Anti-tumor and anti-metastatic effects of intralesional recombinant interferon-alpha and beta on human malignant melanoma xenografts in nude mice

Abstract

Interferon (IFN)-alpha (α) is the most commonly used biologically active cytokine in the treatment for high risk patients with melanoma. Although IFN-α has shown to be clinically effective in the adjuvant setting of high risk for melanoma relapse, the reasons are unknown yet. Malignant melanomas of the skin primarily metastasize to lymph nodes, and the detection of sentinel lymph node metastases serves as an important prognostic marker. Recent evidences strongly revealed that tumor-induced lymphangiogenesis plays an important and active role in the promotion of cancer metastasis to lymph nodes. The purpose of this study was to evaluate and compare the efficacy of IFN-α2b and IFN-β1a on primary tumor growth and lymph node metastasis and investigate the mechanisms regarding lymph node metastasis by using human melanoma xenograft model. Both IFN-α2b and IFN-β1a showed inhibitory effect on tumor cell proliferation and induced apoptosis. IFN-β1a showed significantly potent anti-proliferative and apoptotic effect compared to IFN-α2b in xenograft tumors (p<0.05). Both IFN-α2b and IFN-β1a were effective in inhibiting lymph node metastasis compared to the control. Control group showed lymph node metastasis in 5 out of 6 mice compared to 3 out of 6 in IFN-β1a group and 1 out of 6 in IFN-α2b group. Microvessel density decreased in tumors treated with IFN-α2b and IFN-β1a compared to the control, but it was not statistically significant. As for lymphatic vessel density, it significantly decreased only in tumors treated with IFN-α2b (p<0.05). Both IFN-α2b and IFN-β1a decreased in vitro and in vivo VEGF-C and VEGFR-3 protein expression and secretory VEGF-C level in vitro. IFN-α2b showed earlier and sustained effect in decreasing VEGF-C and VEGFR-3 protein expression and superior effect in decreasing secretory VEGF-C level compared to IFN-β1a. In conclusion, IFN-α2b and IFN-β1a both showed anti-tumor and anti-metastatic effect in human melanoma xenograft through different action mechanisms. IFN-β1a showed stronger anti-proliferative and pro-apoptotic effect while IFN-α2b showed stronger anti-metastatic effect through inhibition of lymphangiogenesis.