Hyperactivation of the endoglin/TGF-β pathway plays a role in CRC invasion and metastasis.
Madelon Paauwe1, Amaya Garcia de Vinuesa1, Hein Verspaget2, Gabi van Pelt3, Wilma Mesker3, Cornelis
Sier3, Peter ten Dijke1, Lukas Hawinkels1
LUMC, Dept. of Molecular Cell Biology1, Dept. of Gasteroenterology-Heptology2, Dept. of Surgery3
The involvement of the tumor microenvironment in colorectal cancer (CRC) progression is becoming
more and more clear. Especially the interaction between epithelial tumor cells and cancer-associated
fibroblasts (CAFs) seems to be important. In this study we evaluated how epithelial cancer cells
functionally interact with CAFs, focusing on the cancer progression-associated transforming growth
factor-β (TGF-β) pathway. Our results show strong activation of the TGF-β pathway in the CAFs of 100
CRC patients. Activation of this pathway in epithelial cancer cells was associated with decreased patient
survival. Next, we evaluated the interaction between epithelial tumor cells and CAFs in vitro. Our data
show that primary CAFs are responsive to TGF-β by enhanced secretion of invasion-related proteases,
like matrix metalloproteases (MMPs). The interaction with epithelial cancer cells hyperactivated the
TGF-β pathway in these CAFs. Co-culture with epithelial tumor cell derived medium increased and
prolonged Smad phosphorylation (downstream in signaling cascade), MMP expression and TGF-β
secretion. To further evaluate this pathway we analyzed the expression of the TGF-β co-receptor
endoglin. In addition to being present on endothelial cells, endoglin was also highly expressed by CAFs,
specifically at invasive areas in human CRC tissue samples. CAFs from CRC expressed high levels of
endoglin in vitro. Additional experiments showed that endoglin plays an important role in determining
the migratory capacity of CAFs in vitro. This observation is further strengthened by the use of a
neutralizing antibody against endoglin, which inhibits migration of CAFs in 3-dimensional invasion
models. Moreover, preliminary data from an in vivo experiment in a breast cancer model suggest an
important role for endoglin during cancer progression.
These data underline the importance of the endoglin/TGF-β pathway in the interaction between
epithelial cancer cells and CAFS, and its role in CRC progression and metastasis.