Systemic Pro-opiomelanocortin Expression Induces Melanogenic Differentiation and Inhibits Tumor Angiogenesis in Established Mouse Melanoma

Abstract

Malignant melanoma is one of the leading causes of cancer mortality worldwide, underlining the need for effective novel therapies. In this study, the therapeutic efficacy and mechanism of systemic pro-opiomelanocortin (POMC) therapy were evaluated in mice bearing established melanoma. Injection of adenovirus encoding POMC (Ad-POMC) led to hepatic POMC overexpression and elevated adrenocorticotropin (ACTH) levels in the circulation. Systemic POMC therapy significantly attenuated the growth of established melanoma and prolonged the survival of tumor-bearing mice. Histological analysis revealed that systemic POMC therapy induced melanogenic differentiation while reducing melanoma growth. In addition, POMC therapy also elicited a significant reduction in the neovascular network of melanoma. Last, we demonstrated that POMC-derived peptides, including ACTH, α-melanocyte-stimulating hormone (α-MSH), and β-MSH, are involved in POMC-mediated melanogenic differentiation and angiogenesis inhibition. In summary, systemic POMC therapy suppresses melanoma growth via induction of melanogenic differentiation and angiogenesis blockade, thereby demonstrating its potential as a novel treatment modality for melanoma.

Downregulation of Hepatoma-Derived Growth Factor Contributes to Retarded Lung Metastasis via Inhibition of Epithelial–Mesenchymal Transition by Systemic POMC Gene Delivery in Melanoma

“…Our previous studies showed that POMC gene transfer disrupted the angiogenic processes of cultured endothelial cells (31,37) and primary tumor neovascularization through a-MSH signaling pathway (21). In the present study, we further showed that systemic POMC therapy elicited the neovascularization blockade in metastatic melanoma by using fluorescent dye tracking and CD31 immunostaining.…”

“…Moreover, exogenously supplied HDGF studies confirm that HDGF expression directly regulates the invasion and EMT of melanoma cells. Together with our early studies showing that POMC therapy suppresses melanoma through MC1R/NFkB signaling and angiogenesis inhibition (20,21), we herewith provide a hypothetical model for POMC-induced metastasis suppression through HDGF depletion, which leads to EMT perturbation, and angiogenesis inhibition (Fig. 5D).…”

“…Current study, POMC therapy was initiated 24 hours after melanoma cells entered the circulation. On the basis of our previous studies (21), an additional 12 to 24 hours was required for the production of anti-inflammatory peptides in circulation after POMC transgene expression and processing in the liver. Despite the delayed therapy, a significant reduction in lung by bioluminescence image was observed in Ad-POMC-treated mice at as early as day 7 after implantation.…”

“…Recent studies indicate that the anti-inflammatory POMC therapy effectively suppresses the growth of murine primary tumors, including B16-F10 (20,21) and Lewis lung carcinoma (22). Furthermore, POMC-derived peptide, a-MSH, has been reported to trigger melanoma/melanocyte differentiation (23,24) and potently inhibits both the in vitro and in vivo invasion of highly invasive B16-BL6 melanoma cells (25,26).…”

Immunoregulatory Effects of Neuropeptides on Endothelial Cells: Relevance to Dermatological Disorders

“…Murine models of inflammatory bowel disease showed that disease activity and tissue injury were suppressed by antiangiogenic agents or genetic overexpression of soluble VEGFR-1 (which is inhibitory in nature) and exacerbated by administration or genetic overexpression of VEGF-A [20]. In vivo studies have also demonstrated that pro­opiomelanocortin gene delivery reduced tumor angiogenesis in melanoma models [21]. …”