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

Background Patients with serrated polyps are at increased risk for post-colonoscopy colorectal cancer (PCCRC); however, evidence for a dedicated serrated polyp detection rate is lacking. The aim of this study was to investigate the association of the proximal serrated polyp detection rate (PSDR) and adenoma detection rate (ADR) with PCCRC death. Methods This was a retrospective analysis within the Austrian quality assurance program for screening colonoscopy. Spearman’s rank coefficient was calculated for the assessment of association between ADR and PSDR. Whether ADR or PSDR were associated with colorectal cancer mortality was assessed by Cox proportional hazards model. Results: 229 /729 screening colonoscopies performed by 308 endoscopists were analyzed. The ADR (hazard ratio [HR] per 1 percentage point increase 0.98, 95 %CI 0.96–0.99) as well as the PSDR (HR per 1 percentage point increase 0.97, 95 %CI 0.94–0.99) were significantly associated with PCCRC death. The correlation coefficient of the ADR and PSDR calculated at every colonoscopy was 0.70 (95 %CI 0.70–0.71), and the corresponding PSDR value for an ADR performance standard of 25 % was 11.1 %. At the end of the study period, 86 endoscopists (27.9 %) reached an ADR of > 25 % and a PSDR of > 11.1 %. Conclusions: The ADR as well as the PSDR were associated with PCCRC death. Striving for a high PSDR in addition to a high ADR might reduce the risk for PCCRC mortality in patients undergoing screening colonoscopy.

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