Abstract
Bone marrow‐derived mesenchymal stem cells (BM‐MSCs) promote gastric cancer progression with chronic inflammation. In culture, BM‐MSCs are prone to mutation with age but whether this occurs in vivo in response to gastritis is unknown. Sonic Hedgehog (Shh) is often secreted by tumors and may contribute to BM‐MSC transformation. We tested the hypothesis that malignant transformation of BM‐MSCs in response to chronic gastric inflammation is mediated by Shh signaling. GKO mice displayed severe atrophic gastritis accompanied by elevated gastric tissue and circulating transforming growth factor‐beta (TGFβ) by 3 months of age. BM‐MSCs isolated from GKO mice displayed an increased proliferative rate and elevated phosphorylated‐Smad3 indicative of active TGFβ signaling when compared to those cells isolated from BL/6 bone marrow. In xenograft assays, mice injected with BM‐MSCs collected from 6 month old GKO animals displayed tumor growth. BM‐MSCs collected from age matched BL/6 mice injected into inflamed GKO animals also developed tumor growth that was mediated by TGFβ or Shh signaling. Shh pathway activity within BM‐MSCs was downstream of the TGFβ signaling. This data establishes chronic gastric inflammation induces the malignant transformation of BM‐MSCs. Funded by American Cancer Society Research Scholar Award 119072‐RSG‐10–167‐01‐MPC (Y. Zavros) and the Albert J. Ryan Foundation Fellowship (J. Donnelly)
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