Combinational Therapy of Interferon-α and Chemotherapy Normalizes Tumor Vasculature by Regulating Pericytes Including the Novel Marker RGS5 in Melanoma

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Several large randomized clinical trials show that chemotherapy in combination with interferon-α (IFN-α) seems superior to single-agent chemotherapy, such as dacarbazine (DTIC) in melanoma, but the molecular mechanism of this better efficacy is unclear. IFN-α has antiangiogenic activity and could downregulate expression of regulator of G-protein signalling-5 (RGS5) recognized as a novel pericyte marker and a master gene loss of which results in pericyte maturation, vascular normalization, and consequent marked reductions in tumor hypoxia and vessel leakiness in pancreatic carcinoma. Here, we investigated the molecular mechanism of the effects of this combination therapy on melanoma tumor growth. In B16 tumor-bearing mice, the addition of IFN-α to DTIC treatment significantly reduced tumor volume, compared with control or DTIC alone. Consistently, Digital Radiography data showed less chaotic vessel morphology and a decrease in microvessel density and mean vessel diameter in the combinational treatment. Furthermore, the combination therapy showed a remarkable reduction in tumor hypoxia, downregulated RGS5 expression, and increased mature pericyte coverage. Our data suggest that the combination of IFN-α and DTIC therapy more efficiently inhibits tumor growth by normalizing tumor vasculature. This study shows a previously unrecognized role of IFN-α in melanoma vascular normalization and suggests that pericyte including its novel marker RGS5 is an important target of IFN-α.