title: 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.
authors.affiliation: Department of Gastroenterology and Hepatology.
authors.forename: Pratika Y
authors.initials: PY
authors.lastname: Hernanda
authors.forename: Alexander
authors.initials: A
authors.lastname: Pedroza-Gonzalez
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.forename: Mirelle E E
authors.initials: ME
authors.lastname: Bröker
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hoogduijn
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Ijzermans
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Bruno
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D047368:Tumor Burden; D014410:Tumor Stem Cell Assay
chemical_list: D000954:Antigens, Surface; C525591:STRO-1 antigen, human