transforming-growth-factor-beta and Urogenital-Neoplasms

Genitourinary cancers (GCs) include a large group of different types of tumors localizing to the kidney, bladder, prostate, testis, and penis. Despite highly divergent molecular patterns, most GCs share commonly disturbed signaling pathways that involve the activity of TGF-β (transforming growth factor beta). TGF-β is a pleiotropic cytokine that regulates key cancer-related molecular and cellular processes, including proliferation, migration, invasion, apoptosis, and chemoresistance. The understanding of the mechanisms of TGF-β actions in cancer is hindered by the "TGF-β paradox" in which early stages of cancerogenic process are suppressed by TGF-β while advanced stages are stimulated by its activity. A growing body of evidence suggests that these paradoxical TGF-β actions could result from the interplay with microRNAs: Short, non-coding RNAs that regulate gene expression by binding to target transcripts and inducing mRNA degradation or inhibition of translation. Here, we discuss the current knowledge of TGF-β signaling in GCs. Importantly, TGF-β signaling and microRNA-mediated regulation of gene expression often act in complicated feedback circuits that involve other crucial regulators of cancer progression (e.g., androgen receptor). Furthermore, recently published in vitro and in vivo studies clearly indicate that the interplay between microRNAs and the TGF-β signaling pathway offers new potential treatment options for GC patients.

Topics: Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Male; MicroRNAs; Prognosis; Signal Transduction; Transforming Growth Factor beta; Urogenital Neoplasms

Topics: Animals; Epidermal Growth Factor; Fibroblast Growth Factors; Growth Substances; Humans; Kidney Neoplasms; Male; Prostatic Hyperplasia; Prostatic Neoplasms; Somatomedins; Transforming Growth Factor beta; Urinary Bladder Neoplasms; Urogenital Neoplasms

TGFbetas are thought to have tumor suppressor activity in many organ systems, but receptor inactivation in mouse models has not previously resulted in increased spontaneous tumorigenesis. A study in this issue of Cancer Cell shows that mice with a targeted knockout of the type II TGFbeta receptor in stratified epithelia specifically develop spontaneous squamous cell carcinomas in the anogenital region, but not in the skin. Loss of TGFbeta signaling appears to destabilize the epithelium such that homeostasis fails in the face of persistent proliferative challenge, a normal feature of the anogenital site, and latent invasive and migratory phenotypes are unmasked.

Topics: Animals; Anus Neoplasms; Apoptosis; Carcinoma, Squamous Cell; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Epithelial Cells; Extracellular Matrix; Focal Adhesion Protein-Tyrosine Kinases; Homeostasis; Humans; Integrins; Keratin-14; Keratinocytes; Mice; Mice, Knockout; Mutation; Neoplasm Invasiveness; Papilloma; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; ras Proteins; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Skin; Skin Neoplasms; src-Family Kinases; Time Factors; Transforming Growth Factor beta; Urogenital Neoplasms; Wound Healing

Although TGFbeta is a potent inhibitor of proliferation, epithelia lacking the essential receptor (TbetaRII) for TGFbeta signaling display normal tissue homeostasis. By studying asymptomatic TbetaRII-deficient stratified epithelia, we show that tissue homeostasis is maintained by balancing hyperproliferation with elevated apoptosis. Moreover, rectal and genital epithelia, which are naturally proliferative, develop spontaneous squamous cell carcinomas with age when TbetaRII is absent. This progression is associated with a reduction in apoptosis and can be accelerated in phenotypically normal epidermis by oncogenic mutations in Ras. We show that TbetaRII deficiency leads to enhanced keratinocyte motility and integrin-FAK-Src signaling. Together, these mechanisms provide a molecular framework to account for many of the characteristics of TbetaRII-deficient invasive SQCCs.

Topics: Animals; Anus Neoplasms; Apoptosis; Carcinoma, Squamous Cell; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Epithelial Cells; Extracellular Matrix; Focal Adhesion Protein-Tyrosine Kinases; Homeostasis; Humans; Integrins; Keratin-14; Keratinocytes; Male; Mice; Mice, Knockout; Mutation; Neoplasm Invasiveness; Papilloma; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; ras Proteins; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Skin; Skin Neoplasms; src-Family Kinases; Time Factors; Transforming Growth Factor beta; Urogenital Neoplasms; Wound Healing