Fat tissue, overgrowing in obesity, promotes the progression of various carcinomas. Clinical and animal model studies indicate that adipose stromal cells (ASC), the progenitors of adipocytes, are recruited by tumors and promote tumor growth as tumor stromal cells. Here, we investigated the role of ASC in cancer chemoresistance and invasiveness, the attributes of tumor aggressiveness. By using human cell co-culture models, we demonstrate that ASC induce epithelial-mesenchymal transition (EMT) in prostate cancer cells. Our results for the first time demonstrate that ASC interaction renders cancer cells more migratory and resistant to docetaxel, cabazitaxel, and cisplatin chemotherapy. To confirm these findings in vivo, we compared cancer aggressiveness in lean and obese mice grafted with prostate tumors. We show that obesity promotes EMT in cancer cells and tumor invasion into the surrounding fat tissue. A hunter-killer peptide D-CAN, previously developed for targeted ASC ablation, suppressed the obesity-associated EMT and cancer progression. Importantly, cisplatin combined with D-CAN was more effective than cisplatin alone in suppressing growth of mouse prostate cancer allografts and xenografts even in non-obese mice. Our data demonstrate that ASC promote tumor aggressiveness and identify them as a target of combination cancer therapy.

中文翻译：

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脂肪基质细胞靶向抑制前列腺癌上皮-间质转化和化学抗性。

肥胖中过度生长的脂肪组织促进了各种癌症的发展。临床和动物模型研究表明，脂肪基质细胞（ASC）是脂肪细胞的祖细胞，被肿瘤募集并促进肿瘤生长为肿瘤基质细胞。在这里，我们调查了ASC在癌症化学抗性和侵袭性中的作用，即肿瘤侵袭性的属性。通过使用人类细胞共培养模型，我们证明了ASC在前列腺癌细胞中诱导上皮-间质转化（EMT）。我们的结果首次证明ASC相互作用使癌细胞更易迁移，并且对多西紫杉醇，卡巴他赛和顺铂化疗具有耐药性。为了在体内证实这些发现，我们比较了移植有前列腺肿瘤的肥胖和肥胖小鼠的癌症侵袭性。我们表明，肥胖会促进癌细胞中的EMT以及肿瘤向周围脂肪组织的侵袭。先前用于靶向ASC消融的猎人杀伤肽D-CAN抑制了肥胖相关的EMT和癌症的进展。重要的是，即使在非肥胖小鼠中，顺铂与D-CAN联合使用也比单独使用顺铂更有效地抑制了小鼠前列腺癌同种异体移植物和异种移植物的生长。我们的数据表明，ASC促进了肿瘤的侵袭性，并将其确定为联合癌症治疗的靶标。顺铂与D-CAN联合使用比单独使用顺铂在抑制小鼠前列腺癌同种异体移植物和异种移植物的生长方面更有效，即使在非肥胖小鼠中也是如此。我们的数据表明，ASC促进了肿瘤的侵袭性，并将其确定为联合癌症治疗的靶标。顺铂与D-CAN联合使用比单独使用顺铂在抑制小鼠前列腺癌同种异体移植物和异种移植物的生长方面更有效，即使在非肥胖小鼠中也是如此。我们的数据表明，ASC促进了肿瘤的侵袭性，并将其确定为联合癌症治疗的靶标。