Abstract 1427: Mesenchymal stem cells derived myofibroblasts function as niche cells in the normal bone marrow and expand during carcinogenesis to promote tumor growth
Authors: Michael Quante, Shuiping Tu, Hiroyuki Tomita, Tamas Gonda, Benjamin Tycko, Timothy C. Wang
Journal: Cancer Research (2010)

Abstract Tumorigenesis is driven by alterations in tumor cells but also by changes in the stromal microenvironment. Bone marrow derived mesenchymal stem cells (MSC) are believed to give rise to various types of tumor contributing cells, such as Carcinoma Associated Fibroblasts (CAFs) that express a-smooth-muscle-actin (aSMA+). These cells have been identified in the stroma of cancers and their contribution to the tumor stroma is known to be increased in tissues exhibiting a chronically inflamed stroma. In this study we aimed to identify and characterize the cell type of origin within the MSCs that gives rise to CAFs in a mouse model of inflammation induced gastric cancer. MSC cultures from whole bone marrow of aSMA-RFP transgenic reporter mice were established based on the ability of MSC to adhere to plastic. In culture, MSC consisted of a heterogeneous population of RFP positive (RFP+) and negative (RFP-) cells (FACS). Endogenous aSMA expression correlated with transgenic RFP expression and other markers of the myofibroblast lineage (vimentin, FSP1, desmin) in contrast to RFP- cells (Collagen-1a or Gremlin1). After sorting, mostly RFP- and RFP+/- cells were able to form colonies and differentiate into adipocytes and osteocytes, suggesting the presence of a RFP- stem cell. Heterogeneous aSMA-MSC (RFP+/-) appeared immortal, in contrast to sorted RFP+. In RFP- and RFP+/- populations, time lapse microscopy revealed that SMA+ cells derive from MSC through asymmetric stem cell division, allowing self renewal of RFP- MSCs. RFP- cultures became RFP+/- but the maintenance of a RFP- population (FACS) resulted in senescence. Histopathologically, aSMA+ cells were present in the mouse bone marrow (IHC). CAFs increased during Helicobacter or IL-1ß induced gastric cancer progression. Interestingly, the number of CAFs also increased in the bone marrow niche and blood during progression to dysplasia. MSC-derived MF expressed IL-6, Wnt5a and BMP4 (PCR) and showed DNA hypomethylation. CAFs were expanded in a TGF-b-dependent matter and recruited through CXCR4/SDF1a signaling together with Gremlin-1 expressing MSC to incipient tumors (xenograft) where they contributed to a niche that appeared to be the important part in the tumor microenvironment to sustains tumor progression. In conclusion, we show for the first time in a mammalian model that MF contribute to the normal stem cell niche in the bone marrow. Moreover, MSC itself gives rise to its own niche cells in asymmetric stem cell division. Chronic inflammation and epithelial dysplasia lead to MF expansion in the bone marrow and blood. Therefore we propose a model in which, during the earliest stages of tumor development, the bone marrow undergoes remodeling and then the MSC-CAF stem cell niche is located to the tumor site where it promotes tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1427.