Tumor promotion through the mesenchymal stem cell compartment in human hepatocellular carcinoma

Abstract

Although the infiltration of mesenchymal stem (stromal) cells (MSCs) into different tumors is widely recognized in animal models, the question whether these MSCs have a positive or negative effect on disease progression remains unanswered. The aim of this study is to investigate whether human hepatocellular carcinoma (HCC) harbors MSCs and whether these MSCs affect tumor growth. We observed that cells capable of differentiation into both adipocyte and osteocyte lineages and expressing MSC markers can be cultured from surgically resected HCC tissues. In situ staining of human HCC tissues with a STRO-1 antibody showed that the tumor and tumor-stromal region are significantly enriched with candidate MSCs compared with adjacent tissue (n = 12, P < 0.01). In mice, coengraftment of a human HCC cell line (Huh7) with MSCs resulted in substantially larger tumors compared with paired engraftment of Huh7 alone (n = 8, P < 0.01). Consistently, coculturing Huh7 with irradiated MSCs significantly increased the number and the size of colonies formed. This enhancement of Huh7 colony formation was also observed by treatment of MSC-conditioned medium (MSC-CM), suggesting that secreted trophic factors contribute to the growth-promoting effects. Genome-wide gene expression array and pathway analysis confirmed the upregulation of cell growth and proliferation-related processes and downregulation of cell death-related pathways by treatment of MSC-CM in Huh7 cells. In conclusion, these results show that MSCs are enriched in human HCC tumor compartment and could exert trophic effects on tumor cells. Thus, targeting of HCC tumor MSCs may represent a new avenue for therapeutic intervention.

Mesenchymal Stem/Stromal Cells Exert Trophic Effect on Colorectal Cancer Metastasis to the Liver

“…Adipogenic andosteogenic differentiation were performed as previously described [16]. Oil Red O staining was used for adipocytes detection.…”

“…Paraffin embedded CRC-LM tumor tissue slides were used to stain with the mouse monoclonal antibody STRO-1 (Invitrogen Corporation) and then counterstained with haematoxylin [16].…”

“…To investigate whether MSCs are present in patient CRC-LM tumors, surgical resection of CRC-LM tissues of 9 patients were collected and submitted to an MSC culturing protocol previous validated for liver tissue [14,16]. Indeed, mesenchymal like cells were easily identified in the resulting cultures ( Figure 1A).…”

“…Previously, we showed that human liver MSCs can exert trophic action on HCC cells [16], but whether these cells have the capacity to foster CRC cell is unknown. Thus we decided to investigate whether factors secreted by MSCs influence colony unit formation and growth of the SW620 CRC cell line.…”

“…We subsequently demonstrated that MSCs are enriched in human primary liver cancer (hepatocellular carcinoma; HCC) and could exert trophic effects on tumor cells [16]. This prompted us to further investigate the presence and the roles of MSCs in liver metastatic CRC (CRC-LM).…”