Endoglin expression on cancer-associated fibroblasts regulates invasion and stimulates colorectal cancer metastasis

Purpose: Cancer-associated fibroblasts (CAFs) are a major component of the colorectal cancer (CRC) tumor microenvironment. CAFs play an important role in tumor progression and metastasis, partly through the transforming growth factor-β (TGF-β) signaling pathway. We investigated whether the TGF-β family co-receptor endoglin is involved in CAF-mediated invasion and metastasis. Experimental design: CAF-specific endoglin expression was studied in CRC resection specimens using immunohistochemistry and related to metastases-free survival. Endoglin-mediated invasion was assessed in vitro by transwell invasion, using primary CRC-derived CAFs. Effects of CAF-specific endoglin expression on tumor cell invasion were investigated in a CRC zebrafish model, while liver metastases were assessed in a mouse model. Results: CAFs specifically at invasive borders of CRC express endoglin and increased expression intensity correlated with increased disease stage. Endoglin-expressing CAFs were also detected in lymph node and liver metastases, suggesting a role in CRC metastasis formation. In stage-II CRC, CAF-specific endoglin expression at invasive borders correlated with poor metastasis-free survival. In vitro experiments revealed that endoglin is indispensable for bone morphogenetic protein (BMP)-9-induced signaling and CAF survival. Targeting endoglin using the neutralizing antibody TRC105 inhibited CAF invasion in vitro. In zebrafish, endoglin-expressing fibroblasts enhanced colorectal tumor cell infiltration into the liver and decreased survival. Finally, CAF-specific endoglin targeting with TRC105 decreased metastatic spread of CRC cells to the mouse liver. Conclusions: Endoglin-expressing CAFs contribute to CRC progression and metastasis. TRC105 Treatment inhibits CAF invasion and tumor metastasis, indicating an additional target beyond the angiogenic endothelium, possibly contributing to beneficial effects reported during clinical evaluations.

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