A newcomer in a cytokine family whose members regulate organism development, the regulatory cytokine transforming growth factor β (TGFβ) made its debut with the rise of the vertebrates. TGFβ evolved to regulate the expanding systems of epithelial and neural tissues, the immune system, and wound repair. Tied to these crucial regulatory roles of TGFβ are the serious consequences that result when this signaling pathway malfunctions, namely tumorigenesis. Virtually all human cell types are responsive to TGFβ. TGFβ maintains tissue homeostasis and prevents incipient tumors from progressing down the path to malignancy by regulating not only cellular proliferation, differentiation, survival, and adhesion but also the cellular microenvironment. But as genetically unstable entities, cancer cells have the capacity to avoid or, worse yet, adulterate the suppressive influence of the TGFβ pathway. Pathological forms of TGFβ signaling promote tumor growth and invasion, evasion of immune surveillance, and cancer cell dissemination and metastasis (). How can a tumor-suppressor pathway be so radically turned on its head? The answer lies in the points of disruption in TGFβ signaling and the context in which these disruptions occur.
Malignant cells can circumvent the suppressive effects of TGFβ either through inactivation of core components of the pathway, such as TGFβ receptors (, Path 1), or by downstream alterations that disable just the tumor-suppressive arm of this pathway (, Path 2). If the latter mode of circumvention is used, cancer cells can then freely usurp the remaining TGFβ regulatory functions to their advantage, acquiring invasion capabilities, producing autocrine mitogens, or releasing prometastatic cytokines. Thus, beheading of the TGFβ pathway by receptor inactivation can eliminate tumor suppression, whereas amputation of just the growth-inhibitory arm of this pathway not only abolishes growth suppression but also creates added potential for tumor progression. Also relevant to cancer development are the effects of TGFβ on the tumor stroma. TGFβ is a key enforcer of immune tolerance, and tumors that produce high levels of this cytokine may be shielded from immune surveillance. On the other hand, defective TGFβ responsiveness in immune cells can lead to chronic inflammation and the production of a protumorigenic environment. Tumor-derived TGFβ may recruit other stromal cell types such as myofibroblasts (at the invading tumor front) and osteoclasts (in bone metastases), thus furthering tumor spread.
A dual role of TGFβ in cancer has long been noted, but its mechanistic basis, operating logic, and clinical relevance have remained elusive. What causes TGFβ signaling to be altered in cancer? What steps in tumor progression may benefit from a faulty TGFβ pathway? When does TGFβ act as a metastatic signal? And, most importantly, how can any of this knowledge be used to treat cancer? A combination of improved model systems, new tools for mechanistic dissection, and diligent mining of clinical data is providing fresh answers. Focusing on this progress, this review pays particular attention to new insights that are relevant to cancer in humans.