TGF-β Family Signaling Pathways in Cellular Dormancy

Clinical cancer dormancy refers to the clinical 'disease-free' period between primary tumor removal or therapy and the subsequent detection of recurrence or metastases. Cellular dormancy refers to a solitary non-proliferating cancer cell (disseminated tumor cell). In this case, dormancy is mediated by cell-intrinsic and/or -extrinsic mechanisms. There is still no clinical proof for cellular dormancy, although preclinical animal models have shown its existence. The TGF-β/BMP pathway is involved in the regulation of cellular dormancy. Depending on the molecular context, it induces the dormancy or proliferation of solitary cancer cells. Currently there are no therapies that specifically eliminate dormant cancer cells. However, new approaches other than the elimination of dormant cells should be considered for preventing cancer relapse. Maintaining cellular dormancy through long-term administration of targeted therapy is one such approach. Individual cancer cells can switch, reversibly, to a non-proliferative dormant state, a process characterized by two principal stages: (i) establishment and maintenance, and (ii) the breaking of dormancy. This phenomenon is of clinical importance because dormant cells resist chemotherapy, and this can result in cancer relapse following years, if not decades, of clinical remission. Although the molecular mechanisms governing tumor cell dormancy have not been clearly delineated, accumulating evidence suggests that members of the transforming growth factor-β (TGF-β) family are integral. We summarize here recent findings which support the view that TGF-β family signaling pathways play a pivotal role in cellular dormancy, and discuss how affected cells could be therapeutically targeted to prevent cancer relapse. Individual cancer cells can switch, reversibly, to a non-proliferative dormant state, a process characterized by two principal stages: (i) establishment and maintenance, and (ii) the breaking of dormancy. This phenomenon is of clinical importance because dormant cells resist chemotherapy, and this can result in cancer relapse following years, if not decades, of clinical remission. Although the molecular mechanisms governing tumor cell dormancy have not been clearly delineated, accumulating evidence suggests that members of the transforming growth factor-β (TGF-β) family are integral. We summarize here recent findings which support the view that TGF-β family signaling pathways play a pivotal role in cellular dormancy, and discuss how affected cells could be therapeutically targeted to prevent cancer relapse. the cancer returns after therapy and/or a period of remission. tumor cells that have detached from the primary tumor and reside in the blood/lymphatic flow. these are CTCs that have successfully reached a distant tissue. DTCs are mainly found in the BM and lymph nodes, and are clinically used to predict, among others, patient relapse. a family of transcription factors that function as intracellular mediators of TGF-β signaling. The name originates from their similarity to the Caenorhabditis elegans SMA protein and the Drosophila gene product MAD (mothers against decapentaplegic). the local environment of a tumor (cell) including fibroblasts, immune cells, cells that compose the blood vessels, extracellular matrix, growth factors, cytokines, and the overall metabolic status of niche.