PUBLICATION
Endoglin expression on cancer-associated fibroblasts regulates invasion and stimulates colorectal cancer metastasis
- Authors
- Paauwe, M., Schoonderwoerd, M.J., Helderman, R.F.C.P.A., Harryvan, T.J., Groenewoud, A., van Pelt, G.W., Bor, R., Hemmer, D.M., Versteeg, H.H., Snaar-Jagalska, E., Theuer, C.P., Hardwick, J.C., Sier, C.F., Ten Dijke, P., Hawinkels, L.J.
- ID
- ZDB-PUB-180628-6
- Date
- 2018
- Source
- Clinical cancer research : an official journal of the American Association for Cancer Research 24(24): 6331-6344 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Immunohistochemistry
- Cell Movement
- Neoplasm Metastasis
- Animals
- Colorectal Neoplasms/genetics*
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/mortality
- Colorectal Neoplasms/pathology*
- Humans
- Signal Transduction
- Neoplasm Staging
- Fluorescent Antibody Technique
- Prognosis
- Gene Expression Regulation, Neoplastic*
- Endoglin/genetics*
- Endoglin/metabolism
- Biomarkers
- Cancer-Associated Fibroblasts/metabolism*
- Cancer-Associated Fibroblasts/pathology
- Fibroblasts/metabolism
- Cell Line, Tumor
- Transforming Growth Factor beta/metabolism
- Mice
- Cell Survival/genetics
- Disease Models, Animal
- Male
- Zebrafish
- Tumor Microenvironment/genetics
- Ligands
- PubMed
- 29945992 Full text @ Clin. Cancer Res.
Citation
Paauwe, M., Schoonderwoerd, M.J., Helderman, R.F.C.P.A., Harryvan, T.J., Groenewoud, A., van Pelt, G.W., Bor, R., Hemmer, D.M., Versteeg, H.H., Snaar-Jagalska, E., Theuer, C.P., Hardwick, J.C., Sier, C.F., Ten Dijke, P., Hawinkels, L.J. (2018) Endoglin expression on cancer-associated fibroblasts regulates invasion and stimulates colorectal cancer metastasis. Clinical cancer research : an official journal of the American Association for Cancer Research. 24(24):6331-6344.
Abstract
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-? (TGF-?) signaling pathway. We investigated whether the TGF-? 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping