Abstract
Endoglin overexpression is associated with highly proliferative tumor endothelium and also with some tumors, including melanoma. Its targeting has anti-tumor effectiveness, which can also be obtained by RNA interference. The aim of our study was to explore the anti-tumor effectiveness of endoglin silencing by electrotransfer of plasmid DNA encoding short hairpin RNA against endoglin in two murine B16 melanoma variants with different metastatic potential on cells, spheroids and subcutaneous tumors in mice. The results demonstrate that endoglin silencing with gene electrotransfer reduces the proliferation, survival and migration of melanoma cells and also has anti-tumor effectiveness, as the therapy resulted in a high percentage of tumor cures (23% and 58% on B16F1 and B16F10 tumors, respectively). The effectiveness of the therapy correlated with endoglin expression in melanoma cells; in vitro the effects were more pronounced in B16F1 cells, which express more endoglin than B16F10. However, the opposite was observed in vivo in tumors, where there was a higher expression of endoglin and better anti-tumor effectiveness in the B16F10 tumor. In conclusion, targeting endoglin for the treatment of melanoma seems to be a concept worthy of further exploration due to the increased therapeutic effect of the therapy based on simultaneous vascular targeting and its direct effect on tumor cells.
Highlights
We firstly examined the expression of endoglin in melanoma cells in vitro and subcutaneously induced melanoma tumors in C57Bl/6 mice in vivo
The results demonstrated that both melanoma cell lines and tumor models express high levels of endoglin (Table 1)
In this study we demonstrate that the targeting of endoglin with Gene Electrotransfer (GET) of plasmid DNA encoding shRNA against endoglin represents a new option for targeted therapy of melanoma
Summary
Patients with early stages of melanoma have a good long-term prognosis compared to patients with advanced stages of melanoma. Later metastatic melanoma poses a persistent therapeutic challenge due to its aggressiveness and poor responsiveness to conventional therapies [1]. A lot of new therapies are being developed and the introduction of immune therapy with monoclonal antibodies against immune checkpoints and targeted therapy with BRAF and MEK inhibitors [1,2,3] was a breakthrough in the treatment of advanced disease. Alternative targets are needed and one possibility for targeted therapy of melanoma is gene therapy, which is mainly used to target specific molecules that are involved in the hallmarks of cancer (e.g., RNA-based therapy for upregulated gene silencing) and DNA vaccination-based therapy for the generation of an immune response [4]
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