macrophages in spo-radic adenomatous polyps [181] that are associated with increased reactive oxygen species (ROS) production [182] and DNA damage. The anti-apoptotic effects of NF-κB involves the transcriptional control of TNF -α and pro-apoptotic mediator [183-185] induced expression of cellular inhibitors of apoptosis (cIAPs), caspase-8/Fas-Associated Death Domain (FADD)-like IL-1β converting enzyme (FL ICE), inhibitory protein (c-FLIP) and members of the Bcl2 family (such as A1/BFL1 and Bcl-xL) [185]. Increased mig ra-tion of cancer cells involves the expression of chemokines [169] and the destruction of the extracellular matrix [186, 187] by NF-κB. By regulating IL-8 expression, NF-κB promotes angiogenesis dur-ing cancer progression and metastasis [188]. NF-κB can block the proliferation of tumor cells and make the tumor cells more sensitive to the action of anti-tumor agents [189]. 2.9. GPCR Signaling Pathway G-Protein Coupled Receptors (GPCRs), the largest family of signaling receptors are seven-transmembrane helical cell surface proteins that act as an important source of communication between the intra- and extracellular environments [190]. These GPCRs re-spond to an array of extracellular signals, including lipids, photons, peptides, proteins, biogenic amines, etc. to regulate many physio- Exploring Dysregulated Signaling Pathways in Cancer Current Pharmaceutical Desig n, 2020, Vol. 26, No. 00 5 logical pro cesses like cell metabolism, differentiation, sensory per-ception and neurotransmission. There are five subcategories of GPCRs namely secretin, glutamate, adhesion, rhodopsin and friz-zled [191]. The structure of GPCR contains three domains: the Ex-tracellular Region (ECR), the Transmembran e Region (TM) and the Intracellular Region (ICR) [192]. While the main function of ECR is the initiation of binding of specific ligands, the TM region con-trols the transduction of extracellular signals through conforma-tional changes. The ICR region is involved in the transduction of intracellular signaling by interacting with coupled trimeric G pro-teins (heterotrimers Gα, β, and γ subunits) [192, 193]. Coupled trimeric G- protein complexes are activated by stimuli such as small ions, amino acids, neurotransmitters, chemokines or protein ligands [194, 195]. Upon activation by ligand binding, GPCRs undergo a conform ational change and interact with Gαβγ heterocomplex re-sulting in exchange of guanosine-5’-triphosphate (GTP) for guanosine-5’-diphosphate (GDP) bound to Gα subunits. This causes separation of the Gα-GTP subunit from the Gαβγ heterocomplex that help it to interact with its downstream signaling effectors and modulate signaling pathways [190, 196]. In addition to normal physiological functions, many recent studies have shown deregulation of GPCR s particularly GPCR68 in various cancers including PC, OC, GC, appendiceal tumors, CLL, CRC, anaplastic thyroid cancers (ATC), GBM, and BC cell lines, PC, atypical fibroxanthoma (AFX), and pleomorphic dermal sar-coma (PDS). [197]. Though rare in cancers, many mutational acti-vations of certain GPCR members have been reported in a variety of endocrine tumors [197]. GPCRs regulate signaling pathways important to modulate many hallmarks of cancer such as cell prolif-eration, inhibition of apoptosis, immune evasion, tumor invasion, angiogenesis, and metastasis and, therefore critical for initiation and progression of tumors. As mentioned earlier the importance of stromal cells in cancer development, overexpression of GPCR has been reported in cancer-associated fibroblasts (CAFs) from PC, GCs, appendiceal [198] and CRCs [199]. Interestingly, decreased extracellular pH induces GPCR expression in CAFs that increase IL-6 expression through cAMP/PKA/CREB signaling pathway activation thereby increasing PC proliferation [198]. In addition to CAFs, GPCR is highly upregulated in medulloblastomas tumors [200]. While GPCR is over expressed in many cancers, its signifi-cant downregulation in metastatic than primary PCa tumors sug-gests its tumor suppressor role [201]. The orthotropic injection of PCa PC3 cells transfected with GPCR develops tumors only in the prostate lobe compared to metastasis to liver, spleen, kidney, stom-ach, lung, lymph nodes, diaphragm, and mesentery by vector-transfected PC3 cells [202]. Similar results were also observed in OC cells with GPCR overexpressed cells resulting in decreased cell proliferation, migration and metastasis [203]. Subsequent studies showed increased infiltrating T-cells in the subcutaneous prostate tumors in GPR68 KO mice [204]. 2.10. Hippo-YAP Signaling Pathway The Hippo-YAP1/TAZ is an evolutionarily conserved pathway that regulates multiple physiological processes like cell growth, metabolism, morphogenesis, cell-cell communication, cell adhe-sion, signal transduction, cytoskeletal remodeling apico-basolateral polarity [205, 206], organ regeneration [207], and angiogenesis [208]. Under physiological conditions, hippo pathway mediated phosphorylation of yes-associated protein-1 (YAP-1; henceforth referred to as YAP) by Large tumor suppressor kinase 1/2 (LATS1/2) results in its interaction with 14-3-3 protein, and its sequestration in the cytoplasm for proteasomes degradation. Along with YAP cytoplasmic retention, its homolog protein transcriptional coactivator with PDZ-binding motif (TAZ), is also prevented from unclear translocation. However, deregulation of this pathway pro-motes constitutive activation and nuclear translocation of these proteins where they bind to TEA Domain transcription factor (TEAD) resulting in transcriptional upregulation of many genes [209]. Many recent studies showed the deregulation of Hippo signal-ing pathway and its role in the development of many human malig-nancies [210], functioning either as oncogene or tumor suppressor. Amplified or hyperactivated in a number of human solid tumors [211], YAP interaction with TEAD regulates the expression of a gene signature that is involved in cell proliferation, invasion and suppression of apoptosis [212, 213]. Interestingly, GPCRs that are deregulated in many cancers are one of the powerful inducers of the YAP oncogenic pathway [214-217], by stimulating the transcrip-tional activity [205, 216, 218-220]. While GPCRs inhibit large tumor suppressor (LATS) through interaction with Gα12/13 and release YAP from LATS inhibition [216], a recent study showed Gαq mutations responsible for YAP activation than by GPCRs [221]. Another study showed activation of YAP/TAZ pathway by Wnt5a/b and Wnt3a mediated signaling [222]. In contrast to these studies, YAP is downregulated in BC and hematological malignan-cies (mu ltiple myeloma, leukemia lymphomas) and functions as a tumor suppressor. Keeping in mind the importance of YAP/TAZ in cancer development, inhibition or activation of this signaling pathway can be an important therapeutic measure [209]. 2.11. JNK MAPK Pathway Jun N-terminal kinase or Stress-Activated Protein Kinase (JNK/SAPK) is a memb er of the Mitogen-Activated Protein Kinase (MAPK) family which is responsive to a diverse array of stimuli such as osmotic stress, heat shock, mitogens and proinflammatory cytokines. The JNK-MAPK pathway interacts with the p53 path-way and the signaling increases stability and transcriptional activa-tion of p53 [223]. Under normal conditions, JNK regulates the function of target proteins in their unphosphorylated state by ubiq-uitination and upon activation in response to stress stimuli mediates the phosphorylation, which protects its substrates from ubiquitina-tion and degradation [224-226]. Both JNK and p53 are regulated by tumor necrosis factor-alpha (TNF-α). They are involved in the regu-lation of apoptosis and autophagy modulation and are mostly found to be dysregulated in cancers. JNK and Extracellular Signal-Regulated Kinases (ERK) are involved in the mediation of TNF α-induced p53 activation in the process of apoptosis and autophagy [227]. 2.12. p38 MAPK Pathway p38, also a member of the MAPK superfamily is deregulated in many cancers. Similar to JNK, p38 MAPK pathway is stress-activated and modulates proliferation, differentiation, migration, and cell su rvival. Interestingly, by regulating gene expression, cell growth, and apoptosis [228], p38 MAPK pathway is involved in the pathogenesis of many cancers including prostate cancer (PCa) [229-231], BC [232, 233], bladder cancer (BlC) [234], liver cancer (LiC) [235], LC [236] transformed follicular lymphoma [237], and leu-kemia [238]. While activated p38 MAPK signaling pathway has been shown to contribute to invasion and migration of Epithelial-Mesenchymal Transition (EMT), thus promoting extravasation of migrating tumor cells [239, 240] and cell dormancy [241], its tumor suppressor role has also been reported. In this connection, TNF-α regulated p38 MAPKs has been shown to promote apoptosis and autophagy of cancer cells [242] and inhibition of this signaling pathway result in anoikis (death of cells detached from basement membrane) resistance [243]. These tumor-suppressing activities of the p38 MAPK signaling pathway are mediated through Ras/Raf/ERK suppression [244, 245], p53-induced apoptosis and by negatively regulating cell cycle progression [246-249]. These observations were further corroborated using mice models with disrupted p38α or MEK3 and MEK6 genes [246, 250-252]. While both tumor-promoting and tumor-suppressing roles are evident, the 6 Current Pharmaceutical Design, 2020, Vol. 26, No. 00 Nisar et al. p38 MAPK signaling pathway seems to be a valuable therapeutic target in various solid tumors [253]. 2.13. p53 Pathway p53, also called a guardian of the genome is a well-known tu-mor suppressor that plays an important role in maintaining genomic integrity and regulates cell cycle progression, programmed cell death, and senescence [254]. Under normal conditions, p53 is ex-pressed at very low levels due to a negative feedback loop involv-ing MDM2 [255] mediated proteasome degradation [256-258], blocking its tumor suppressor function [259]. However, elevated p53 levels due to stress conditions or oncogene activation result in disruption of the cell cycle, apoptosis or senescence by upregulating p21, Bcl-2 associated X protein (BAX), p53 up-regulated modula-tor of apoptosis (PUMA) and phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) [260-262]. Ubiquitously mutated in solid tumors, deregulation of p53 pathway is observed in many cancers including breast cancer (BC) [263], colorectal cancer (CRC) [264], pancreatic cancer [265], ovarian cancer (OVC) [266], lung cancer (LC) [267], and Head and Neck Squamous cell carci-noma (HNSCC) [268]. 2.14. Salmonella and CDC42RAC Pathway The Salmonella and CDC42RAC pathway are involved in the processes of cell invasion and migration. In the pancreatic tumors, the CDC42 gene plays an important role as it is differentially ex-pressed in four dysregulated pathways. Cell migration is regulated by the CDC42RAC pathway through interaction with p85, a subunit of Phosphatidylinositol-3 Kinases (PI3Ks). CDC42 gene is acti-vated by p85 and stimulated the migration process [227, 269]. 3. ALTERED CELLULAR METABOLIC PATHWAYS IN CANCER Dysregulation of cellular metabolism is one of the major hall-marks of can cer. Oxygen radicals that are produced in metabolism contribute to oncogenic mutations. Altered metabolism leads to the activation of oncogenes and contributes to the loss of tumor sup-pressor genes, which induce aerobic glycolysis or Warburg effect. There is high uptake and utilization of glucose in cancer cell me-tabolism to support the growth and proliferation of cancer cells. Glutamine, glucose produced via glycolysis, ATP and NADPH, all together promote the growth of cancer cells in hypoxic conditions that in turn, lead to the rewiring of metabolic pathways to enhance cancer cell growth and survival. Th e two major metabolic pathways that are dysregulated in cancer are the pentose phosphate pathway (PPP) and the Glycolytic metabolism pathway, which will be dis-cussed in detail in the sections below. 3.1. Pentose Phosphate Pathway (PPP) The Pentose Phosphate Pathway (PPP) is a metabolic pathway that is parallel to glycolysis. This pathway plays an important role in cancer cell survival and is a major source for nicotinamide-adenine dinucleotide phosphate (NADPH) required for anabolic processes such as synthesis of fatty acids and cell survival under stress [270, 271]. Even in the presence of oxygen, most of the can-cer cells consume glucose through the process of gly colysis, known as the Warburg effect resulting in the production of pyruvate and lactate [272]. This utilization of glucose through aerobic glycolysis allows the efficient proliferation of cancer cells by the generation of sufficient amounts of ATP, amino acids, fatty acids and other bio-molecules [273]. High expression of Glucose-6-Phosphate Dehy-drogenase (G6PD) is found to be associated with Hepatocellular Carcinoma (HCC) and the proliferation and migration of HCC cell lines is found to be inhibited by knockdown of G6PD [274]. G6PD promotes the proliferation and migration of HCC cells and induces EMT by activating the signal transduction and activator of tran-scription 3 (STAT3) pathway [274]. There are many key enzymes in the glyco lysis pathway involved in the carcinogenesis of HC C and the enzymes that catalyze the first step of glucose metabolism vary in both normal hepatocytes and HCC cells. In normal hepato-cytes, the enzyme that cataly zes the first step of glucose metabolism is glucokinase, while in HCC, th is enzyme is replaced by hexokinase-2 (HK2) [275]. G6PD is also found to be upregulated in breast cancer [276, 277]. Silencing of G6PD is found to increase glutamine uptake and glycolysis flux and reduce lipid synthesis in breast cancer cells [278]. The inhibition of G6PD has been found to increase 5′AMP-activated protein kinase (AMPK) signaling, lead-ing to a reduction in lipid biosynthesis, ultimately inhibiting the growth of BC cells [279]. Overexpression of G6PD has also been reported in NSCLC [280]. The sensitivity of lung cancer cell lines to cisplatin is enhanced by inhibiting G6PD by the induction of oxidative stress [281]. On the other hand, 6 -Phosphogluconate De-hydrogenase (6PGD) plays a role in the promotion of cisplatin re-sistance in lung cancer cells by decreasing the expression of miR-NAs (miR-206 and miR-613) [282]. 6PGD also aids in the migra-tion of lung tumor cells by promoting the phosphorylation of c-MET at tyrosine residues [283]. 3.2. Warburg Effect (Glycolytic Metabolism Pathway) The glycolytic rate of cancer cells is abnormally high due to the large consumption of glucose and most of the glucose is converted to lactate due to the Warburg effect [284]. Oncogenes and tumor suppressor genes regulate the altered expressions of glyco lytic en-zymes that lead to the disruption of growth signaling pathways causing increased cell division, proliferation and apoptosis inhibi-tion. Transcription factors such as hypoxia-inducib le factor (HIF-1) and c-MYC play an important role in glucose metabolism [285-287]. HIF-1 helps to shift the glucose metabolism in hypoxic tumor cells from the efficient oxidative phosphorylation pathway to the glycolytic pathway in order to maintain a steady energy level [284]. Moreover, activated HIF-1 inhibits th e oxidative phosphorylation pathway by upregulation of pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase-A (LDH-A) genes [288, 289]. HIF-1 also promotes the synthesis of fatty acids by upregulating sterol regulatory-element binding protein (SREBP)-1 and fatty acid synthase (FASN) [290]. On the other hand, c-Myc is involved in cellular processes such as cell growth, proliferation and metabolism and in th e pro cess of angiogenesis in normal cell s [291]. Myc ex-pression is involved in the promotion of anabolic processes that are responsible for rapid proliferation and their overexpression leads to increased tumor cell proliferation and survival [284]. It has been found that gene amplification, chromosomal translocations and single nucleotide polymorphisms are responsible for the aberrant activation of proto-oncogene Myc in many tumors [292]. Onco-genic c-Myc levels cause glutamine addiction in cancer cells and when glutamine is unavailable, the cancer cells undergo apoptosis [284, 293]. Therefore, the involvement of HIF-1 in the process of glycolysis, angiogenesis and fatty acid synthesis [294-296] and the role of c-Myc in ribosomes biogenesis and translation processes [297, 298] shows the significance of these transcription factors in promoting cancer progression and they can be used as an effective target for cancer therapy. 4. INHIBITORS OF ONCOGENIC SIGNALING PATHWAYS Screening of drug libraries using in vitro cell line models is an efficient and economical strategy to identify inhibitors against dys-regulated signaling pathways in cancer [299] (Fig. 2). Using this strategy, Chetomin (CTM), a natural anti-cancer compound from fungus has been shown to restore p53 function and induce expres-sion of downstream targets such as PUMA, p21 and MDM2 in p53 R175H mutant cells [300]. In addition to fungus/plant extracts, cell-penetrating peptide ReACp53 also inhibits p53 amyloid formation and rescues its function in cancer cell lines and high-grade serous ovarian carcinomas organoids (HGSOC) [301]. Similarly, a selec-tive JNK kinase inhibitor SP600125 [302] was shown to inhibit the growth of thyroid cancer [303], GC [304], HNSCC [305], LC Exploring Dysregulated Signaling Pathways in Cancer Current Pharmaceutical Desig n, 2020, Vol. 26, No. 00 7 [306], cholangiocarcinoma [307], CRC [308], PC [309] and GBM [310]. BIRB-796 also called doramapimod is a p38 inhibitor [302] that was used against multiple myeloma (MM) cells to inhibit cell growth [311]. In addition, BIRB-796 also enhanced the therapeutic efficacy of chemotherapeutic agents such as paclitaxel in oral epi-dermoid carcinoma cells overexpressing multidrug resistance pro-tein 1 (ABCB1) [312], and aurora kinase inhibitor VX680 in cervi-cal cancer (CC) [311]. Among the many PI3K inhibitors, GDC-0941 and BKM120 have been shown antitumor clinical efficacy against many cancers. While GDC-0941 synergizes BC, Non-Hodgkin’s Lymphoma (NHL), and NSCLC patients to rapamycin and EGFR targeting agents, BKM120 is being tested in BC, CRC, endometrial, gastrointestinal stromal tumor (GIST ), leukemia, melanoma, NSCLC, PC, renal cell carcinoma (RCC), transitional cell carcinoma, and HNSCC [313]. GSK690693 (GSK) signifi-cantly reduced tumor growth in mice with LNCaP prostate, SKOV-3 ovarian and BT474 breast tumors, and XL-418 (Exelixis, inhibitor of Akt and p70S6K), when combined with XL647, which is a tyro-sine kinase inhibito r, enhanced apoptosis [313]. RO4929097, a γ-Secretase inhibitor of the Notch signaling pathway, was used in metastatic sarcoma [314] and melanoma patients [315]. Two inhibi-tors (ruxolitinib navitoclax) against the Jak-Stat signaling path-way induced apoptosis and showed antitumor efficacy in a mouse model of human adult T-cell leukemia [316]. The underlying mechanisms revealed that a combination of ruxolitinib navitoclax activated pro-apoptotic protein Bax that was associated with in-creased mitochondrial depolarization, enhanced caspase 3/7 activ-ity, and cleavage of poly ADP ribose polymerase (PARP) mye-loid cell leukemia-1 (Mcl-1) [103]. Human papillomavirus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) cells have in-creased Porcupin e expression. Interestingly, the progression of these cSCCs was slowed using porcupine inhibitor LGK974 that blocked the secretion of Wnt ligands [317]. Another Wnt signaling inhibitor, ETC-159 along with the PI-3K/mTOR inhibitor GDC-0941 suppressed the growth of multiple Wnt-addicted pancreatic cancer cell lines [318]. In addition, a Wnt5a mimicking peptide, Foxy-5 suppressed the growth of Wnt5a expressing PCa cells [319]. D-tripeptide (DTP3), that disrupts the GADD45b/MKK7 complex, which is critical for survival driven by NF-kB, effectively kills MM cells with no toxicity to normal cells [320] (Table 1). FUTURE ASPECTS Studies using cancer cells and animals as models have assisted in investigating the underlying molecular mechanisms in pathobiol-ogy, elucidating the signaling perturbations and thus identifying potential therapeutic targets. These deregulated signaling p athways have helped understand the process of carcinogenesis, including identification of altered cellular functions that sustain tumorigenesis Fig. (2). Drugs in clinical trials or approved for clinical use that interfere with the commonly dysregulated signaling pathways necessary for tu mor growth and progression. The drugs listed are illustrative examples; there is a deep pipeline of candidate drugs with different molecular targets and modes of action in de-velopment for most of these signaling pathways. Reproduced with permission from [3]. (A higher resolution / colour version of this figure is available in the electronic copy of the article). 8 Current Pharmaceutical Design, 2020, Vol. 26, No. 00 Nisar et al. and identification of diagnostic/prognostic biomarkers. Moreover, there have been numerous associations between the Warburg phe-notype and aggressiveness of the tumor with poor clinical outcomes that can be used for further characterizing and treating specific tumors. Moreover, aberrations in the cancer signaling pathways can be identified that can help to reveal the mutations in cancer cells at DNA, mRNA and protein levels. The mutational profile of a tumor can influence th e efficacy of a drug, but the identification of altered pathways can help in the identification of novel cancer drug targets. In addition, recent high throughput sequencing data revealed the importance of these deregulated signaling pathways not only in tumor cells but also in maintaining supportive TME that promote the development and progression of many solid tumors. Malignant cells show various characterizing attributes and one of these is dys-regulation of cell signal transduction initiated by the genetic and epigenetic changes that drive malignant growth. A significant im-pact on anticancer treatments is shown by pharmacologic based inhibitors that target signaling proteins mutated in tumors. The development of anticancer drugs is a massive challenge because of the complexity of cancer signaling pathways that control cancer cell proliferation and survival, crosstalk between different pathways and feedback mechanisms. Targeting Ras-ERK and Akt-PI3K signaling pathways might prove successful as these pathways are common to many cancers and control various characteristics of a cancer cell. There is a limitation in targeting these signaling pathways as their rewiring can induce the activation of other stress pathways. Sec-ondly, factors from the tumor microenvironment can activate alter-native cell viability pathways instead of inhibiting the targeted pathways. While many signaling pathway inhibitors have been designed and used for the treatment of various cancers, unfortu-nately, the clinical efficacy of these inhibitors was limited by the complex ity of the signaling networks. Further, the activation of alternate signaling pathways limits the utility of these inhibitors. In addition, the use of tumor-derived cell lines as preclinical models without taking into consideration the complex TME has also re-sulted in the failure to translate these studies into clinical settings. However, there has been a recent upsurge in the use of combination therapies targeting many signaling pathways with enhanced effi-cacy. The major challenge in targeting the dysregulated pathw ays in cancer is the complexity of the cancer signaling net work. There are various factors that interfere with the targeted signaling pathways such as crosstalk and feedback inhibition mechanisms and in order to develop anti-cancer drugs by using dysregulated cancer signaling pathways as targets, these factors can be overawed. To ascertain the functional dependency between various signaling pathways by con-structing a pathway interaction network may not only provide in-sights into disease mechanisms but also provide alternative ways to develop more efficient drugs. Future studies should be more fo-cused on using combination therapies targeting both oncogenic signaling pathways and TME using genetically engineered mouse models, patient-derived xenografts, and organoids/tumoroids. CONFLICT OF INTEREST All authors declare no conflicts of interest. ACKNOWLEDGEMENTS This study was supported by a grant from Sidra Medicine (5011041002) to Ajaz A. Bh at. Muzafar A. Macha is a recipient of Ramanujan Fellowship from Science Engineering Research Table 1. Drugs/inhibitors and their mechanism of action in common oncogenic signaling pathways. Pathways Drug/inhibitors Mechanism of Action References P53 CTM ReACp53 Restores p53 function by inducing p 53 targe t gen es A cell-penetrating peptide that inhibits p53 amyloid formation and restores p53 function [300, 301] JNK MAPK SP600125 • Induces cell death in thyroid cancer • Reduces viability of doxorubicin resistant stomach cancer cells • Sensitizes oral squamous cancer cells • Enhances apoptosis in lung adenocarcinoma and cholangiocarcinoma cells • Kills p53-deficient colon cancer cells • Suppresses glioblastoma cells [303] [308] [305] [304] [309] [310] [306] [307] P38 BIRB-796 Inhibits tumor growth in multiple myeloma cells [302, 321] AKT GSK690693 XL-418 Enhances apoptosis in pre-clinical tumor models when used in combination [313] NOTCH RO4929097 gamma secretase inhibitor of Notch signaling that p roduces a slow growing pheno-type of tumor cells [314] [315] [322] JAK-STAT Ruxolitinib Navitoclax Activates Bax protein affecting tumor cell proliferation [323] Wnt 1. LGK974 2. ETC-159 3. Foxy-5 1. Porcupine inhibitor that blocks secretion of Wnt ligands 2. Porcupine inhibitor that suppresses growth of Wnt addicted cancer cells 3. Wnt5a mimicking peptide [317] [318] [319] PI-3K GDC-0941 BKM120 Synergizes with different agents Ability to penetrate the blood brain barrier [313] Nuclear factor-κB (NF-κB) DTP3 Disrupts the GADD45b/ MKK complex, effectively killing multiple myelo ma cells [320] Exploring Dysregulated Signaling Pathways in Cancer Current Pharmaceutical Desig n, 2020, Vol. 26, No. 00 9 Board (SERB), Department of Science and Technology, Govt. of India, N ew Delhi. REFERENCES [1] Garraway LA, Lander ES. Lessons from the cancer genome. Cell 2013; 153(1): 17-37. http://dx.doi.org/10.1016/j.cell.2013.03.002 PMID: 23540688 [2] Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic Signaling Pathway s in The Cancer Genome Atlas. Cell 2018; 173(2): 321-337.e10. http://dx.doi.org/10.1016/j.cell.2018.03.035 PMID: 29625050 [3] Hanahan D, Weinberg RA. 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Activation of STAT3 by its major inducers, IL-6, and IL-6Rα, has been associated with poor prognosis in patients undergoing esophagectomy [52]. ...Cytokine-chemokine network driven metastasis in esophageal cancer; promising avenue for targeted therapyArticleFull-text availableJan 2021MOL CANCER Ajaz Bhat Mayank Singh Muzafar A MachaEsophageal cancer (EC) is a disease often marked by aggressive growth and poor prognosis. Lack of targetedtherapies, resistance to chemoradiation therapy, and distant metastases among patients with advanced diseaseaccount for the high mortality rate. The tumor microenvironment (TME) contains several cell types, includingfibroblasts, immune cells, adipocytes, stromal proteins, and growth factors, which play a significant role insupporting the growth and aggressive behavior of cancer cells. The complex and dynamic interactions of thesecreted cytokines, chemokines, growth factors, and their receptors mediate chronic inflammation andimmunosuppressive TME favoring tumor progression, metastasis, and decreased response to therapy. The molecularchanges in the TME are used as biological markers for diagnosis, prognosis, and response to treatment in patients.This review highlighted the novel insights into the understanding and functional impact of deregulated cytokinesand chemokines in imparting aggressive EC, stressing the nature and therapeutic consequences of the cytokinechemokinenetwork. We also discuss cytokine-chemokine oncogenic potential by contributing to the Epithelial-Mesenchymal Transition (EMT), angiogenesis, immunosuppression, metastatic niche, and therapeutic resistancedevelopment. In addition, it discusses the wide range of changes and intracellular signaling pathways that occur inthe TME. Overall, this is a relatively unexplored field that could provide crucial insights into tumor immunology andencourage the effective application of modulatory cytokine-chemokine therapy to EC.ViewShow abstract... The cytokines and chemokines secreted by the immune cells mediate cancer-stromal interactions and activate several downstream effector pathways such as JAK/ STAT, NF-κβ, NOTCH to mediate various properties of cancer hallmarks [51]. Activation of STAT3 by its major inducers, IL-6, and IL-6Rα, has been associated with poor prognosis in patients undergoing esophagectomy [52]. ...Cytokine-chemokine network driven metastasis in esophageal cancer; promising avenue for targeted therapy.ArticleJan 2021MOL CANCER Ajaz Bhat Sabah Nisar Selma MaachaMohammad HarisEsophageal cancer (EC) is a disease often marked by aggressive growth and poor prognosis. Lack of targeted therapies, resistance to chemoradiation therapy, and distant metastases among patients with advanced disease account for the high mortality rate. The tumor microenvironment (TME) contains several cell types, including fibroblasts, immune cells, adipocytes, stromal proteins, and growth factors, which play a significant role in supporting the growth and aggressive behavior of cancer cells. The complex and dynamic interactions of the secreted cytokines, chemokines, growth factors, and their receptors mediate chronic inflammation and immunosuppressive TME favoring tumor progression, metastasis, and decreased response to therapy. The molecular changes in the TME are used as biological markers for diagnosis, prognosis, and response to treatment in patients. This review highlighted the novel insights into the understanding and functional impact of deregulated cytokines and chemokines in imparting aggressive EC, stressing the nature and therapeutic consequences of the cytokine-chemokine network. We also discuss cytokine-chemokine oncogenic potential by contributing to the Epithelial-Mesenchymal Transition (EMT), angiogenesis, immunosuppression, metastatic niche, and therapeutic resistance development. In addition, it discusses the wide range of changes and intracellular signaling pathways that occur in the TME. Overall, this is a relatively unexplored field that could provide crucial insights into tumor immunology and encourage the effective application of modulatory cytokine-chemokine therapy to EC.ViewShow abstract... More impressively, this module also involves some carcinogenic pathways, such as Pathways in cancer , Cell cycle , and Bladder cancer (Fig. 9e). The defects of these pathways are reflected in the pathogenesis of various types of tumors including bladder cancer [38]- [40]. ...Identification of MicroRNA Regulatory Modules by Clustering MicroRNA-Target InteractionsArticleFull-text availableAug 2020Yi YangXuting WanIdentification of microRNA regulatory modules can help decipher microRNA synergistic regulatory mechanism in the development and progression of complex diseases, especially cancers. Experimentally validated microRNA-target interactions provide strong direct evidence for the analysis of microRNA regulatory functions. We here developed a novel computational framework named CMIN to identify microRNA regulatory modules by performing link clustering on such experimentally verified microRNA-target interactions. CMIN runs in two main steps: it first utilizes convolutional autoencoders to extract high-level microRNA-target interaction features from the expression profile data, and then applied affinity propagation clustering algorithm to interaction feature to obtain overlapping microRNA-target clusters. Clusters with significant synergy correlations are considered as microRNA regulatory modules. We tested the proposed framework and other three existing methods on three types of cancer data sets from TCGA (The Cancer Genome Atlas). The results showed that the microRNA regulatory modules detected by CMIN exhibit stronger topological correlation and more functional enrichment compared with other methods. Availability: The supplementary files of CMIN are available at https://github.com/snryou/CMIN.ViewShow abstract... The realization that cancer can be seen as a complex group of diseases rather than a unique one opened up the possibilities for different approaches to its treatment since it was clear that there is not a single, decisive event that leads to tumor formation (1-3) Instead, tumor development is the result of the cumulative and simultaneous deregulation of a significant number of cellular processes. Active research has generated a great deal of information on cellular events that underlie many of the Hallmarks of Cancer, and hence, are common to several tumors (4). These metabolic or signaling pathways are, thus, ideal targets for targeted therapy. ...Interplay Between Autophagy and Wnt/β-Catenin Signaling in Cancer: Therapeutic Potential Through Drug RepositioningArticleFull-text availableAug 2020 Carlos Perez-Plasencia Eduardo López-Urrutia Verónica García-Castillo Alma D. Campos-ParraThe widespread dysregulation that characterizes cancer cells has been dissected and many regulation pathways common to multiple cancer types have been described in depth. Wnt/β-catenin signaling and autophagy are among these principal pathways, which contribute to tumor growth and resistance to anticancer therapies. Currently, several therapeutic strategies that target either Wnt/β-catenin signaling or autophagy are in various stages of development. Targeted therapies that block specific elements that participate in both pathways; are subject to in vitro studies as well as pre-clinical and early clinical trials. Strikingly, drugs designed for other diseases also impact these pathways, which is relevant since they are already FDA-approved and sometimes even routinely used in the clinic. The main focus of this mini-review is to highlight the importance of drug repositioning to inhibit the Wnt/β-catenin and autophagy pathways, with an emphasis on the interplay between them. The data we found strongly suggested that this field is worth further examination.ViewShow abstractAssociation of sonic hedgehog signaling pathway genes IHH, BOC, RAB23a and MIR195-5p, MIR509-3-5p, MIR6738-3p with gastric cancer stageArticleFull-text availableApr 2021Sadegh Fattahi Novin NikbakhshMohammad Ranaei Haleh AkhavanGastric cancer is the leading cause of cancer-related mortality worldwide. Given the importance of gastric cancer in public health, identifying biomarkers associated with disease onset is an important part of precision medicine. The hedgehog signaling pathway is considered as one of the most significant widespread pathways of intracellular signaling in the early events of embryonic development. This pathway contributes also to the maintenance of pluripotency of cancer stem cells pluripotency. In this study, we analyzed the expression levels of sonic hedgehog (Shh) signaling pathway genes IHH, BOC, RAB23a and their regulatory miRNAs including MIR-195-5p, MIR-509-3-5p, MIR-6738-3p in gastric cancer patients. In addition, the impact of infection status on the expression level of those genes and their regulatory miRNAs was investigated. One hundred samples taken from 50 gastric cancer patients (50 tumoral tissues and their adjacent non-tumoral counterparts) were included in this study. There was a significant difference in all studied genes and miRNAs in tumoral tissues in comparison with their adjacent non-tumoral counterparts. The lower expression of IHH, BOC, RAB23, miR-195-5p, and miR-6738-3p was significantly associated with more advanced cancer stage. Additionally, IHH upregulation was significantly associated with CMV infection (P 0.001). Also, receiver operating characteristic (ROC) curve analysis indicated that mir-195 was significantly related to several clinicopathological features including tumor stage, grade, age, gender, and infection status of gastric cancer and can be considered as a potential diagnostic biomarker for gastric cancer. This study confirms the important role of Shh signaling pathway genes in gastric cancer tumorigenesis and their potential as novel molecular biomarkers and therapeutic targets.ViewShow abstractThe potential and controversy of targeting STAT family members in cancerArticleFull-text availableOct 2019SEMIN CANCER BIOL Yannick Verhoeven Sam Tilborghs Julie Jacobs Peter van DamThe Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors that play a complex and essential role in the regulation of physiologic cell processes, such as proliferation, differentiation, apoptosis and angiogenesis, and serves to organize the epigenetic landscape of immune cells. To date, seven STAT genes have been identified in the human genome; STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. They all account for diverse effects in response to extracellular signaling proteins, mainly by altering gene transcription in the effector cells. Members of the STAT family have been implicated in human cancer development, progression, metastasis, survival and resistance to treatment. Particularly STAT3 and STAT5 are of interest in cancer biology. They are currently considered as oncogenes, but their signaling is embedded into a complex and delicate balance between different (counteracting) transcription factors, and thus, in some contexts they can have a tumor suppressive role. Assessing STAT signaling mutations as well as screening for aberrant STAT pathway activation may have a role to predict sensitivity to immunotherapy and targeted STAT inhibition. In the present comprehensive review of the literature, we discuss in-depth the role of each STAT family member in cancer, assemble cutting-edge information on the use of these molecules as potential biomarkers and targets for treatment, and address why their clinical implementation is controversy.ViewShow abstractPORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancersArticleFull-text availableOct 2019 Zheng ZhongSugunavathi SepramaniamXin Hui Chew David M VirshupPancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is aggressive and lethal. Although there is an urgent need for effective therapeutics in treating pancreatic cancer, none of the targeted therapies tested in clinical trials to date significantly improve its outcome. PORCN inhibitors show efficacy in preclinical models of Wnt-addicted cancers, including RNF43-mutant pancreatic cancers and have advanced to clinical trials. In this study, we aimed to develop drug combination strategies to further enhance the therapeutic efficacy of the PORCN inhibitor ETC-159. To identify additional druggable vulnerabilities in Wnt-driven pancreatic cancers, we performed an in vivo CRISPR loss-of-function screen. CTNNB1, KRAS, and MYC were reidentified as key oncogenic drivers. Notably, glucose metabolism pathway genes were important in vivo but less so in vitro. Knockout of multiple genes regulating PI3K/mTOR signaling impacted the growth of Wnt-driven pancreatic cancer cells in vivo. Importantly, multiple PI3K/mTOR pathway inhibitors in combination with ETC-159 synergistically suppressed the growth of multiple Wnt-addicted cancer cell lines in soft agar. Furthermore, the combination of the PORCN inhibitor ETC-159 and the pan-PI3K inhibitor GDC-0941 potently suppressed the in vivo growth of RNF43-mutant pancreatic cancer xenografts. This was largely due to enhanced suppressive effects on both cell proliferation and glucose metabolism. These findings demonstrate that dual PORCN and PI3K/mTOR inhibition is a potential strategy for treating Wnt-driven pancreatic cancers.ViewShow abstractCripto‑1 overexpression in U87 glioblastoma cells activates MAPK, focal adhesion and ErbB pathwaysArticleFull-text availableJul 2019Oncol Lett Faisal Alowaidi Saeed Mujahid Hashimi Naif Alqurashi Ming Q WeiDiscovering the underlying signalling pathways that control cancer cells is crucial for understanding their biology and to develop therapeutic regimens. Thus, the aim of the present study was to determine the effect of Cripto-1 on pathways controlling glioblastoma (GBM) cell function. To this end, changes in protein phosphorylation in cells overexpressing Cripto-1 were analysed using the Kyoto Encyclopedia of Genes and Genomes pathway analysis tool, as well as the Uniprot resource to identify the functions of Cripto-1-dependent phosphorylated proteins. This revealed that proteins affected by Cripto-1 overexpression are involved in multiple signalling pathways. The mitogen-activated protein kinase (MAPK), focal adhesion (FA) and ErbB pathways were found to be enriched by Cripto-1 overexpression with 35, 27 and 24% of pathway proteins phosphorylated, respectively. These pathways control important cellular processes in cancer cells that correlate with the observed functional changes described in earlier studies. More specifically, Cripto-1 may regulate MAPK cellular proliferation and survival pathways by activating epithelial growth factor receptor (EGFR; Ser1070) or fibroblast GFR1 (Tyr654). Its effect on cellular proliferation and survival could be mediated through Src (Tyr418), FA kinase (FAK; Tyr396), p130CAS (Tyr410), c-Jun (Ser63), Paxillin (PXN; Tyr118) and BCL2 (Thr69) of the FA pathway. Cripto-1 may also control cellular motility and invasion by activating Src (Tyr418), FAK (Tyr396) and PXN (Tyr118) of the FA pathway. However, Cripto-1 regulation of cellular invasion and migration might be not limited to the FA pathway, it may also control these cellular mechanisms through signalling via EGFR (Ser1070)/Her2 (Tyr877) to mediate the Src (Tyr418) and FAK (Tyr396) cascade activation of the ErbB signalling pathway. Angiogenesis could be mediated by Cripto-1 by activating c-Jun (Ser63) through EGFR (Ser1070)/Her2 (Tyr877) of the ErbB pathway. To conclude, the present study has augmented and enriched our current knowledge on the crucial roles that Cripto-1 may play in controlling different cellular mechanisms in GBM cells.ViewShow abstractCrosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapyArticleFull-text availableMay 2019MOL CANCERHong-Tao Chen Hao LiuMin-Jie MaoGuan-Min JiangAutophagy is a highly conserved catabolic process that mediates degradation of pernicious or dysfunctional cellular components, such as invasive pathogens, senescent proteins, and organelles. It can promote or suppress tumor development, so it is a \"double-edged sword” in tumors that depends on the cell and tissue types and the stages of tumor. The epithelial-mesenchymal transition (EMT) is a complex biological trans-differentiation process that allows epithelial cells to transiently obtain mesenchymal features, including motility and metastatic potential. EMT is considered as an important contributor to the invasion and metastasis of cancers. Thus, clarifying the crosstalk between autophagy and EMT will provide novel targets for cancer therapy. It was reported that EMT-related signal pathways have an impact on autophagy; conversely, autophagy activation can suppress or strengthen EMT by regulating various signaling pathways. On one hand, autophagy activation provides energy and basic nutrients for EMT during metastatic spreading, which assists cells to survive in stressful environmental and intracellular conditions. On the other hand, autophagy, acting as a cancer-suppressive function, is inclined to hinder metastasis by selectively down-regulating critical transcription factors of EMT in the early phases. Therefore, the inhibition of EMT by autophagy inhibitors or activators might be a novel strategy that provides thought and enlightenment for the treatment of cancer. In this article, we discuss in detail the role of autophagy and EMT in the development of cancers, the regulatory mechanisms between autophagy and EMT, the effects of autophagy inhibition or activation on EMT, and the potential applications in anticancer therapy.ViewShow abstractRole of Hippo Pathway-YAP/TAZ signaling in angiogenesisArticleFull-text availableApr 2019 Gandhi T. K. BoopathyWanjin HongAngiogenesis is a highly coordinated process of formation of new blood vessels from pre-existing blood vessels. The process of development of the proper vascular network is a complex process that is crucial for the vertebrate development. Several studies have defined essential roles of Hippo pathway-YAP/TAZ in organ size control, tissue regeneration, and self-renewal. Thus Hippo pathway is one of the central components in tissue homeostasis. There are mounting evidences on the eminence of Hippo pathway-YAP/TAZ in angiogenesis in multiple model organisms. Hippo pathway-YAP/TAZ is now demonstrated to regulate endothelial cell proliferation, migration and survival; subsequently regulating vascular sprouting, vascular barrier formation, and vascular remodeling. Major intracellular signaling programs that regulate angiogenesis concomitantly activate YAP/TAZ to regulate key events in angiogenesis. In this review, we provide a brief overview of the recent findings in the Hippo pathway and YAP/TAZ signaling in angiogenesis.ViewShow abstractAnalysis of the role of the Hippo pathway in cancerArticleFull-text availableApr 2019J TRANSL MEDYanyan HanAbstract Cancer is a serious health issue in the world due to a large body of cancer-related human deaths, and there is no current treatment available to efficiently treat the disease as the tumor is often diagnosed at a serious stage. Moreover, Cancer cells are often resistant to chemotherapy, radiotherapy, and molecular-targeted therapy. Upon further knowledge of mechanisms of tumorigenesis, aggressiveness, metastasis, and resistance to treatments, it is necessary to detect the disease at an earlier stage and for a better response to therapy. The hippo pathway possesses the unique capacity to lead to tumorigenesis. Mutations and altered expression of its core components (MST1/2, LATS1/2, YAP and TAZ) promote the migration, invasion, malignancy of cancer cells. The biological significance and deregulation of it have received a large body of interests in the past few years. Further understanding of hippo pathway will be responsible for cancer treatment. In this review, we try to discover the function of hippo pathway in different diversity of cancers, and discuss how Hippo pathway contributes to other cellular signaling pathways. Also, we try to describe how microRNAs, circRNAs, and ZNFs regulate hippo pathway in the process of cancer. It is necessary to find new therapy strategies for cancer.ViewShow abstractMolecular Mechanisms Controlled by mTOR in Male Reproductive SystemArticleFull-text availableApr 2019INT J MOL SCI Bruno Moreira Pedro F Oliveira Marco G. AlvesIn recent years, the mammalian target of rapamycin (mTOR) has emerged as a master integrator of upstream inputs, such as amino acids, growth factors and insulin availability, energy status and many others. The integration of these signals promotes a response through several downstream effectors that regulate protein synthesis, glucose metabolism and cytoskeleton organization, among others. All these biological processes are essential for male fertility, thus it is not surprising that novel molecular mechanisms controlled by mTOR in the male reproductive tract have been described. Indeed, since the first clinical evidence showed that men taking rapamycin were infertile, several studies have evidenced distinct roles for mTOR in spermatogenesis. However, there is a lack of consensus whether mTOR inhibition, which remains the experimental approach that originates the majority of available data, has a negative or positive impact on male reproductive health. Herein we discuss the latest findings concerning mTOR activity in testes, particularly its role on spermatogonial stem cell (SSC) maintenance and differentiation, as well as in the physiology of Sertoli cells (SCs), responsible for blood–testis barrier maintenance/restructuring and the nutritional support of spermatogenesis. Taken together, these recent advances highlight a crucial role for mTOR in determining the male reproductive potential.ViewShow abstractras Gene Mutations in Salivary Gland TumorsArticleJun 2000ARCH PATHOL LAB MEDJinyoung YooRobert A. RobinsonObjective.—To assess the prevalence of activating mutations in K-ras and H-ras genes in salivary gland tumors with ductal or acinar differentiation and to evaluate their potential correlation with clinical parameters.Design.—Paraffin-embedded tissue samples of salivary gland carcinomas were investigated by the application of a direct sequence analysis procedure with automated DNA sequencing of polymerase chain reaction–amplified ras sequences.Setting.—Tertiary care teaching hospital.Patients.—Twenty-four patients with salivary gland carcinoma were surgically treated. Nine had adenocarcinoma, 1 had adenosquamous carcinoma, 11 had mucoepidermoid carcinoma, and 3 had acinic cell carcinoma.Results.—Point mutations were detected in 7 (29%) of the 24 carcinomas examined. The K-ras gene was mutated in only 2 samples (8%): a GGC-to-ATC mutation at codon 13 in an adenocarcinoma and a GGC-to-GTC transversion mutation at codon 13 in a mucoepidermoid carcinoma. Five (21%) harbored H-ras mutations: 4 contained a GGC-to-GTC transversion mutation at codon 12 and 1 had 2 distinct mutations, the same G-to-T at codon 12 as was shown in the other cases and a GGT-to-GGA heterozygous mutation at codon 13. All the H-ras mutations were in the group of mucoepidermoid carcinoma lesions (45%; 5/11).Conclusion.—Our data suggest that K-ras gene alteration is probably not an important factor in the oncogenesis of human salivary gland tumors. However, mutational activation of the H-ras gene appears to play a role in the development and/or progression of salivary gland mucoepidermoid carcinomas.ViewShow abstractTargeting the PI3K/AKT/mTOR Pathway: Biomarkers of Success and TribulationArticleMay 2013 Taofeek Owonikoko Fadlo R KhuriPI3K/AKT/mTOR pathway is an established oncogenic driver in humans. Targeted biologic agents against components of this pathway have shown promising activity leading to the approval of the allosteric inhibitors of mTOR, everolimus, and temsirolimus for the treatment of advanced cancers of the kidney, breast, and pancreas. Despite the established and promising activity of this therapeutic strategy, the duration and quality of benefit remains suboptimal in unselected patients. Improved understanding of the biologic consequence of altered PI3K/AKT/mTOR signaling is informing the development of protein (phosphorylated forms of S6, AKT, eIF4e) and genetic ( PIK3CA mutation, PTEN loss of function, TSC1 and TSC2 mutation, PIK3CA-GS genetic profile) biomarkers to identify patients most likely to benefit from this therapeutic strategy. This review provides an overview of the biologic rational and promising results of protein and genetic biomarkers for selecting patients appropriate for therapy with inhibitors of this pathway.ViewShow abstractCrucial role of the pentose phosphate pathway in malignant tumors (Review)ArticleMar 2019Oncol LettLin JinYanhong ZhouInterest in cancer metabolism has increased in recent years. The pentose phosphate pathway (PPP) is a major glucose catabolism pathway that directs glucose flux to its oxidative branch and leads to the production of a reduced form of nicotinamide adenine dinucleotide phosphate and nucleic acid. The PPP serves a vital role in regulating cancer cell growth and involves many enzymes. The aim of the present review was to describe the recent discoveries associated with the deregulatory mechanisms of the PPP and glycolysis in malignant tumors, particularly in hepatocellular carcinoma, breast and lung cancer.ViewShow abstractShow moreAdvertisementRecommendationsDiscover moreProjectNatural products and cancer Rahat Jahan Surinder Batra Muzafar A Macha[...]Zafar SyedView projectProjectNeurogenomics Model for Children affected with Attention Deficit Hyperactivity Disorder (ADHD) in Qatari population Santosh YadavIntegrating cognitive, imaging and genomics View projectProjectDeregulated signaling pathways are potential target for anticancer drugs Shahab Uddin, Ph.D Kodappully Sivaraman Siveen Kirti Sathyananda Prabhu[...] Sarita PrabhakaranTo identify potential prognostic and therapeutic targets for the treatment of various malignancies View projectArticleFull-text availableTherapeutic Effects of Curcumol in Several Diseases; An OverviewApril 2020 · Nutrition and Cancer Sheema Hashem Sabah Nisar Ajaz Bhat[...] Geetanjali SageenaCurcumae Rhizoma, also known as Ezhu is a traditional Chinese medicine that has been used for many centuries against several diseases. The rhizome of the plant is composed of curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin), and essential volatile oils including curcumol, curdione, and germacrone. While curcuminoids have been extensively studied for their antimicrobial, ... [Show full abstract] antioxidant, anti-inflammatory and anticancer properties, the therapeutic efficacy of curcumol is still emerging. Recent studies have shown anticancer properties of curcumol against multiple solid tumors such as breast, colorectal, head and neck, and lung adenocarcinomas. The underlying anti-tumor mechanisms revealed inhibition of several signaling pathways (NF-jB, MAPK, PI-3K/AKT, and GSK-3b) associated with cell proliferation, survival, anti-apoptosis, invasion and metastasis. Besides curcumol, extracts from the Curcumae Rhizoma roots possess many other terpenoids such as b-ele-mene, d-elemene, germacrone, furanodiene and furanodienone with known anticancer properties. In this review, we comprehensively focused on the composition of Curcumae Rhizoma essential oils, their structure, isolation and therapeutic uses of curcumol to aid in the improvement and development of novel drugs with minimal cytotoxicity, enhanced efficacy, and less cost. ARTICLE HISTORYView full-textArticleFull-text availableChemokine-Cytokine Networks in the Head and Neck Tumor MicroenvironmentApril 2021 · International Journal of Molecular Sciences Sabah Nisar Ajaz Bhat Muzafar A Macha[...] Deepika MishraHead and neck squamous cell carcinomas (HNSCCs) are aggressive diseases with a dismal patient prognosis. Despite significant advances in treatment modalities, the five-year survival rate in patients with HNSCC has improved marginally and therefore warrants a comprehensive understanding of the HNSCC biology. Alterations in the cellular and non-cellular components of the HNSCC tumor ... [Show full abstract] micro-environment (TME) play a critical role in regulating many hallmarks of cancer development including evasion of apoptosis, activation of invasion, metastasis, angiogenesis, response to therapy, immune escape mechanisms, deregulation of energetics, and therefore the development of an overall aggressive HNSCC phenotype. Cytokines and chemokines are small secretory proteins produced by neoplastic or stromal cells, controlling complex and dynamic cell–cell interactions in the TME to regulate many cancer hallmarks. This review summarizes the current understanding of the complex cytokine/chemokine networks in the HNSCC TME, their role in activating diverse signaling pathways and promoting tumor progression, metastasis, and therapeutic resistance development.View full-textArticleFull-text availableCytokine-chemokine network driven metastasis in esophageal cancer; promising avenue for targeted the...January 2021 · Molecular Cancer Ajaz Bhat Mayank Singh Muzafar A MachaEsophageal cancer (EC) is a disease often marked by aggressive growth and poor prognosis. Lack of targetedtherapies, resistance to chemoradiation therapy, and distant metastases among patients with advanced diseaseaccount for the high mortality rate. The tumor microenvironment (TME) contains several cell types, includingfibroblasts, immune cells, adipocytes, stromal proteins, and growth ... [Show full abstract] factors, which play a significant role insupporting the growth and aggressive behavior of cancer cells. The complex and dynamic interactions of thesecreted cytokines, chemokines, growth factors, and their receptors mediate chronic inflammation andimmunosuppressive TME favoring tumor progression, metastasis, and decreased response to therapy. The molecularchanges in the TME are used as biological markers for diagnosis, prognosis, and response to treatment in patients.This review highlighted the novel insights into the understanding and functional impact of deregulated cytokinesand chemokines in imparting aggressive EC, stressing the nature and therapeutic consequences of the cytokinechemokinenetwork. We also discuss cytokine-chemokine oncogenic potential by contributing to the Epithelial-Mesenchymal Transition (EMT), angiogenesis, immunosuppression, metastatic niche, and therapeutic resistancedevelopment. In addition, it discusses the wide range of changes and intracellular signaling pathways that occur inthe TME. Overall, this is a relatively unexplored field that could provide crucial insights into tumor immunology andencourage the effective application of modulatory cytokine-chemokine therapy to EC.View full-textArticleFull-text availableNon-invasive biomarkers for monitoring the immunotherapeutic response to cancerDecember 2020 · Journal of Translational Medicine Sabah Nisar Ajaz Bhat Sheema Hashem[...]Mohammad HarisImmunotherapy is an efficient way to cure cancer by modulating the patient’s immune response. However, the immunotherapy response is heterogeneous and varies between individual patients and cancer subtypes, reinforcing the need for early benefit predictors. Evaluating the infiltration of immune cells in the tumor and changes in cell-intrinsic tumor characteristics provide potential response ... [Show full abstract] markers to treatment. However, this approach requires invasive sampling and may not be suitable for real-time monitoring of treatment response. The recent emergence of quantitative imaging biomarkers provides promising opportunities. In vivo imaging technologies that interrogate T cell responses, metabolic activities, and immune microenvironment could offer a powerful tool to monitor the cancer response to immunotherapy. Advances in imaging techniques to identify tumors immunological characteristics can help stratify patients who are more likely to respond to immunotherapy. This review discusses the metabolic events that occur during T cell activation and differentiation, anti-cancer immunotherapy-induced T cell responses, focusing on non-invasive imaging techniques to monitor T cell metabolism in the search for novel biomarkers of response to cancer immunotherapy.View full-textChapterFunctional In Vivo Imaging of TumorsMarch 2020 · Cancer Treatment and ResearchMohammad Haris Sabah Nisar Sheema Hashem[...]Ravinder ReddyNoninvasive imaging of functional and molecular changes in cancer has become an indispensable tool for studying cancer in vivo. Targeting the functional and molecular changes in cancer imaging provides a platform for the in vivo analysis of the mechanisms such as gene expression, signal transduction, biochemical reactions, regulatory pathways, cell trafficking, and drug action underlying cancer ... [Show full abstract] noninvasively. The main focus of imaging in cancer is the development of new contrast methods/molecular probes for the early diagnosis and the precise evaluation of therapy response. In clinical setup, imaging modalities facilitate screening, prediction, staging, biopsy and therapy guidance, therapy response, therapy planning, and prognosis of cancer. In this book chapter, we review different established and emerging in vivo imaging modalities and their applications in monitoring functional, molecular, and metabolic changes in cancer.Read moreDiscover the world s researchJoin ResearchGate to find the people and research you need to help your work.Join for free ResearchGate iOS AppGet it from the App Store now.InstallKeep up with your stats and moreAccess scientific knowledge from anywhere orDiscover by subject areaRecruit researchersJoin for freeLoginEmail Tip: Most researchers use their institutional email address as their ResearchGate loginPasswordForgot password? 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