1050 HUMAN LIVER CARCINOMAS RECRUIT MESENCHYMAL STEM/STROMAL CELLS THAT CAN PROMOTE TUMOR GROWTH VIA PARACRINE SIGNALING

Abstract

Background and Aims: Bone marrow mesenchymal stem/stromal cells (MSCs) can migrate to tumor sites and contribute to the tumor microenvironment. However, it is still hotly debated whether MSCs have a positive or negative effect on tumor growth. This study aims to investigate whether human liver carcinomas contain MSCs and whether MSCs may affect tumor growth. Methods: MSCs were cultured from surgical resected hepatocellular carcinoma (HCC) (n = 6) and liver metastatic colorectal tumor (LMCRC) (n = 7). Immunohistochemical staining of STRO-1 (the bestknown MSCs marker for in vivo detection) was performed in paraffin-embedded patient HCC and LM-CRC tissues (n = 24). The effects of MSCs on tumor growth were evaluated in immunedeficient mice. Results: Solid tumors formed in mice by subcutaneous engraftment of human hepatoma Huh7 cells were able to recruit MSCs. MSCs were also found in patient liver tumors (successfully cultured from 11 out of 13 liver tumors). Their MSC properties were characterized by adipocyte and osteocyte differentiation and common mesenchymal markers. Notably, in situ staining showed that STRO-1 positive cells are significantly enriched in the tumor, in particular the tumor-stromal region, compared with the adjacent area in HCC and LM-CRC tissues (n = 24, p < 0.01). In mice, coengraftment of Huh7 and MSCs resulted in significant larger tumors than engraftment of Huh7 alone (tumor weight 1.56±0.27 g Vs 0.44±0.19 g, Mean±SEM, n = 8, p < 0.01). Consistently, co-culturing Huh7 with irradiated MSCs significantly increased the number (196±29 Vs 123±36 clonies/5000 Huh7, Mean±SD, n = 5, p < 0.01) and the size (1329±258 Vs 570±155 pixels, n = 5, p < 0.01) of formed colonies. This effect was also observed by treatment of MSCs conditioned medium (MSC-CM), suggesting secreted tropic factors contributing to the tumor promoting effect. Genome-wide gene expression array and pathway analysis confirmed the upregulation of cell growth and proliferation-related processes and down-regulation of cell death-related pathways by treatment of MSC-CM in Huh7 cells. Conclusion: Human liver carcinomas recruit MSCs, which in turn can promote tumor growth. These results shed new light on the crosstalk between MSCs with liver cancer cells but also caution stem cell therapy of using MSCs for liver cancer and other liver diseases with high risk of developing malignancy.