TGF-beta signaling alterations and susceptibility to colorectal cancer

Abstract

In 2006, more than 55,000 patients died of colorectal cancer in the US, accounting for approximately 10% of all cancer deaths. Despite significant progress in screening combined with the development of novel effective therapies, colorectal cancer ranks second to lung cancer as a cause of cancer death. Twin studies indicate that 35% of all colorectal cancers are inherited, but high-penetrance tumor susceptibility genes only account for approximately 3-6% of all cases. The remainder of the unexplained familial risk is presumably due to other high-penetrance genes, but polygenic mechanisms and low-penetrance tumor susceptibility genes are likely to account for a greater proportion of familial colorectal cancers. In this regard, there is growing evidence that a common hypomorphic variant of the type I TGF-beta receptor, TGFBR1*6A, may account for approximately 3% of all colorectal cancer cases, a fraction higher than that attributable to mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Furthermore, TGFBR1*6A is emerging as a potent modifier of colorectal cancer risk among individuals with a strong family of colorectal cancer. The TGF-beta signaling pathway plays a central but paradoxical role in the predisposition and progression of colorectal cancer. TGF-beta is a potent inhibitor of normal colonic epithelial cells acting as a tumor suppressor. However, TGF-beta promotes the survival, invasion and metastasis of colorectal cancer cells, thereby acting as an oncogene. Understanding how selective alterations of the TGF-beta signaling pathway contribute to colorectal cancer development and progression will likely permit the identification of an additional fraction of inherited colorectal cancer cases and provide novel opportunities for therapeutic intervention.

Figure 1

TGF-β/SMAD signaling pathway. TGF-β (TGFB1, TGFB2 or TGFB3) binds to the type II TGF-β receptor (TGFBR2: R2), which then binds to the type I TGF-β receptor (TGFBR1: R1) and forms a heterodimeric complex in which TGFBR1 kinase becomes activated. SMAD2 and SMAD3 are phosphorylated by activated TGFBR1. Once phosphorylated, they associate with SMAD4 and move to the nucleus where they act as transcription factors.

Fig. 2

Secondary signaling effects of TGFBR1*6A. Amino terminus sequencing has shown that the polyalanine tract that contains the 3-Ala deletion, which differentiates TGFBR1*6A from TGFBR1, is part of the signal sequence. Given the fact that TGFBR1*6A and TGFBR1 mature receptors are identical, the biological actions of TGFBR1*6A are likely due to its signal sequence secondary signaling effects.