LAUSR

BACKGROUND: Recent studies have shown that metastasis-initiating cells (MICs) in the pre-metastatic niche play a key role in triggering tumor metastasis. In addition, bone marrow-derived endothelial progenitor cells (BM-EPCs), which are key components of the pre-metastatic microenvironment, can serve as “metastasis-initiators”. Our previous studies have revealed that the periostin (POSTN) expression in HCC is positively correlated with the amount of EPCs and POSTNhigh hepatocarcinoma cells possess cancer stem cell-like properties. Meanwhile, CD36, a biomarker of MICs, is highly expressed in recurrent HCC. This study aims to clarify whether BM-EPCs in the pre-metastatic niche promote the generation of CD36-positive MICs and stimulate tumor metastasis through interacting with POSTNhigh hepatocarcinoma cells in HCC. AIMS and METHODS: Cell co-culture experiments were conducted to investigate the effect of EPCs on malignant biological behaviors of POSTNhigh hepatocarcinoma cells. In addition, the change in the expression of CD36 antibody in co-cultured HCC cells was evaluated to investigate the generation of CD36-positive MICs. Furthermore, NF-E2-related factor 2 (Nrf2) was identified as a transcription factor that increases the expression of CD36 antigen and promotes stem cell-like properties of HCC cells. Finally, the changes in HCC invasion and metastasis by manipulating the POSTN/Nrf2/CD36 signal axis were evaluated. RESULTS: POSTNhigh HCC cells co-cultured with EPCs showed enhanced proliferation, invasion and spheroid formation. Flow cytometry demonstrated that the expression level of CD36 on cell surface was significantly up-regulated in these co-cultured cells. ELISA tests showed that CCL2 secreted by EPCs was the key factor promoting the transformation of POSTNhigh HCC cells to a CD36-positive phenotype. Further experiments revealed that, after binding to the CCR2 receptor on HCC cell membrane, EPC-secreted CCL2 promoted the direct binding of Nrf2 to the promoter region of CD36 gene and upregulated CD36 expression when the αvβ3 pathway was activated, which eventually induced the transformation of POSTNHigh HCC cells into CD36-expressing MICs. The CCL2 monoclonal antibody and αvβ3 antagonist Cilengitide effectively blocked the POSTN/Nrf2 /CD36 axis, inhibiting the formation of CD36-positive MICs of HCC and suppressing tumor invasion and metastasis. CONCLUSIONS: CCL2 protein secreted by BM-EPCs can promote the transformation of POSTNhigh HCC cells into CD36-positive MICs, thereby promoting formation of metastases. Citation Format: Xiaozai Xie, Pengyi Guo, Haitao Yu, Yi Wang, Gang Chen. Human bone marrow-derived endothelial progenitor cells promote the transformation of periostin-positive hepatocellular carcinoma cells into CD36-positive metastasis-initialing cells in pre-metastatic niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 101.