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


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Madelon Paauwe1,Mark Schoonderwoerd2,Roxan Helderman2,Tom Harryvan2,Arwin Groenewoud3,Gabi van Pelt2,Rosalie Bor2,Danielle Hemmer2,Henri Versteeg2,Ewa Snaar-Jagalska3,Charles Theuer4,James Hardwick2,Cornelis Sier2,Peter ten Dijke2,Lukas Hawinkels2
1Beatson Institute for Cancer Research,2Leiden University Medical Center,3Institute of Biology, Leiden University,4Tracon Pharmaceuticals

Abstract

Background

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment in colorectal cancer (CRC). 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.

Method

CAF-specific endoglin expression was studied in resection specimens from CRC patients using immunohistochemistry and related to metastases-free survival. Endoglin-mediated invasion was assessed in vitro by transwell invasion, using primary CRC-derived CAFs. The effect of CAF-specific endoglin expression on tumor cell invasion was investigated in a zebrafish model for CRC, while effects on liver metastasis were assessed in a mouse model.

Results

CAFs located 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 the 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. CAF invasion in vitro was inhibited by targeting endoglin using the neutralizing antibody TRC105. In zebrafish, endoglin-expressing fibroblasts enhanced colorectal tumor cell infiltration into the liver and decreased survival. Finally, endoglin targeting, specifically on CAFs, with TRC105 decreased metastatic spread of CRC cells to the mouse liver.

Conclusion

Endoglin-expressing CAFs contribute to CRC progression and metastasis. Treatment with TRC105 inhibits CAF invasion and tumor metastasis, indicating an additional target beyond the angiogenic endothelium, possibly contributing to beneficial effects reported during clinical evaluations.