Cancer-Associated Fibroblasts Exert Proangiogenic Activity in Merkel Cell Carcinoma

The tumor microenvironment is a complex niche enveloping a tumor formed by extracellular matrix, blood vessels, immune cells, and fibroblasts constantly interacting with cancer cells. Although tumor microenvi-ronment is increasingly recognized as a major player in cancer initiation and progression in many tumor types, its involvement in Merkel cell carcinoma (MCC) pathogenesis is currently unknown. In this study, we provide a molecular and functional characterization of cancer-associated fibroblasts (CAFs), the major tumor microen-vironment component, in patient-derived xenografts of patients with MCC. We show that subcutaneous coinjection of patient-derived CAFs and human MCC MKL-1 cells into severe combined immunodeficient mice significantly promotes tumor growth and metastasis. These fast-growing xenografts are characterized by areas densely populated with human CAFs, mainly localized around blood vessels. We provide evidence that the growth-promoting activity of MCC-derived CAFs is mediated by the aminopeptidase A/angiotensin II and III/ angiotensin II type 1 receptor axis, with the expression of aminopeptidase A in CAFs being a triggering event. Together, our findings point to aminopeptidase A as a potential marker for MCC prognostic stratification and as a candidate for therapeutic intervention.

Automated summary

The tumor microenvironment, consisting of extracellular matrix, blood vessels, immune cells, and fibroblasts, plays a crucial role in cancer development. However, its involvement in Merkel cell carcinoma (MCC) is unknown. In this study, we characterized cancer-associated fibroblasts (CAFs) in patient-derived xenografts of MCC. We found that injection of patient-derived CAFs with MCC cells promoted tumor growth and metastasis, mainly localized around blood vessels. We identified aminopeptidase A as a potential marker for MCC prognosis and therapeutic target.