Abstract 4904
Background
Metastasis is the main cause of death for most solid tumors. The liver is a metastasis-susceptible organ and represents the first most common site for colorectal cancer (CRC). During tumor progression, the unique hepatic microenvironment suffers a reorganization involving the interaction between the tumor, the different hepatic stromal cells and the extracellular matrix (ECM), which is under an extreme remodeling. Among the receptors involved, discoidin domain receptors (DDR-1 and -2), a class of tyrosine kinase receptors for fibrillar collagen, are emerging as new therapeutic targets in cancer treatment, including colorectal. Aim: We aim to elucidate the implication of DDRs in the prometastatic properties of the CRC cells and stromal cells in the liver.
Methods
First, the expression of DDRs on the stromal cells under tumor activated conditions and on tumor cells in the presence of tumor-activated stromal factors was assessed at protein levels. Second, this was related to the migratory potential under the same conditions. Finally, metalloproteinases expression, known to be induced by DDRs activation and involved in cell migration and ECM remodeling, was determined by western blot and zymography.
Results
DDRs expression was inversely altered in macrophages and fibroblasts after their activation by tumor derived factors. The expression of DDRs on CRC cells was decreased by factors derived from stromal cells. These DDRs deregulated expression was related to changes in the migratory capacity of tumor and stromal cells. Moreover, MMP-9 and MMP-14 expression increased in the stromal cells activated by tumor factors, while TIMP-2 expression was higher in fibroblasts but lower in macrophages. Also, the activation of CRC cells by either fibroblasts or macrophages derived factors induced a differential expression of MMP-2, MMP-9 and MMP-14.
Conclusions
The differential expression of DDRs by cells in the tumor microenvironment could redirect the expression of MMPs inducing the migratory capacity of CRC cells. In conclusion, tumor and stromal cells crosstalk may dysregulate the ECM deposition related to DDRs expression contributing to the extensive stroma remodeling in CRC metastatic diseases.
Clinical trial identification
Legal entity responsible for the study
University of the Basque Country (UPV/EHU)
Funding
University of the Basque Country (UPV/EHU)
Disclosure
All authors have declared no conflicts of interest.