The currently used anti-cancer therapies work by killing cancer cells but result in adverse effects and resistance to treatment, which accelerates aging and causes damage to normal somatic cells. On one hand, chicken and zebrafish embryos can reprogram cancer cells towards a non-tumorigenic phenotype; however, they cannot be used in the clinical practice. On the other hand, embryonic stem cells (ESCs) mimic the early embryonic microenvironment and are easily available. We investigated the therapeutic efficacy of the ESC microenvironment (ESCMe) in human uveal melanoma in vitro and in vivo. Methods: Human uveal melanoma C918 cells co-cultured with ESCs were used to measure the levels of mRNA and protein of the phosphoinositide 3-kinase (PI3K) pathway. Cell proliferation, invasiveness, and tumorigenicity of C918 cells were also analyzed. To mimic the tumor microenvironment in vivo, we co-cultured C918 cells and normal somatic cells with ESCs in a co-culture system and evaluated the therapeutic potential of ESCMe in both cell types. For an in vivo study, a mouse tumor model was used to test the safety and efficacy of the transplanted ESC. Elimination of the transplanted ESCs in mice was carried out by using the ESC-transfected with a thymidine kinase suicidal gene followed by administration of ganciclovir to prevent the formation of teratomas by ESCs. Results: In vitro studies confirmed that ESCMe inhibits the proliferation, invasiveness, and tumorigenicity of C918 cells, and the PI3K agonist abolished these effects. ESCMe suppressed the various malignant behaviors of uveal melanoma cells but enhanced the proliferation of normal somatic cells both in vitro and in vivo. Further, we demonstrated that ESCMe suppressed the PI3K pathway in tumor cells but activated in somatic cells. Conclusions: The ESCMe can effectively suppress the malignant phenotype of uveal melanoma cells and modulate the tumor-promoting aging environment by preventing the senescence of normal cells through the bidirectional regulation of the PI3K signaling. Our results suggest that ESC transplantation can serve as an effective and safe approach for treating cancer without killing cells.
Keywords: PI3K pathway; embryonic stem cells; microenvironment; neoplasms; uveal melanoma.