Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope
Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope
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DOI：
10.1016/j.ajpath.2016.01.015
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发表时间：
2016-06-01
影响因子：
6
通讯作者：
Brooks, Peter C.
中科院分区：
文献类型：
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作者：
Caron, Jennifer M.;Ames, Jacquelyn J.;Brooks, Peter C.
有证据表明，基质细胞在肿瘤生长中起关键作用。揭示控制基质细胞行为及其在肿瘤内积累的新机制可能会导致开发更有效的治疗方法。我们提供的证据表明，HU 177隐蔽的胶原蛋白表位是选择性地产生在人类卵巢癌和这种胶原蛋白表位在体内SKOV-3卵巢肿瘤生长中发挥作用。HU 177表位调节SKOV-3肿瘤生长的能力部分取决于其调节基质细胞行为的能力，因为靶向该表位抑制血管生成，并且令人惊讶地抑制表达α-平滑肌肌动蛋白的基质细胞的积累。整合素β 10 β 1可作为α-平滑肌肌动蛋白表达基质细胞中HU 177表位的受体，随后调节ERK依赖性迁移。这些发现与HU 177胶原表位的产生提供了一种以前未识别的α（10）β（1）配体的机制一致，该配体选择性地控制血管生成和基质细胞的积累，基质细胞反过来分泌促肿瘤发生因子，促进卵巢肿瘤生长。我们的研究结果为HU 177表位调节卵巢肿瘤生长的作用提供了新的机制理解，并为单克隆抗体D93/TRC 093在晚期恶性肿瘤患者中的1期人类临床研究的临床结果提供了新的见解。
Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis and, surprisingly, the accumulation of alpha-smooth muscle actin-expressing stromal cells. Integrin beta 10 beta 1 can serve as a receptor for the HU177 epitope in alpha-smooth muscle actin-expressing stromal cells and subsequently regulates Erk-dependent migration. These findings are consistent with a mechanism by which the generation of the HU177 collagen epitope provides a previously unrecognized alpha(10)beta(1) ligand that selectively governs angiogenesis and the accumulation of stromal cells, which in turn secrete protumorigenic factors that contribute to ovarian tumor growth. Our findings provide a new mechanistic understanding into the roles by which the HU177 epitope regulates ovarian tumor growth and provide new insight into the clinical results from a phase 1 human clinical study of the monoclonal antibody D93/TRC093 in patients with advanced malignant tumors.