Abstract B46: Umbilical cord matrix-derived stem cells control tumor growth by their tumor suppressor and promoter gene expression

Abstract

Abstract Umbilical cord matrix-derived stem cells (UCMSC) have the potential to treat various diseases including cancer. We have shown that naïve human and rat UCMSC significantly attenuate proliferation of multiple cancer cells. However, our previous study showed that the growth attenuation ability of rat UCMSC is stronger than that of human UCMSC. To clarify their different tumoricidal abilities, differential gene expression profiles were studied by microarray analysis using IIIumina HumanRef-8 V2 BeadChip for human and RatRef-12 BeadChip for rat UCMSC. The differential gene expression profile between untreated human UCMSC and those co-cultured with MDA-MB 231 human breast carcinoma cells was compared with that between untreated rat UCMSC and those co-cultured with Mat B III rat mammary gland carcinoma cells. Strict screening criteria used to identify putative genes associated with UCMSC-dependent tumoricidal activity were as follows: gene expression should (1) be over than 1.5 fold different, (2) encode secretory proteins, and (3) be associated with cell growth regulation. Seventeen genes were identified as being associated with either human or rat UCMSC-dependent tumor growth regulation. Among these genes, eight were up-regulated in both human and rat UCMSC (two being known tumor suppressor and six being putative tumor promoter genes). Seven out of seventeen genes were up-regulated in human UCMSC but not in rat UCMSC (three were identified to be tumor suppressor and four were tumor promoter genes). Two out of the seventeen genes, adipose-differentiation related protein (ADRP) and follistatin (FST), which are known tumor suppressor genes, were specifically up-regulated in rat UCMSC, whereas they were down-regulated in human UCMSC when they were co-cultured with carcinoma cells. These results strongly suggest that the balance of the up-regulation of tumor suppressor genes and down-regulation of tumor promoter genes in UCMSC appear to control tumor growth. Since both ADRP and FST are considered to be tumor suppressor genes and were specifically up-regulated in only rat UCMSC, these two genes expression may play central role in strong tumoricidal activity by rat UCMSC. In support of this hypothesis, suppression of ADRP and FST protein by adding a neutralizing antibody (4 µg/ml) in culture medium of rat UCMSC significantly abrogated their ability to attenuate DNA synthesis. Over-expression of ADRP and FST genes by adenoviral vector (100 MOI) in human UCMSC promoted their ability to suppress the DNA synthesis of MDA-MB 231 cells in [3H]-thymidine uptake assay. Interestingly, ADRP expression in human UCMSC stimulated differentiation to adipose type cell morphology (cell enlargement and oil droplet accumulations in cytoplasm). This result suggests that ADRP may stimulate adiponectin production in vivo thereby attenuating tumor growth. Taken together, these results suggest that both ADRP and FST may be key genes that exhibit stronger tumoricidal ability in rat UCMSC than human UCMSC. This work was supported by the Kansas State University (KSU) Terry C. Johnson Center for Basic Cancer Research, KSU College of Veterinary Medicine Dean's Fund, NIH RR017686, RR15563, CA135599, Kansas Bioscience Authority Collaborative Cancer Research grant and by the Intramural Research Program of the NIH, National Institute on Aging. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B46.