Abstract 220: Human umbilical cord matrix-derived stem cells control tumor growth by tumor suppressor gene expression.
Authors: Ohta Naomi , Ishiguro Susumu , Kawabata Atsushi , Uppalapati Deepthi , Pyle Marla , Troyer Deryl , De Supriyo , Zhang Yongqing , Becker Kevin G. , Tamura Masaaki 
Published: August 2014

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 (Ganta et al., Cancer Res., 2009. Ayuzawa et al., Cancer Lett., 2009). However, the growth attenuation ability of rat UCMSC is stronger than that of human UCMSC. To clarify their different tumoricidal abilities, differential gene expression profiles of these two cells were studied by micro-array analysis using Illumina HumanRef-8 V2 for human and RatRef-12 BeadChip for rat UCMSC. The gene expression profiles were compared between UCMSC untreated and co-cultured with either human (MDA-231) or rat breast carcinoma cells (Mat B III). Selection criteria used for the screening of candidate genes associated with UCMSC-dependent tumoricidal ability are as follows; 1) gene expression difference should be at least a 1.5 fold between naive UCMSC and those co-cultured with mammary tumor cells; 2) they must encode secretory proteins; and 3) they must encode cell growth regulation-related proteins. These analyses screened 16 common genes from both human and rat UCMSC. The comparison between two sets of gene expression profiles identified that two genes, adipose-differentiation related protein (ADRP) and follistatin (FST), were specifically up-regulated in rat UCMSC, whereas they were down-regulated in human UCMSC when they were co-cultured with the corresponding species’ breast cancer cells. The suppression of either protein by adding specific neutralizing antibody in culture of rat UCMSC significantly abrogated their ability to attenuate cell growth. Over-expression of both genes by adenovirus vector in human UCMSC enhanced their ability to suppress the growth of MDA-231 cells. FST over-expression in MDA 231 cells also decreased their growth significantly. In the experimental lung metastasis model with MDA 231 cells in immunodeficient mice, the treatment with FST-over-expressing human UCMSC was administered three times, at one week intervals, via tail vein injection, starting 6 days after tumor cell inoculation. Examination 4 weeks after tumor inoculation showed a significant decrease in the number of tumor nodules in the lungs. Both ADRP and FST are considered to be tumor suppressor genes. These results suggest that both ADRP and FST may play important roles in exhibiting a stronger tumoricidal ability in rat UCMSC than human UCMSC. These results imply that human UCMSC can be transformed into stronger tumoricidal cells by enhancing tumor suppressor gene expression. 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 research grant.

Citation Format: Naomi Ohta, Susumu Ishiguro, Atsushi Kawabata, Deepthi Uppalapati, Marla Pyle, Deryl Troyer, Supriyo De, Yongqing Zhang, Kevin G. Becker, Masaaki Tamura. Human umbilical cord matrix-derived stem cells control tumor growth by tumor suppressor gene expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 220. doi:10.1158/1538-7445.AM2013-220