Endoglin Expression on Cancer-Associated Fibroblasts Regulates Invasion and Stimulates Colorectal Cancer Metastasis

Abstract

Cancer-associated fibroblasts (CAF) are a major component of the colorectal cancer tumor microenvironment. CAFs play an important role in tumor progression and metastasis, partly through TGF-β signaling pathway. We investigated whether the TGF-β family coreceptor endoglin is involved in CAF-mediated invasion and metastasis. CAF-specific endoglin expression was studied in colorectal cancer resection specimens using IHC and related to metastases-free survival. Endoglin-mediated invasion was assessed by transwell invasion, using primary colorectal cancer-derived CAFs. Effects of CAF-specific endoglin expression on tumor cell invasion were investigated in a colorectal cancer zebrafish model, whereas liver metastases were assessed in a mouse model. CAFs specifically at invasive borders of colorectal cancer 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 colorectal cancer metastasis formation. In stage II colorectal cancer, CAF-specific endoglin expression at invasive borders correlated with poor metastasis-free survival. 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 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 colorectal cancer cells to the mouse liver. Endoglin-expressing CAFs contribute to colorectal cancer 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.

CD26 expression is attenuated by TGF‐β and SDF‐1 autocrine signaling on stromal myofibroblasts in human breast cancers

“…CD26 expression has been demonstrated to serve as a marker for stratification of the stromal cell type in human breast and skin tissues . CD105/endoglin, a coreceptor for TGF‐β family members, is also expressed on a subset of stromal myofibroblasts at the invasive borders of human colon carcinomas . Moreover, CD26 low CD105 high fibroblasts with myofibroblast‐related characteristics are abundant in the terminal duct lobular unit of the human breast, while interlobular ducts are rich in CD26 high CD105 low fibroblasts .…”

“…38,39,44 CD105/endoglin, a coreceptor for TGF-β family members, is also expressed on a subset of stromal myofibroblasts at the invasive borders of human colon carcinomas. 45 Moreover, CD26 low CD105 high fibroblasts with myofibroblast-related characteristics are abundant in the terminal duct lobular unit of the human breast, while interlobular ducts are rich in CD26 high CD105 low fibroblasts. 38 Collectively, these observations indicate the importance of CD26 and CD105 expressions for identifying the particular fibroblast lineages in human mammary tissues including those of breast cancer.…”

Continuous Endoglin (CD105) Overexpression Disrupts Angiogenesis and Facilitates Tumor Cell Metastasis

“…One limitation of our study is that endoglin overexpression is ubiquitous, which means that endoglin levels are above the physiological level in all cell types other than ECs, including those in the tumor microenvironment, which may also play an important role in the malignancy of tumors. For example, beyond its antiangiogenic effect on the endothelium, antiendoglin treatment inhibits cancer-associated fibroblast (CAF) invasion and metastasis (51). However, our in vitro results show that endoglin overexpression results in a permanent activation of the endothelium that prevents the maturation of the vessels.…”

Genome‐wide expression profiling‐based copy number variations and colorectal cancer risk in Chinese

“…During the past decades, most studies on the susceptibility of colorectal cancer have been based on detecting candidate genes, which helps decipher the underlying biological mechanisms of colorectal cancer. These studies mainly focused on genes involved in oncogenic pathways, such as TGF‐β and Wnt . Recent whole‐genome sequencing provides us a perfect method to detect all kinds of genetic alterations potentially associated with various cancers.…”

“…These studies mainly focused on genes involved in oncogenic pathways, such as TGF-β and Wnt. 14,15 Recent wholegenome sequencing provides us a perfect method to detect all kinds of genetic alterations potentially associated with various cancers.…”