Abstract 1412: Bone marrow-derived myofibrolasts promote gastric cancer growth and invasion
Authors: Shuiping Tu, Shuiping Tu, Michael Quante, Xiangdong Yang, Shigeo Takaishi, Guangchun Jin, Hiroyuki Tomita, Shengwen Wang, Chung S Yang, Timothy C. Wang
Journal: Cancer Research (2010)

Abstract Background: The tumor microenvironment plays a pivotal role in carcinogenesis. Myofibroblasts, a major component of tumor stroma, have been demonstrated to be derived in a large part from bone marrow. However, the specific contributions of bone marrow-derived myofibroblasts to cancer growth and progression are not completely understood. In this study, we established bone marrow-derived (BMD) inflammation-related gastric myofibroblasts (MF) and investigated the role of BMD-MF in tumor growth. Methods: Gastric myofibroblast were isolated from EGFP bone marrow-transplanted IL-1β transgenic mice and wild type mice. Gene expression was assessed by real-time RT-PCR, immunocytochemistry staining and Western blot. The levels of cytokines and chemokines were measured by ELISA. Cell migration and invasion were determined by transwell migration assay and 3-D organic co-culture system, respectively. Tumor growth in vivo was determined in a SCID xenograft model. Results: We isolated and cultured successfully gastric myofibroblasts from BMT-IL-1β mice and WT mice. The pure BMD-MF (EGFP+) expressed myofibroblast markers (a-SMA and vimentin), but did not expressed markers of epithelial cells (E-cadherin). The mRNA expression of IL-1β, TNF-α, IL-6, SDF-1, MMP-1, TGF-β and COX-2 was significantly higher in the BMD-IL-1β-MF than WT-MF. Furthermore, BMD-IL-1β-MF secreted much higher levels IL-6 and SDF1 peptides in the culture medium than did WF-MF. The BMD-IL-1β MF significantly increased gastric cancer cell migration and invasion compared to WT-MF, and CXCR4 inhibitor (AMD3100) reduced cell migration induced by both myofibroblasts, indicating that the SDF1/CXCR4 axis is responsible for cell migration and invasion. Furthermore, in xenograft studies SCID mice co-injected gastric cancer cells (105 MKN45) and BMD-IL-1β MF formed larger size tumor compared those co-injected with WT-MF and those injected alone with gastric cancer cells. Mice injected with MKN45 alone on the left side and BMD-IL-1β-MF alone on the right side, surprisingly formed larger size tumors on the left side compared to those non-injected with BMD-IL-1β-MF on the right side. Furthermore, the EGFP+ MF could be detected in the xenograft tumor on the left side, suggesting that MF can migrate to the contralateral tumor and promote tumor growth. Moreover, treatment of CXCR4 inhibition (AMD3100) reduced tumor growth and the migration of MF to the contralateral tumor, indicating that SDF1/CXCR4 axis plays an important in the migration of myofibroblast and tumor growth. Conclusion: Our results for the first time show that tumor-associated myofibroblasts in the IL-1β gastric cancer model are bone marrow derived and have a stronger capacity to promote growth and invasion. The project was support by NIH grant 5U54CA126513, R01CA093405 and R01CA120979 (Wang TC) and NIH grant R01A120915 (Yang CS). 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 1412.