Interplay Between Extracellular Matrix Remodeling and Angiogenesis in Tumor Ecosystem.

Studying the complex mechanisms of tumorigenesis and examining the interactions of neoplastic cells within tumor ecosystem are critical to explore the possibility of effective cancer treatment modalities. Dynamic tumor ecosystem is constantly evolving and is composed of tumor cells, extracellular matrix (ECM), secreted factors, and stromal cancer-associated fibroblasts (CAF), pericytes, endothelial cells (EC), adipocytes, and immune cells. ECM remodeling by synthesis, contraction, and/or proteolytic degradation of ECM components and release of matrix-sequestered growth factors create a microenvironment that promotes EC proliferation, migration, and angiogenesis. Stromal CAFs release multiple angiogenic cues (angiogenic growth factors, cytokines, and proteolytic enzymes) which interact with ECM proteins, thus contribute to enhance proangiogenic/promigratory properties and support aggressive tumor growth. Targeting angiogenesis brings about vascular changes including reduced adherence junction proteins, basement membrane and pericyte coverage, and increased leakiness. This facilitates ECM remodeling, metastatic colonization and chemoresistance. Owing to significant role of denser and stiffer ECM in inducing chemoresistance, direct or indirect targeting of ECM components is being reported as major axis of anticancer treatment. Exploring the agents targeting angiogenesis and ECM in a context specific manner may lead to reduced tumor burden by promoting conventional therapeutic effectiveness and overcoming the hurdles of therapy resistance.

Immunohistochemical expressions of EMT markers in pan-RAS-pERK1/2-positive tumors improve diagnosis and prognosis assessment of non-muscle invasive bladder cancer and muscle invasive bladder cancer patients.

Mutation or overexpression renders pan-RAS (rat sarcoma) proteins insensitive to inactivation. Activated pan-RAS communicates signal from the cell surface receptor to activate RAS-MAPK/ERK (RAS-mitogen-activated protein kinases/extracellular signal regulated kinases) signaling and orchestrates epithelial-to-mesenchymal transition-activating transcription factors (EMT-ATFs) reprogramming to induce EMT. Owing to limited studies available in bladder cancer, the present study is taken up to examine the expressions of the EMT-associated markers in pan-RAS-pERK1/2 (pan-RAS-phosphoERK1/2)-positive well-characterized cohort of forty-two non-muscle invasive bladder cancer (NMIBC) and forty-five muscle invasive bladder cancer (MIBC) patients. Immunohistochemical staining was performed on paraffin embedded tissue sections to determine the immunolevels and cellular localization of marker proteins. Semi-quantitative expressions of pan-RAS, pERK1/2, and EMT markers (E-cadherin, Vimentin, N-cadherin, Snail, Slug Twist, and Zeb1) were statistically examined with clinicohistopathological profile of the patients using SPSS, version 20.0 software. The study documents the diagnostic relevance of immunohistochemical expressions of pan-RAS-pERK1/2/EMT-associated markers in order to stratify NMIBC and MIBC patients. Follow-up studies supported the role of altered EMT phenotype in pan-RAS-pERK1/2-activated positive tumors with disease aggressiveness. To the best of our knowledge, our study is the first concluding the impact of altered EMT phenotype via pan-RAS-pERK1/2 axis on the short survival outcome [short overall survival (OS) (p = 0.04), short progression-free survival (PFS) (p = 0.02) and short cancer-specific survival (CSS) (p = 0.03)] of muscle invasive bladder cancer patients.

Emerging roles of epithelial-mesenchymal plasticity in invasion-metastasis cascade and therapy resistance.

Strong association of cancer incidence and its progression with mortality highlights the need to decipher the cellular and molecular mechanisms that drive tumor cells to rapidly progress to metastatic disease and therapy resistance. Epithelial-mesenchymal plasticity (EMP) emerged as a key regulator of metastatic outgrowth. It allows neoplastic epithelial cells to delaminate from their neighbors either individually or collectively, traverse the extracellular matrix (ECM) barrier, enter into the circulation, and establish distal metastases. Plasticity between epithelial and mesenchymal states and the existence of hybrid epithelial/mesenchymal (E/M) phenotypes are increasingly being reported in different tumor contexts. Small subset of cancer cells with stemness called cancer stem cells (CSCs) exhibit plasticity, possess high tumorigenic potential, and contribute to high degree of tumoral heterogeneity. EMP characterized by the presence of dynamic intermediate states is reported to be influenced by (epi)genomic reprograming, growth factor signaling, inflammation, and low oxygen generated by tumor stromal microenvironment. EMP alters the genotypic and phenotypic characteristics of tumor cells/CSCs, disrupts tissue homeostasis, induces the reprogramming of angiogenic and immune recognition functions, and renders tumor cells to survive hostile microenvironments and resist therapy. The present review summarizes the roles of EMP in tumor invasion and metastasis and provides an update on therapeutic strategies to target the metastatic and refractory cancers.

Emerging roles of autophagy in the development and treatment of urothelial carcinoma of the bladder.

INTRODUCTION: High recurrence rates, frequent surveillance strategies, and current multidisciplinary treatment approaches make urothelial carcinoma of bladder (UCB) one of the most expensive cancers to clinically manage. Recent studies have demonstrated a role for autophagy in bladder tumorigenesis. It serves as a tumor suppressor by maintaining genomic integrity and preventing tumor proliferation during initial stages of tumor development. Nevertheless, once established, cancer cells may utilize protective autophagy to endure cellular stress and survive in the adverse environment. Its excessive stimulation supports cancer cells' resistance to therapeutic modalities. AREAS COVERED: PubMed and Google Scholar electronic databases were searched for recently published studies. This review summarizes emerging roles of autophagy in development/progression of UCB and treatment resistance and explores novel therapeutic targets for prevention of cancer invasion, metastatic spread', and disease relapse. EXPERT OPINION: The development of novel therapies via targeting of autophagy may augment current treatment regimens and improve clinical outcomes. Synthetic compounds or plant-based metabolites are reported to enhance cancer therapies by modulating autophagic flux. Successful autophagy-focused therapeutic intervention requires a mechanistic understanding of autophagic effects on tumor initiation and progression and the development of efficient biomarkers to monitor it in tumor tissues.

Molecular and clinical insights of matrix metalloproteinases into cancer spread and potential therapeutic interventions.

Matrix metalloproteinases (MMPs) are the group of enzymes that belong to the family of zinc dependent endopeptidases. These proteases degrade collagen and other important proteins in extracellular matrix (ECM) and regulate cytoskeletal proteins, growth factors, chemokines and cytokines, thereby play significant role during organogenesis and normal tissue turnover. Recent studies highlight the tumorigenic functions of MMPs by modulating tumor microenvironment. Dysregulated MMPs/TIMPs cause an imbalance in crucial cell signals, and lead to serious pathological conditions related to inflammation, uncontrolled cell growth, ECM degradation, increased cell migration, cell death resistance, replicative immortality and the establishment of metastatic niche at secondary sites. Recently established correlation between the higher expression of active MMPs and cancer aggressiveness makes them probable target candidate of cancer diagnosis, prognosis and therapy. The present review focuses on the tumourigenic functions of MMPs and recent advancements in the development of MMP inhibitors of therapeutic potential in cancer treatment.

Promoter hypomethylation as potential confounder of Ras gene overexpression and their clinical significance in subsets of urothelial carcinoma of bladder.

Overexpression of normal Ras and its aberrant CpG island methylation in the promoter regions have been shown to direct cells for uncontrolled abnormal growth and bladder tumor formation and therefore, fetched recent attention as a marker of diagnosis and prognosis to predict the biological behavior of urothelial carcinoma of bladder (UCB). Methylation pattern at CpG islands of the promoter regions of rat sarcoma (Ras) gene homologues namely Kristen-Ras (K-Ras), Harvey (H-Ras), and Neuroblastoma (N-Ras) were examined by methylation specific polymerase chain reaction (MSP). Real time-quantitative polymerase chain reaction (RT-qPCR) was done to determine transcriptomic expressions of these Ras isoforms in the prospective series of 42 NMIBC (non-muscle invasive bladder cancer) and 45 MIBC (muscle invasive bladder cancer) biopsies. CpG loci in H-Ras and K-Ras were observed to be more hypomethylated in MIBC, whereas more hypomethylation in N-Ras was noted in NMIBC. Strong association of hypomethylation index with tumor stage, grade, type and size validate them it as marker of diagnosis in UCB patients. Differential overexpression of H-Ras, N-Ras and K-Ras genes in NMIBC and MIBC and their association with patients' demographics identify them as important diagnostic markers in pathogenesis of UCB. Given the reported ability of promoter hypomethylation to activate Ras expression, correlation studies examined positive significant association between hypomethylation index and expression. Study concludes that promoter hypomethylation of N-Ras and K-Ras could be a potential confounder of their increased expression in NMIBC. Biological significance of simultaneous presence of higher expression and promoter hypomethylation of Ras gene isoforms in MIBC is difficult to resolve in a given cohort of patients.

Mutational analysis of Ras hotspots in patients with urothelial carcinoma of the bladder.

BACKGROUND: Mutational activation of Ras genes is established as a prognostic factor for the genesis of a constitutively active RAS-mitogen activated protein kinase pathway that leads to cancer. Heterogeneity among the distribution of the most frequent mutations in Ras isoforms is reported in different patient populations with urothelial carcinoma of the bladder (UCB). AIM: To determine the presence/absence of mutations in Ras isoforms in patients with UCB in order to predict disease outcome. METHODS: This study was performed to determine the mutational spectrum at the hotspot regions of H-Ras, K-Ras and N-Ras genes by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing followed by their clinical impact (if any) by examining the relationship of mutational spectrum with clinical histopathological variables in 87 UCB patients. RESULTS: None of the 87 UCB patients showed point mutations in codon 12 of H-Ras gene; codon 61 of N-Ras gene and codons 12, 13 of K-Ras gene by PCR-RFLP. Direct DNA sequencing of tumor and normal control bladder mucosal specimens followed by Blastn alignment with the reference wild-type sequences failed to identify even one nucleotide difference in the coding exons 1 and 2 of H-Ras, N-Ras and K-Ras genes in the tumor and control bladder mucosal specimens. CONCLUSION: Our findings on the lack of mutations in H-Ras, K-Ras and N-Ras genes could be explained on the basis of different etiological mechanisms involved in tumor development/progression, inherent genetic susceptibility, tissue specificity or alternative Ras dysfunction such as gene amplification and/or overexpression in a given cohort of patients.

Epithelial Plasticity, Autophagy and Metastasis: Potential Modifiers of the Crosstalk to Overcome Therapeutic Resistance.

Epithelial-to-mesenchymal transition (EMT) initiates malignant transformation of cancer cells and is responsible for the generation of heterogenic subsets of cancer stem cells (CSCs). Signals in the form of environmental cues and paracrine factors within tumor microenvironment (TME) niche, support the possibility of generation of pool of CSCs with two distinct functional transition states. Cyclic CSCs with predominant epithelial phenotype, self-renew and differentiate into mature cancer cells. Subsets of autophagic/ non-cyclic CSCs with predominant mesenchymal phenotype have capacity to invade, metastasize, resist to apoptosis, escape immunosurveillance, survive chemotherapies and are majorly responsible for cancer mortality. Differences in phenotypic plasticity may form the basis of differential impact of therapeutic outcomes on heterogeneous subpopulations of CSCs. Activation of autophagy is responsible for the recycling of damaged organelles and protein aggregates, regulates EMT, confers the survival advantage to neoplastic cells to anti-cancer therapies, significantly affects the invasive potential of cancer cells and supports their metastatic dissemination in a tissue and tumor stage dependent manner. Therapy resistance is the primary obstacle in the complete ablation of tumor cells. Combinational treatments based on targeting autophagic CSCs and inhibiting EMT regulators may represent potential anticancer strategies for the prevention of cancer invasion, metastatic spread and disease relapse.

WNT/ß-catenin signaling in urothelial carcinoma of bladder.

Urothelial carcinoma of bladder is the second most prevalent genitourinary disease. It is a highly heterogeneous disease as it represents a spectrum of neoplasms, including non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and metastatic lesions. Genome-wide approaches and candidate gene analysis suggest that malignant transformation of the bladder is multifactorial and a multitude of genes are involved in the development of MIBC or NMIBC phenotypes. Wnt signaling is being examined to control and maintain balance between stemness and differentiation in adult stem cell niches. Owing to its participation in urothelial development and maintenance of adult urothelial tissue homeostasis, the components of Wnt signaling are reported as an important diagnostic and prognostic markers as well as novel therapeutic targets. Mutations/epigenetic alterations in the key molecules of Wnt/ß-catenin canonical pathway have been linked with tumorigenesis, development of drug resistance and enhanced survival. Present review extends our understanding on the functions of key regulatory molecules of canonical Wnt/ß-catenin pathway in urothelial tumorigenesis by inducing cancer stem cell phenotype (UCSCs). UCSCs may be responsible for tumor heterogeneity, high recurrence rates and complex biological behavior of bladder cancer. Therefore, understanding the role of UCSCs and the regulatory mechanisms that are responsible for high relapse rates and metastasis could help to develop pathway inhibitors and augment current therapies. Potential implications in the treatment of urothelial carcinoma of bladder by targeting this pathway primarily in UCSCs as well as in bulk tumor population that are responsible for high relapse rates and metastasis may facilitate potential therapeutic avenues and better prognosis.

Clinicohistopathological implications of phosphoserine 9 glycogen synthase kinase-3ß/ ß-catenin in urinary bladder cancer patients.

BACKGROUND: Aberrant activation of phosphorylated form of glycogen synthase kinase-3ß [pS9GSK-3ß (Serine 9 phosphorylation)] is known to trigger Wnt/ß-catenin signal cascade but its clinicohistopathological implications in bladder carcinogenesis remain unknown. AIM: To investigate the diagnostic and prognostic relevance of expressions of pS9GSK-3ß, ß-catenin and its target genes in the pathobiology of bladder cancer. METHODS: Bladder tumor tissues from ninety patients were analyzed for quantitative expression and cellular localization of pS9GSK-3ß by immunohistochemical (IHC) staining. Real time-quantitative polymerase chain reaction and IHC were done to check the expression of ß-catenin, Cyclin D1, Snail and Slug at transcriptome and protein level respectively. Clinicohistopathological variables were obtained from histology reports, follow up and OPD visits of patients. Expressions of the markers were statistically correlated with these variables to determine their significance in clinical setting. Results were analysed using SPSS 20.0 software. RESULTS: Aberrant (low or no membranous/high nuclear/high cytoplasmic) expression of pS9GSK-3ß was noted in 51% patients and found to be significantly associated with tumor stage and tumor grade (P = 0.01 and 0.04; Mann Whitney U test). Thirty one percent tumors exhibited aberrant co-expression of pS9GSK-3ß and ß-catenin proteins and showed strong statistical association with tumor stage, tumor type, smoking/tobacco chewing status (P = 0.01, 0.02 and 0.04, Mann-Whitney U test) and shorter overall survival probabilities of patients (P = 0.02; Kaplan Meier test). Nuclear immunostaining of Cyclin D1 in tumors with altered pS9GSK-3ß/ß-catenin showed relevance with tumor stage, grade and type. CONCLUSION: ß-catenin and pS9GSK-3ß proteins are identified as markers of diagnostic/prognostic significance in disease pathogenesis. Observed histopathological association of Cyclin D1 identifies it as marker of potential relevance in tumors with altered pS9GSK-3ß/ß-catenin.

Epithelial-to-mesenchymal transition: Event and core associates in bladder cancer.

Urothelial carcinoma of the bladder (UCB) shows different biological outcomes, diverse biological propensities for invading the muscularis as well as epithelial-to-mesenchymal transition (EMT), a dynamic key event during developmental processes, wound healing, and tissue repair. The EMT core molecules include EMT-activating transcription factors (EMT-ATFs), and a host of downstream effectors and target genes including extracellular inducers and growth factors. Here, we describe molecular regulatory determinants of mesenchymal-to-epithelial transition (MET) and more specifically EMT that allows a subset of urothelial cancer cells to gain mesenchymal traits with self-renewal potential. EMT accelerates tumor progression and poses a clinical challenge to anticancer therapies. Targeting the populations of tumor-initiating cells and those with a metastable phenotype provide the basis for the development of more reliable risk assessment of tumor progression and risk, and better treatment strategies of UCB.

Positive Correlation between Matrix Metalloproteinases and Epithelial-to-Mesenchymal Transition and its Association with Clinical Outcome in Bladder Cancer Patients.

Involvement of matrix metalloproteinases (MMPs) in the pathogenesis of urothelial carcinoma elects them to be sensitive marker for clinical and prognostic implications. MMPs regulate tumor growth and invasion by inducing epithelial-to-mesenchymal transition (EMT) which is characterized by the complex reprogramming of epithelial cells and ultimately bring about major changes in the structural organization of bladder urothelium. The present study has been undertaken to evaluate the clinical relevance of MMPs in two distinct types of bladder cancer disease. Expression analysis of MMPs namely MMP-2, MMP-7, MMP-9 and EMT markers including epithelial marker, E-cadherin; mesenchymal markers, N-cadherin and Vimentin; and EMT-activating transcriptional factors (EMT-ATFs), Snail, Slug, Twist and Zeb was done in 64 cases of bladder tumor tissues [{Non-muscle invasive bladder cancer (NMIBC): 35 cases} and {Muscle invasive bladder cancer (MIBC): 29 cases}] by real-time quantitative polymerase chain reaction (RT-qPCR). Immunohistochemistry (IHC) staining was done in matched bladder tumor tissues to evaluate the protein expression and localization of E-cadherin, N-cadherin, Vimentin, Snail, and Slug. Our data showed overexpression of MMP-2, MMP-7 and MMP-9 at transcriptome level in 32.8%, 25% and 37.5% bladder tumor cases respectively. These tumor tissues were examined for higher expression of mesenchymal markers (N-cadherin and Vimentin) at mRNA and protein level and exhibited statistical association with tumor stage and tumor grade (p = 0.02, p = 0.04, Mann-Whitney test). Significant statistical correlation in tumor tissues with overexpressed MMPs has also been observed between gain of transcriptional factors and weak expression of E-cadherin with tumor stage, grade, gender, presence of hematuria and smoking history of the patients. Gene expression patterns of EMT markers in bladder tumors with overexpressed MMPs and their significant association with clinical profile validate the important role of MMPs in the pathogenesis of urothelial carcinoma of bladder (UCB). Increased expression of specific MMPs may affect several downstream EMT programs and thus may improve its diagnostic and prognostic utility in clinical setting.

Mechanistic regulation of epithelial-to-mesenchymal transition through RAS signaling pathway and therapeutic implications in human cancer.

RAS effector signaling instead of being simple, unidirectional and linear cascade, is actually recognized as highly complex and dynamic signaling network. RAF-MEK-ERK cascade, being at the center of complex signaling network, links to multiple scaffold proteins through feed forward and feedback mechanisms and dynamically regulate tumor initiation and progression. Three isoforms of Ras harbor mutations in a cell and tissue specific manner. Besides mutations, their epigenetic silencing also attributes them to exhibit oncogenic activities. Recent evidences support the functions of RAS oncoproteins in the acquisition of tumor cells with Epithelial-to-mesenchymal transition (EMT) features/ epithelial plasticity, enhanced metastatic potential and poor patient survival. Google Scholar electronic databases and PubMed were searched for original papers and reviews available till date to collect information on stimulation of EMT core inducers in a Ras driven cancer and their regulation in metastatic spread. Improved understanding of the mechanistic basis of regulatory interactions of microRNAs (miRs) and EMT by reprogramming the expression of targets in Ras activated cancer, may help in designing effective anticancer therapies. Apparent lack of adverse events associated with the delivery of miRs and tissue response make 'drug target miRNA' an ideal therapeutic tool to achieve progression free clinical response.

Epithelial plasticity and cancer stem cells: Major mechanisms of cancer pathogenesis and therapy resistance.

Epithelial-mesenchymal transition (EMT) has been linked with aggressive tumor biology and therapy resistance. It plays central role not only in the generation of cancer stem cells (CSCs) but also direct them across the multiple organ systems to promote tumor recurrence and metastasis. CSCs are reported to express stem cell genes as well as specific cell surface markers and allow aberrant differentiation of progenies. It facilitates cancer cells to leave primary tumor, acquire migratory characteristics, grow into new environment and develop radio-chemo-resistance. Based on the current information, present review discusses and summarizes the recent advancements on the molecular mechanisms that derive epithelial plasticity and its major role in generating a subset of tumor cells with stemness properties and pathophysiological spread of tumor. This paper further highlights the critical need to examine the regulation of EMT and CSC pathways in identifying the novel probable therapeutic targets. These improved therapeutic strategies based on the co-administration of inhibitors of EMT, CSCs as well as differentiated tumor cells may provide improved anti-neoplastic response with no tumor relapse.

Epithelial, mesenchymal and hybrid epithelial/mesenchymal phenotypes and their clinical relevance in cancer metastasis.

Cancer metastasis occurs through local invasion of circulating tumour cells (CTCs), intravasation, transportation to distant sites, and their extravasation followed by colonisation at secondary sites. Epithelial-mesenchymal transition (EMT) is a normal developmental phenomenon, but its aberrant activation confers tumour cells with enhanced cell motility, metastatic properties, resistant to therapies and cancer stem cell (CSC) phenotype in epithelium-derived carcinoma. Experimental studies from various research papers have been reviewed to determine the factors, which interlink cancer stemness and cellular plasticity with EMT. Although existence of CSCs has been linked with EMT, nevertheless, there are controversies with the involvement of type of tumour cells, including cells with E (epithelial) and M (mesenchymal) phenotype alone or hybrid E/M phenotype in different types of cancers. Studies on CTCs with hybrid E/M phenotypes during different stages of cancer metastasis reveal strong association with tumour -initiation potential, cellular plasticity and types of cancer cells. Cells with the hybrid E/M state are strictly controlled by phenotypic stability factors coupled to core EMT decision-making circuits, miR200/ZEB and miR-34/Snail. Understanding the regulatory functions of EMT program in cancer metastasis can help us to characterise the biomarkers of prognostic and therapeutic potential. These biomarkers when targeted may act as metastatic suppressors, inhibit cellular plasticity and stemness ability of tumour cells and can block metastatic growth.

Epithelial-To-Mesenchymal Transition and Its Correlation With Clinicopathologic Features in Patients With Urothelial Carcinoma of the Bladder.

INTRODUCTION: Epithelial-to-mesenchymal transition (EMT) is a dynamic process in the pathogenesis of urinary bladder cancer. Despite significant advancements in its diagnosis and treatment, the outcomes have more or less remained the same. In the present study, the expression of EMT markers was investigated to evaluate its prognostic significance in patients with non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: The present study was undertaken to examine the expression of EMT markers, including E-cadherin, N-cadherin, vimentin, Snail, Twist, Zeb, and Slug, on 28 bladder tumor tissues (15 cases of NMIBC and 13 of MIBC) using reverse transcription-polymerase chain reaction. Immunohistochemical (IHC) staining was performed to check the protein expression and localization of E-cadherin, N-cadherin, vimentin, Snail, and Slug. RESULTS: At the message level, reduced expression of E-cadherin correlated with gender (P = .004), enhanced expression of N-cadherin correlated with stage and age (P = .02, for both), and increased expression of EMT transcription factors correlated significantly with stage, grade, or age. Inverse correlation of reduced levels of E-cadherin were observed with new expression of N-cadherin (P = .001; Mann-Whitney U test) and vimentin (P = .001; Mann-Whitney U test). On IHC, novel expression of vimentin and N-cadherin was associated with enhanced expression of Snail and Slug (P = .005; Wilcoxon signed rank test). CONCLUSION: Molecular validation of the EMT marker profile proved to be a sensitive and an effective prognostic tool for objective and systematic investigation of EMT function in the pathogenesis of urinary bladder cancer. Nevertheless, further studies are required with a greater number of clinical samples.

Epithelial plasticity in urothelial carcinoma: Current advancements and future challenges.

Urothelial carcinoma (UC) of the bladder is characterized by high recurrence rate where a subset of these cells undergoes transition to deadly muscle invasive disease and later metastasizes. Urothelial cancer stem cells (UroCSCs), a tumor subpopulation derived from transformation of urothelial stem cells, are responsible for heterogeneous tumor formation and resistance to systemic treatment in UC of the bladder. Although the precise reason for pathophysiologic spread of tumor is not clear, transcriptome analysis of microdissected cancer cells expressing multiple progenitor/stem cell markers validates the upregulation of genes that derive epithelial-to-mesenchymal transition. Experimental studies on human bladder cancer xenografts describe the mechanistic functions and regulation of epithelial plasticity for its cancer-restraining effects. It has been further examined to be associated with the recruitment of a pool of UroCSCs into cell division in response to damages induced by adjuvant therapies. This paper also discusses the various probable therapeutic approaches to attenuate the progressive manifestation of chemoresistance by co-administration of inhibitors of epithelial plasticity and chemotherapeutic drugs by abrogating the early tumor repopulation as well as killing differentiated cancer cells.

Emerging role of microRNAs in cancer stem cells: Implications in cancer therapy.

A small subset of cancer cells that act as tumor initiating cells or cancer stem cells (CSCs) maintain self-renewal and growth promoting capabilities of cancer and are responsible for drug/treatment resistance, tumor recurrence and metastasis. Due to their potential clinical importance, many researchers have put their efforts over decades to unravel the molecular mechanisms that regulate CSCs functions. MicroRNAs (miRNAs) which are 21-23 nucleotide long, endogenous non-coding RNAs, regulate gene expression through gene silencing at post-transcriptional level by binding to the 3'-untranslated regions or the open reading frames of target genes, thereby result in target mRNA degradation or its translational repression and serve important role in several cellular, physiological and developmental processes. Aberrant miRNAs expression and their implication in CSCs regulation by controlling asymmetric cell division, drug/treatment resistance and metastasis make miRNAs a tool of great therapeutic potential against cancer. Recent advancements on the biological complexities of CSCs, modulation in CSCs properties by miRNA network and development of miRNA based treatment strategies specifically targeting the CSCs as an attractive therapeutic targets for clinical application are being critically analysed.

Urothelial cancer stem cells and epithelial plasticity: current concepts and therapeutic implications in bladder cancer.

Urothelial carcinoma is a highly heterogeneous disease that develops along two distinct biological tracks as evident by candidate gene analysis and genome-wide screening and therefore, offers different challenges for clinical management. Tumors representing the truly distinct molecular entities express molecular markers characteristic of a developmental process and a major mechanism of cancer metastasis, known as epithelial-to-mesenchymal transition (EMT). Recently identified subset of cells known as urothelial cancer stem cells (UroCSCs) in urothelial cell carcinoma (UCC) have self-renewal properties, ability to generate cellular tumor heterogeneity via differentiation and are ultimately responsible for tumor growth and viability. In this review paper, PubMed and Google Scholar electronic databases were searched for original research papers and review articles to extract relevant information on the molecular mechanisms delineating the relationship between EMT and cancer stemness and their clinical implications for different subsets of urothelial cell carcinomas. Experimental and clinical studies over the past few years in bladder cancer cell lines and tumor tissues of different cancer subtypes provide evidences and new insights for mechanistic complexity for induction of EMT, tumorigenicity, and cancer stemness in malignant transformation of urothelial cell carcinomas. Differentiation and elimination therapies targeting EMT-cancer stemness pathway have been proposed as cynosure in the molecular biology of urothelial cell carcinomas and could prove to be clinically beneficial in an ability to reverse the EMT phenotype of tumor cells, suppress the properties of UroCSCs, inhibit bladder cancer progression and tumor relapse, and provide rationale in the treatment and clinical management of urothelial cancer.