The Decrease of Mineralcorticoid Receptor Drives Angiogenic Pathways in Colorectal Cancer

Angiogenesis plays a crucial role in tumor growth and progression. Low expression of mineralocorticoid receptor (MR) in
several malignant tumors correlates with disease recurrence and overall survival. Previous studies have shown that MR
expression is decreased in colorectal cancer (CRC). Here we hypothesize that decreased MR expression can contribute to
angiogenesis and poor patient survival in colorectal malignancies. In a cohort of CRC patients, we analyzed tumor MR
expression, its correlation with tumor microvascular density and its impact on survival. Subsequently, we interrogated the
role of MR in angiogenesis in an in vitro model, based on the colon cancer cell line HCT116, ingenierized to re-express a
physiologically controlled MR. In CRC, decreased MR expression was associated with increased microvascular density and
poor patient survival. In pchMR transfected HCT116, aldosterone or natural serum steroids largely inhibited mRNA
expression levels of both VEGFA and its receptor 2/KDR. In CRC, MR activation may significantly decrease angiogenesis by
directly inhibiting dysregulated VEGFA and hypoxia-induced VEGFA mRNA expression. In addition, MR activation attenuates
the expression of the VEGF receptor 2/KDR, possibly dampening the activation of a VEGFA/KDR dependent signaling
pathway important for the survival of tumor cells under hypoxic conditions.