Abstract
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.
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References
van der Horst, G., Bos, L., & van der Pluijm, G. (2012). Epithelial plasticity, cancer stem cells, and the tumor-supportive stroma in bladder carcinoma. Molecular Cancer Research, 10(8), 995–1009.
Castillo-Martin, M., Domingo-Domenech, J., Karni-Schmidt, O., Matos, T., & Cordon-Cardo, C. (2010). Molecular pathways of urothelial development and bladder tumorigenesis. Urologic Oncology, 28(4), 401–408.
Brandt, W. D., Matsui, W., Rosenberg, J. E., He, X., Ling, S., Schaeffer, E. M., & Berman, D. M. (2009). Urothelial carcinoma: stem cells on the edge. Cancer and Metastasis Reviews, 28(3–4), 291–304.
Kurzrock, E. A., Lieu, D. K., Degraffenried, L. A., Chan, C. W., & Isseroff, R. R. (2008). Label-retaining cells of the bladder: candidate urothelial stem cells. American Journal of Physiology. Renal Physiology, 294(6), F1415-21.
Hatina, J., & Schulz, W. A. (2012). Stem cells in the biology of normal urothelium and urothelial carcinoma. Neoplasma, 59(6), 728–736.
Ho, P. L., Kurtova, A., & Chan, K. S. (2012). Normal and neoplastic urothelial stem cells: getting to the root of the problem. Nature Reviews. Urology, 9(10), 583–594.
Thangappan, R., & Kurzrock, E. A. (2009). Three clonal types of urothelium with different capacities for replication. Cell Proliferation, 42(6), 770–779.
Ning, Z. F., Huang, Y. J., Lin, T. X., Zhou, Y. X., Jiang, C., Xu, K. W., Huang, H., Yin, X. B., & Huang, J. (2009). Subpopulations of stem-like cells in side population cells from the human bladder transitional cell cancer cell line T24. The Journal of International Medical Research, 37(3), 621–630.
She, J. J., Zhang, P. G., Wang, Z. M., Gan, W. M., & Che, X. M. (2008). Identification of side population cells from bladder cancer cells by DyeCycle Violet staining. Cancer Biology & Therapy, 7(10), 1663–1668.
Chan, K. S., Espinosa, I., Chao, M., Wong, D., Ailles, L., Diehn, M., Gill, H., Presti, J., Jr., Chang, H. Y., van de Rijn, M., Shortliffe, L., & Weissman, I. L. (2009). Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proceedings of the National Academy of Sciences of the United States of America, 106(33), 14016–14021.
Yang, Y. M., & Chang, J. W. (2008). Bladdercancer initiating cells (BCICs) are among EMA-CD44v6+ subset: novel methods for isolating undetermined cancer stem (initiating) cells. Cancer Investigation, 26(7), 725–733.
He, X., Marchionni, L., Hansel, D. E., Yu, W., Sood, A., Yang, J., Parmigiani, G., Matsui, W., & Berman, D. M. (2009). Differentiation of a highly tumorigenic basal cell compartment in urothelial carcinoma. Stem Cells, 27(7), 1487–1495.
Su, Y., Qiu, Q., Zhang, X., Jiang, Z., Leng, Q., Liu, Z., Stass, S. A., & Jiang, F. (2010). Aldehyde dehydrogenase 1 A1-positive cell population is enriched in tumor-initiating cells and associated with progression of bladder cancer. Cancer Epidemiology, Biomarkers & Prevention, 19(2), 327–337.
Bentivegna, A., Conconi, D., Panzeri, E., Sala, E., Bovo, G., Viganò, P., Brunelli, S., Bossi, M., Tredici, G., Strada, G., & Dalprà, L. (2009). Biological heterogeneity of putative bladder cancer stem-like cell populations from human bladder transitional cell carcinoma samples. Cancer Science, 101(2), 416–424.
Oates, J. E., Grey, B. R., Addla, S. K., Samuel, J. D., Hart, C. A., Ramani, V. A., Brown, M. D., & Clarke, N. W. (2009). Hoechst 33342 side population identification is a conserved and unified mechanism in urological cancers. Stem Cells and Development, 18(10), 1515–1522.
Massard, C., Deutsch, E., & Soria, J. C. (2006). Tumor stem cell-targeted treatment: elimination or differentiation. Annals of Oncology, 17(11), 1620–1624.
Shin, K., Lee, J., Guo, N., Kim, J., Lim, A., Qu, L., Mysorekar, I. U., & Beachy, P. A. (2011). Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature, 472(7341), 110–114.
Herzig, M., Savarese, F., Novatchkova, M., Semb, H., & Christofori, G. (2007). Tumor progression induced by the loss of E-cadherin independent of beta catenin/Tcf-mediated Wnt signaling. Oncogene, 26, 2290–2298.
Suyama, K., Shapiro, I., Guttman, M., & Hazan, R. B. (2002). A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell, 2, 301–314.
Mandeville, J. A., Silva, N. B., Vanni, A. J., Smith, G. L., Rieger-Christ, K. M., Zeheb, R., Loda, M., Libertino, J. A., & Summerhayes, I. C. (2008). P-cadherin as a prognostic indicator and a modulator of migratory behavior in bladder carcinoma cells. BJU International, 102, 1707–1714.
Islam, S. S., Mokhtari, R. B., Noman, A. S., Uddin, M., Rahman, M. Z., Azadi, M. A., Zlotta, A., van der Kwast, T., Yeger, H., & Farhat, W. A. (2015). Sonic hedgehog (Shh) signaling promotes tumorigenicity and stemness via activation of epithelial-to-mesenchymal transition (EMT) in bladder cancer. Molecular Carcinogenesis. doi:10.1002/mc.22300.
Fondrevelle, M. E., Kantelip, B., Reiter, R. E., Chopin, D. K., Thiery, J. P., Monnien, F., Bittard, H., & Wallerand, H. (2009). The expression of Twist has an impact on survival in human bladder cancer and is influenced by the smoking status. Urologic Oncology, 27, 268–276.
Garg, M. (2013). Epithelial-mesenchymal transition—activating transcription factors—multifunctional regulators in cancer. World Journal of Stem Cells, 5(4), 188–195.
Yu, Q., Zhang, K., Wang, X., Liu, X., & Zhang, Z. (2010). Expression of transcription factors snail, slug, and twist in human bladder carcinoma. Journal of Experimental & Clinical Cancer Research, 29, 119.
Bruyere, F., Namdarian, B., Corcoran, N. M., Pedersen, J., Ockrim, J., Voelzke, B. B., Mete, U., Costello, A. J., & Hovens, C. M. (2010). Snail expression is an independent predictor of tumor recurrence in superficial bladder cancers. Urologic Oncology, 28, 591–596.
Zhao, D., Besser, A. H., Wander, S. A., Sun, J., Zhou, W., Wang, B., Ince, T., Durante, M. A., Guo, W., Mills, G., Theodorescu, D., & Slingerland, J. (2015). Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation. Oncogene. doi:10.1038/onc.2014.473.
Garg, M. (2015). Targeting microRNAs in epithelial-to-mesenchymal transition-induced cancer stem cells: therapeutic approaches in cancer. Expert Opinion on Therapeutic Targets, 19(2), 285–297.
Majid, S., Dar, A. A., Saini, S., Deng, G., Chang, I., Greene, K., Tanaka, Y., Dahiya, R., & Yamamura, S. (2013). MicroRNA-23b functions as a tumor suppressor by regulating Zeb1 in bladder cancer. PloS One, 8(7), e67686.
Wiklund, E. D., Bramsen, J. B., Hulf, T., Dyrskjøt, L., Ramanathan, R., Hansen, T. B., Villadsen, S. B., Gao, S., Ostenfeld, M. S., Borre, M., Peter, M. E., Ørntoft, T. F., Kjems, J., & Clark, S. J. (2011). Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. International Journal of Cancer, 128(6), 1327–1334.
Garg, M. (2014). Prognostic and therapeutic applications of the molecular events in clinical management of urothelial carcinoma of bladder. Journal of Experimental and Therapeutic Oncology, 10(4), 301–316.
Zhang, Y., Wang, Z., Yu, J., Jz, S., Wang, C., Wh, F., Zw, C., & Yang, J. (2012). Cancer stem-like cells contribute to cisplatin resistance and progression in bladder cancer. Cancer Letters, 322(1), 70–77.
Massari F, Ciccarese C, Santoni M, Brunelli M, Conti A, Modena A, Montironi R, Santini D, Cheng L, Martignoni G, Cascinu S, Tortora G (2015). The route to personalized medicine in bladder cancer: where do we stand? Target Oncology
Adam, L., Zhong, M., Choi, W., Qi, W., Nicoloso, M., Arora, A., Calin, G., Wang, H., Siefker-Radtke, A., McConkey, D., Bar-Eli, M., & Dinney, C. (2009). miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clinical Cancer Research, 15(16), 5060–5072.
Singh, S. V., & Singh, K. (2012). Cancer chemoprevention with dietary isothiocyanates mature for clinical translational research. Carcinogenesis, 33(10), 1833–1842.
Wu, K., Ning, Z., Zeng, J., Fan, J., Zhou, J., Zhang, T., Zhang, L., Chen, Y., Gao, Y., Wang, B., Guo, P., Li, L., Wang, X., & He, D. (2013). Silibinin inhibits β-catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial-mesenchymal transition and stemness. Cellular Signalling, 25(12), 2625–2633.
Katoh, M., & Nakagama, H. (2014). FGF receptors: cancer biology and therapeutics.Med. Research Reviews, 34(2), 280–300.
Chan, E., Patel, A., Heston, W., & Larchian, W. (2009). Mouse orthotopic models for bladder cancer research. BJU International, 104(9), 1286–1291.
Zhang, Z. T., Pak, J., Shapiro, E., Sun, T. T., & Wu, X. R. (1999). Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma. Cancer Research, 59(14), 3512–3517.
Kenny, P. A., Lee, G. Y., & Bissell, M. J. (2007). Targeting the tumor microenvironment. Frontiers in Bioscience, 12, 3468–3474.
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Sincere thanks goes to the Department of Science and Technology, Govt. of India for providing research grant (grant no. SR/SO/HS-0113/2010).
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Garg, M. Urothelial cancer stem cells and epithelial plasticity: current concepts and therapeutic implications in bladder cancer. Cancer Metastasis Rev 34, 691–701 (2015). https://doi.org/10.1007/s10555-015-9589-6
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DOI: https://doi.org/10.1007/s10555-015-9589-6