In many forms of cancer, the growth-inhibiting effects of the TGF-β pathways are impaired by mutations affecting TGF-β signaling. These mutations may alter the type II TGF-β receptor or SMAD molecules that serve to transduce anti-proliferative signals from the receptor to the nucleus. Mutations affecting the type II receptor are seen in cancers of the colon, stomach, and endometrium. Mutational inactivation of SMAD4, 1 of the 10 proteins known to be involved in TGF-β signaling, is common in pancreatic cancers. In other cancers, by contrast, loss of TGF-β–mediated growth control occurs at a level downstream of the core TGF-β signaling pathway; for example, there may be loss of p21 expression and/or overexpression of MYC. These tumor cells can then use other elements of the TGF-β–induced program, including immune system suppression or promotion of angiogenesis, to facilitate tumor progression. Thus, TGF-β can function to prevent or promote tumor growth, depending on the state of other genes in the cell. Indeed, in many late-stage tumors, TGF-β signaling activates epithelial-to-mesenchymal transition (EMT), a process that promotes migration, invasion, and metastasis, as discussed later.
Contact Inhibition, NF2, and APC
When cancer cells are grown in the laboratory, their proliferation fails to be inhibited when they come in contact with each other. This is in sharp contrast to nontransformed cells, which stop proliferating once they form confluent monolayers. The mechanisms that govern contact inhibition are only now being discovered.
Cell–cell contacts in many tissues are mediated by homodimeric interactions between transmembrane proteins called cadherins. E-cadherin (E for epithelial) mediates cell–cell contact in epithelial layers. Two mechanisms have been proposed to explain how E-cadherin maintains contact inhibition: • One mechanism is mediated by the tumor suppressor gene NF2. Its product, neurofibromin-2, more commonly called merlin, acts downstream of E-cadherin in a signling pathway that helps fo maintain contact inhibition. Homozygous loss of NF2 is known to cause certain neural tumors, and germ line mutations in NF2 are associated with a tumor-prone hereditary condition called neurofibromatosis type 2.
• A second mechanism by which E-cadherin may regulate contact inhibition involves its ability to bind β-catenin, another signaling protein. β-catenin is a key component of the WNT signaling pathway (described below), which has broad but as of yet incompletely understood roles in regulating the morphology and organization of epithelial cells lining structures such as the gut.
A further clue to the important of E-cadherin and β-catenin in epithelial cancers is illustrated by the rare hereditary disease adenomatous polyposis coli (APC). This disorder is characterized by the development of numerous adenomatous polyps in the colon that have a very high incidence of transformation into colonic cancers. The polyps consistently show loss of a tumor suppressor gene called APC (named for the disease), which exerts anti-proliferative effects in an unusual manner. APC encodes a cytoplasmic protein whose dominant function is to promote the degradation of β-catenin, which has several functions. In addition to binding E-cadherin, β-catenin also is a key component of the WNT signaling pathway (illustrated in
Fig. 6.22).