Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop.
Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop.
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DOI：
10.18632/oncotarget.6870
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发表时间：
2016-02-09
期刊：
影响因子：
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通讯作者：
Buckanovich RJ
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文献类型：
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作者：
Coffman LG;Choi YJ;McLean K;Allen BL;di Magliano MP;Buckanovich RJ
肿瘤微环境对肿瘤生长和治疗耐药起着至关重要的作用。我们先前研究了人卵巢癌相关间充质干细胞(CA-MSCs)。CA-MSCs是一种多能细胞，可分化为肿瘤微环境成分，包括成纤维细胞、肌成纤维细胞和脂肪细胞。我们先前报道，与正常MSCs相比，CA-MSCs表达高水平的BMP蛋白，并通过增加肿瘤干细胞(CSCs)数量促进肿瘤生长。我们在这里证明了卵巢肿瘤细胞分泌的Hedgehog(HH)诱导CA-MSC BMP4的表达。CA-MSC来源的BMP4相互促进卵巢肿瘤细胞HH的表达，表明是一个正反馈循环。用HH途径抑制剂或BMP4阻断抗体阻断这一环，可减少CA-MSC来源的BMP4和肿瘤来源的HH，防止CSCs的浓缩和逆转化疗耐药。HH抑制的影响仅见于含有CA-MSC的肿瘤，表明人源化间质的重要性。这些结果与胰腺癌和膀胱癌的研究结果相反，表明HH信号效应是肿瘤组织特有的，值得在每种肿瘤类型中仔细研究。总之，我们定义了CA-MSC来源的BMP4和卵巢肿瘤细胞分泌的HH之间的关键正反馈环，并为进一步研究HH作为卵巢癌的临床靶点提供了证据。
The tumor microenvironment is critical to cancer growth and therapy resistance. We previously characterized human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are multi-potent cells that can differentiate into tumor microenvironment components including fibroblasts, myofibroblasts and adipocytes. We previously reported CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We demonstrate here that ovarian tumor cell-secreted Hedgehog (HH) induces CA-MSC BMP4 expression. CA-MSC-derived BMP4 reciprocally increases ovarian tumor cell HH expression indicating a positive feedback loop. Interruption of this loop with a HH pathway inhibitor or BMP4 blocking antibody decreases CA-MSC-derived BMP4 and tumor-derived HH preventing enrichment of CSCs and reversing chemotherapy resistance. The impact of HH inhibition was only seen in CA-MSC-containing tumors, indicating the importance of a humanized stroma. These results are reciprocal to findings in pancreatic and bladder cancer, suggesting HH signaling effects are tumor tissue specific warranting careful investigation in each tumor type. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH and present evidence for the further investigation of HH as a clinical target in ovarian cancer.