Abundance of Microvascular Endothelial Cells Is Associated with Response to Chemotherapy and Prognosis in Colorectal Cancer

SIMPLE SUMMARY: The generation of pathologic, immature, and dysfunctional vessels by angiogenesis is a well-known mechanism of metastasis and has been a therapeutic target for colorectal cancer (CRC). In this study, we investigated the clinical relevance of microvascular endothelial (mvE) cells in CRC by analyzing tumor gene expression profiles of large patient cohorts. We found that the abundance of mvE cells does not mirror angiogenesis, but rather is associated with the number of mature blood vessels in the tumor microenvironment and predicts the response to chemotherapy as well as patient survival in CRC. This is the first study suggesting the clinical relevance of mvE cells in CRC. ABSTRACT: The generation of pathologic, immature, and dysfunctional vessels by angiogenesis is a mechanism of metastasis that has been a therapeutic target for colorectal cancer (CRC). In this study, we investigated the clinical relevance of intra-tumoral microvascular endothelial (mvE) cells in CRC using the xCell algorithm on transcriptome. A total of 1244 CRC patients in discovery and validation cohorts were analyzed. We found that an abundance of mvE cells did not mirror angiogenesis but reflected mature blood vessels because it was significantly associated with a high expression of vascular stability-related genes, including sphingosine-1-phosphate receptor genes and pericytes. Epithelial–mesenchymal transition and myogenesis gene sets were enriched in mvE cell abundant CRC, while mvE cell-less CRC enriched cell proliferation, oxidative phosphorylation, and protein secretion gene sets. mvE cell abundant CRC was associated with infiltration of M2 macrophages, dendritic cells, and less gamma-delta T cells (all p < 0.001), but not with the interferon-γ response. mvE cell abundant CRC was significantly associated with worse patient survival in CRC. Interestingly, mvE cell abundant CRC was significantly associated with a high response rate to chemotherapy (p = 0.012) and worse patient survival for those that did not receive chemotherapy. However, there was no survival difference in patients who underwent chemotherapy. In conclusion, we estimated the abundance of mvE cells using the xCell algorithm on tumor transcriptome finding its association with the number of mature blood vessels in a tumor microenvironment and its ability to predict response to chemotherapy, thereby patient survival in CRC.