Transforming growth factor (TGF)-β cytokines signal via a complex network of pathways to regulate proliferation, differentiation, adhesion, migration, and other functions in many cell types. A high percentage of colorectal tumors contain mutations that disrupt TGF-β family member signaling. We review how TGF-β family member signaling is altered during development of colorectal cancer, models of study, interaction of pathways, and potential therapeutic strategies.

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BackgroundUnderstanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGFβ or activin-induced metastatic phenotype of colon cancer.MethodMitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) −/− or wild type mice. Colon cancer cell lines (+/− SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays.ResultsIn primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFβ/MEK/ERK pathway activation. Activin, but not TGFβ, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFβ increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFβ induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling.ConclusionAlthough activin and TGFβ share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGFβ ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFβ family receptors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0456-4) contains supplementary material, which is available to authorized users.

Colorectal cancer (CRC) is the second deadliest cancer in the US due to its propensity to metastasize. Stromal cells and especially cancer-associated fibroblasts (CAF) play a critical biophysical role in cancer progression, but the precise pro-metastatic mechanisms are not clear. Activin A, a TGF-β family member, is a strong pro-metastatic cytokine in the context of CRC. Here, we assessed the link between biophysical forces and pro-metastatic signaling by testing the hypothesis that CAF-generated mechanical forces lead to activin A release and associated downstream effects. Consistent with our hypothesis, we first determined that stromal activin A secretion increased with increasing substrate stiffness. Then we found that stromally-secreted activin A induced ligand-dependent CRC epithelial cell migration and epithelial to mesenchymal transition (EMT). In addition, serum activin A levels are significantly increased in metastatic (stage IV) CRC patients (1.558 ng/ml versus 0.4179 ng/ml, p < 0.05). We propose that increased tumor microenvironment stiffness leads to stromal cell-mediated TGF-β family signaling relying on the induction and utilization of activin A signaling. Colorectal cancer (CRC) remains a significant challenge from both public health and clinical perspectives. With approximately 50,000 deaths per year in the US, CRC is the second leading cause of cancer-related mortality in the US 1. Despite the decreased incidence of CRC over the previous decades, largely due to early detection through enhanced screening, there is now an alarming increase in late-stage CRC in younger patients 2,3. Five-year mortality of patients with stage IV disease remains as high as 90% 1,4 , and novel approaches are needed for effective risk stratification and treatment. CRC metastatic potential is strongly influenced by the stroma. Fibroblasts within the stroma, the major cell type composing the stromal cell population 5 , are critical determinants of stromal cross-talk and cancer progression. A subpopulation of these fibroblasts is activated into cancer-associated fibroblasts (CAFs) (also known as myofibroblasts) expressing alpha-smooth muscle actin (α-SMA) 5-9. Fibroblast can be activated to CAFs by Transforming growth factor β (TGF-β) 7,10. These CAFs contribute to a dense myofibroblastic component and deposition of extra-cellular matrix (ECM) proteins associate with tumor fibrosis 11. CAFs generate increasing force leading to increased stiffness on 2D soft substrates in vitro 12,13. In vivo, they produce growth factors promoting metastatic progression of cancer cells 14 and produce collagen and the collagen crosslinker Lysyl oxidase (LOX), which stiffen the extra-cellular matrix (ECM) and remodel its composition and architecture 15. CAF contractile force can further contribute to changes in tumor biomechanical properties by mechanical non-linear stress-strain deformation leading to compressive stress in the tumor and pressure gradients on the proliferating