Zhang Yan, Nowicka Aleksandra, Solley Travis N, Wei Caimiao, Parikh Aaroh, Court Laurence, Burks Jared K, Andreeff Michael, Woodward Wendy A, Dadbin Ali, Kolonin Mikhail G, Lu Karen H, Klopp Ann H
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2015 Aug 28;10(8):e0136361. doi: 10.1371/journal.pone.0136361. eCollection 2015.
Obesity, and in particular visceral obesity, has been associated with an increased risk of developing cancers as well as higher rates of mortality following diagnosis. The impact of obesity on adipose-derived stromal cells (ASC), which contribute to the formation of tumor stroma, is unknown. Here we hypothesized that visceral source and diet-induced obesity (DIO) changes the ASC phenotype, contributing to the tumor promoting effects of obesity. We found that ASC isolated from subcutaneous (SC-ASC) and visceral (V-ASC) white adipose tissue(WAT) of lean(Le) and obese(Ob) mice exhibited similar mesenchymal cell surface markers expression, and had comparable effects on ovarian cancer cell proliferation and migration. Obese and visceral derived ASC proliferated slower and exhibited impaired differentiation into adipocytes and osteocytes in vitro as compared to ASC derived from subcutaneous WAT of lean mice. Intraperitoneal co-injection of ovarian cancer cells with obese or visceral derived ASC, but not lean SC-ASC, increased growth of intraperitoneal ID8 tumors as compared to controls. Obese and V-ASC increased stromal infiltration of inflammatory cells, including CD3+ T cells and F4/80+ macrophages. Obese and visceral derived ASC, but not lean SC-ASC, increased expression of chemotactic factors IL-6, MIP-2, and MCP-1 when cultured with tumor cells. Overall, these results demonstrate that obese and V-ASC have a unique phenotype, with more limited proliferation and differentiation capacity but enhanced expression of chemotactic factors in response to malignant cells which support infiltration of inflammatory cells and support tumor growth and dissemination.
肥胖，尤其是内脏型肥胖，与患癌风险增加以及诊断后更高的死亡率相关。肥胖对有助于肿瘤基质形成的脂肪来源基质细胞（ASC）的影响尚不清楚。在此，我们假设内脏来源和饮食诱导的肥胖（DIO）会改变ASC表型，从而导致肥胖的促肿瘤作用。我们发现，从瘦（Le）小鼠和肥胖（Ob）小鼠的皮下（SC-ASC）和内脏（V-ASC）白色脂肪组织（WAT）中分离出的ASC表现出相似的间充质细胞表面标志物表达，并且对卵巢癌细胞增殖和迁移的影响相当。与来自瘦小鼠皮下WAT的ASC相比，肥胖和内脏来源的ASC在体外增殖较慢，并且向脂肪细胞和骨细胞的分化受损。与对照组相比，将卵巢癌细胞与肥胖或内脏来源的ASC而非瘦的SC-ASC进行腹腔共同注射，可增加腹腔内ID8肿瘤的生长。肥胖和V-ASC增加了炎症细胞的基质浸润，包括CD3 + T细胞和F4/80 +巨噬细胞。与肿瘤细胞一起培养时，肥胖和内脏来源的ASC而非瘦的SC-ASC增加了趋化因子IL-6、MIP-2和MCP-1的表达。总体而言，这些结果表明，肥胖和V-ASC具有独特的表型，增殖和分化能力更有限，但对恶性细胞的趋化因子表达增强，这支持炎症细胞浸润并支持肿瘤生长和扩散。
