TGF-β 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.

Ellagic Acid Exerts Anti-proliferation Effects via Modulation of Tgf-Β/Smad3 Signaling in MCF-7 Breast Cancer Cells

“…Moreover, MCF-7 cells overexpressing Smad3 were more sensitive to ellagic acid. Previous studies have suggested that SMAD mutation and dysfunction plays an important role in the development of tumors (Tian et al, 2003;Leaslc and Abraham, 2004;Xu and Pasche, 2007;Su et al, 2010). Some downstream targets of the TGF-β signaling pathway are key regulators of cell cycle progression, including p21, p27 and p15.…”

“…Some downstream targets of the TGF-β signaling pathway are key regulators of cell cycle progression, including p21, p27 and p15. The activation of these genes will suppress tumor cell growth (Xu and Pasche, 2007). SIS3 is a specific inhibitor of Smad3 phosphorylation without affecting Smad2 and Smad4 (Jinnin et al, 2006).…”

The expression of RUNX3 in colorectal cancer is associated with disease stage and patient outcome

“…Overexpression of the enhancer of zeste homologue 2 (EZH2) protein was recently shown to downregulate RUNX3 expression by increasing histone H3 methylation, thus providing yet another mechanism for inactivation of RUNX3 (Fujii et al, 2008). As might be expected, if RUNX3 were behaving as a tumour suppressor, the decreased expression of this protein in gastric (Wei et al, 2005), lung (Araki et al, 2005) and oesophageal (Sakakura et al, 2007) cancers has been associated with worse patient outcome.As the TGF-b signalling pathway plays an important role in the growth control of human colonic epithelial cells (Xu and Pasche, 2007), RUNX3 may also act as a tumour suppressor gene in this tissue. Approximately 20% of primary CRCs show hypermethylation of RUNX3 (Goel et al, 2004;Ogino et al, 2007), and this has been linked to transcriptional silencing in two studies (Goel et al, 2004;Ku et al, 2004).…”

“…As the TGF-b signalling pathway plays an important role in the growth control of human colonic epithelial cells (Xu and Pasche, 2007), RUNX3 may also act as a tumour suppressor gene in this tissue. Approximately 20% of primary CRCs show hypermethylation of RUNX3 (Goel et al, 2004;Ogino et al, 2007), and this has been linked to transcriptional silencing in two studies (Goel et al, 2004;Ku et al, 2004).…”

Signalisation et prédispositions métaboliques liées au cancer colorectal

“…Une fois activée, cette dernière phosphoryle les facteurs de transcription Smad2 et Smad3, leur permettant de se complexer à Smad4, qui est nécessaire à la translocation nucléaire du complexe. Le complexe Smad2/3/4 s'associe avec d'autres protéines telles que p21 ou la survivine pour les réguler [11]. Cette voie de signalisation doit être désactivée pour la progression tumorale des cellules coliques.…”