Fig. 7

Parallel activin and TGFβ signaling in advanced colon cancer. TGFβ and activin both share SMAD4 signaling to upregulate p21. However, in colon cancer, there is ligand-specific SMAD4-independent signaling utilizing distinct mitogenic signaling. Moreover, activin dominantly induces downregulation of p21 via PI3K/Akt signaling over early SMAD4-dependent p21 upregulation in colon cancer (non-dominant pathway indicated in grey). Net nuclear p21 expression in colon cancer may be a functional surrogate of intact TGFβ/SMAD growth suppression and a negative possible predictor of growth enhancing response to TGFβ pathway inhibition. In contrast, colon cancers with loss of nuclear p21 may benefit from activin, TGFβ or combination inhibitory therapy. In summary, there is complex parallel signaling with feedback loops operative in colon cancer downstream of activin and TGFβ. In order to predict net functional effects of targeted pathway disruption on tumor behavior, it is crucial that the interplay of pathways is fully appreciated to minimize unwanted side effects