Theranostics 2019; 9(16):4764-4778. doi:10.7150/thno.33139 This issue

Research Paper

Embryonic Stem Cells Modulate the Cancer-Permissive Microenvironment of Human Uveal Melanoma

Jiahui Liu1*, Zheqian Huang1*, Liu Yang1, Xiaoran Wang1, Shoubi Wang1, Chaoyang Li1, Ying Liu1, Yaqi Cheng1, Bowen Wang1, Xuan Sang1, Xiongjun He1, Chenjie Wang1, Tengfei Liu1, ChengXiu Liu2, Lin Jin1, Chang Liu1, Xiaoran Zhang3, Linghua Wang4, Zhichong Wang1✉

1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, P. R. China.
2. Department of Ophthalmology, Affiliated Hospital of Qingdao University Medical College, Qingdao 266000, P. R. China
3. Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510275, P. R. China
4. Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Liu J, Huang Z, Yang L, Wang X, Wang S, Li C, Liu Y, Cheng Y, Wang B, Sang X, He X, Wang C, Liu T, Liu C, Jin L, Liu C, Zhang X, Wang L, Wang Z. Embryonic Stem Cells Modulate the Cancer-Permissive Microenvironment of Human Uveal Melanoma. Theranostics 2019; 9(16):4764-4778. doi:10.7150/thno.33139. Available from

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Graphic abstract

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: embryonic stem cells, neoplasms, microenvironment, PI3K pathway, uveal melanoma