Malignant cells can circumvent the suppressive effects of TGF-beta either through inactivation of core components of the pathway, such as TGF-beta receptors (Figure 1, Path 1), or by downstream alterations that disable just the tumor-suppressive arm of this pathway (Figure 1, Path 2). If the latter mode of circumvention is used, cancer cells can then freely usurp the remaining TGF-beta regulatory functions to their advantage, acquiring invasion capabilities, producing autocrine mitogens, or releasing prometastatic cytokines. TGF-beta induces tumor-suppressive effects that cancer cells must circumvent in order to develop into malignancies. Cancer cells can take two alternative paths to this end: (1) decapitate the pathway with receptor-inactivating mutations or (2) selectively amputate the tumor-suppressive arm of the pathway. The latter path allows cancer cells to extract additional benefits by co-opting the TGF-beta response for protumorigenic purposes. In both cases, cancer cells can use TGF-beta to modulate the microenvironment to avert immune surveillance or to induce the production of protumorigenic cytokines. (Fig. 1)
Figure 1. TGF-beta and tumor progression
Transforming growth factor-beta (TGF-beta) is a multifunctional regulatory polypeptide that is the prototypical member of a large family of cytokines that controls many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival.
Figure 2. The Role of TGF-beta in Cancer.
The actions of TGF-beta are dependent on several factors including cell type, growth conditions, and the presence of other polypeptide growth factors. One of the biological effects of TGF-beta is the inhibition of proliferation of most normal epithelial cells using an autocrine mechanism of action, and this suggests a tumor suppressor role for TGF-beta. Loss of autocrine TGF-beta activity and/or responsiveness to exogenous TGF-beta appears to provide some epithelial cells with a growth advantage leading to malignant progression. This suggests a pro-oncogenic role for TGF-beta in addition to its tumor suppressor role. (Fig.2) In normal and premalignant cells, TGF-beta enforces homeostasis and suppresses tumor progression directly through cell-autonomous tumor-suppressive effects (cytostasis, differentiation, apoptosis) or indirectly through effects on the stroma (suppression of inflammation and stroma-derived mitogens). However, when cancer cells lose TGF-beta tumor- suppressive responses, they can use TGF-beta to their advantage to initiate immune evasion, growth factor production, differentiation into an invasive phenotype, and metastatic dissemination or to establish and expand metastatic colonies.
With growing clinical evidence that TGF-beta acts as a tumor-derived immunosuppressor, an inducer of tumor mitogens, a promoter of carcinoma invasion, and a trigger of prometastat cytokine secretion, there is growing interest in TGF-beta as a therapeutic target.
Therapeutic targeting of the TGF-beta pathway in tumors such as glioma, melanoma, and renal cell carcinoma is based on the rationale that TGF-beta exerts strong immunosuppressive effects in these tumors. Thus, blocking TGF-beta function might empower the immune system against the tumor. Blocking TGF-beta action may also have additional tumor-specific benefits. For example, TGF-beta inhibition in gliomas may curtail the production of autocrine survival factors, such as PDGF. Blocking TGF-beta in ER − breast cancer, on the other hand, might prevent primary or metastatic tumors from seeding and reseeding metastasis. Finally, in osteolytic bone metastasis, blocking TGF-beta might interrupt the cycle of TGF-beta-induced osteoclastogenic factors and halt tumor growth. Although these examples show the great potential of the pathway as a therapeutic target, there are potential negative consequences, as well. Inhibition of TGF-beta might lead to chronic inflammatory and autoimmune reactions, although this problem has not yet materialized in the preclinical or clinical trials of systemic TGF-beta blockers. Inhibition of TGF-beta receptor function might also lead to runaway compensatory mechanisms by other activators of the Smad pathway, similar to what occurs in individuals with inactivating mutations in TGFBRI or TGFBRII (Loeys et al., 2006). Lastly, inhibition of TGF-beta signaling might enhance the progression of premalignant lesions. Of course, this would be a lesser concern in cancer patients whose malignancies are thriving on TGF-beta. Reassuringly however, systemic administration of TGF-beta blockers has not been reported to increase spontaneous tumor development in animal models.