TGF-β Family Signaling in Tumor Suppression and Cancer Progression

Abstract

Transforming growth factor-β (TGF-β) induces a pleiotropic pathway that is modulated by the cellular context and its integration with other signaling pathways. In cancer, the pleiotropic reaction to TGF-β leads to a diverse and varied set of gene responses that range from cytostatic and apoptotic tumor-suppressive ones in early stage tumors, to proliferative, invasive, angiogenic, and oncogenic ones in advanced cancer. Here, we review the knowledge accumulated about the molecular mechanisms involved in the dual response to TGF-β in cancer, and how tumor cells evolve to evade the tumor-suppressive responses of this signaling pathway and then hijack the signal, converting it into an oncogenic factor. Only through the detailed study of this complexity can the suitability of the TGF-β pathway as a therapeutic target against cancer be evaluated.

Figure 1.

Transforming growth factor β (TGF-β) in tumor progression and metastasis. TGF-β limits the growth of normal epithelium and premalignant lesions. Loss of the cytostatic response to TGF-β can occur by mutations in or loss of TGF-β receptors, Smads, or by specific loss of mediators of the TGF-β cytostatic responses. In addition, tumors evade the immune response and increase autocrine mitogenic signals and motility and migration during malignancy. Tumor cells that have lost the cytostatic response may undergo epithelial-to-mesenchymal transition (EMT) in response to TGF-β and become more invasive. Concurrently, these cells may use TGF-β to evade the immunosuppressive environment and induce angiogenesis and systemic dissemination. Finally, adherence of tumor cells to the endothelium and/or extravasation of tumor cells at sites of metastasis, such as lung, can be enhanced by TGF-β signaling. Similarly, stroma-modifying factors, such as those that promote osteolytic bone metastasis by breast cancer cells, are driven by TGF-β signaling. BMD, bone marrow–derived.

Figure 2.

The transforming growth factor β (TGF-β)-induced Smad signaling pathway. TGF-β binds to the type II receptor and recruits the type I receptor, whereby the type II receptor phosphorylates and activates type I receptor. The type I receptor, in turn, phosphorylates receptor-activated Smads (Smad2 and Smad3) at the carboxy-terminal SXS motif, which results in release of these Smads from the receptor complex in the cytoplasm and triggers their translocation into the nucleus. Smad4 acts as a common partner of activated Smads to help execute their function. Smad proteins continuously undergo nucleocytoplasmic shuttling and interact with nuclear pore complexes. Once in the nucleus, activated Smad proteins form complexes that regulate target gene transcription, generating hundreds of early gene responses. Mechanisms of phosphorylation and polyubiquitylation account for the signal termination of the activated Smads. On the right, TGF-β target genes in epithelial cells are grouped on the basis of their biological responses. Highlighted in red are gene responses repressed by TGF-β, and in green are gene responses induced by TGF-β. These are central for the cytostatic program induced by TGF-β.

Figure 3.

The transforming growth factor β (TGF-β)-induced transcriptional program and its alterations in cancer. The diagram depicts mutations or alterations that occur in genes that encode mediators of the TGF-β signaling pathway in distinct types of human cancers. Shown are the transcriptional components underlying the principal TGF-β cytostatic responses in epithelial cells. Indicated in red are the targets of alterations present in distinct types of human cancers converging on the TGF-β target genes that mediate cell cycle arrest.

Figure 4.

Pleiotropic effects of TGF-β on the immune system. TGF-β plays a role by controlling immune tolerance by the combined inhibition of most components of the innate (brown) and adaptive (blue) immune system directly or indirectly (green) through regulatory T cells. NK, Natural killer.

Figure 5.

TGF-β signaling in cells adjacent to carcinoma cells and not in the malignant carcinoma cells. TGF-β is produced and activates signals in various cell types in the tumor environment. These include tumor epithelial cells, fibroblasts, endothelial cells, mesenchymal cells, and adipocytes.