Comprehensive Cancer Center, Solid Tumor Program, Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Division of Cardiology, Department of Internal Medicine, UTHealth - The University of Texas Health Science Center at Houston, Houston, Texas.
Cancer Res. 2021 Nov 15;81(22):5666-5677. doi: 10.1158/0008-5472.CAN-20-3982. Epub 2021 Aug 12.
Collagen remodeling contributes to many physiologic and pathologic processes. In primary tumors, the linearization of collagen fibers promotes cancer cell invasion and metastasis and is indicative of poor prognosis. However, it remains unknown whether there are endogenous inhibitors of collagen linearization that could be exploited therapeutically. Here, we show that collagen linearization is controlled by two secreted matricellular proteins with antagonistic functions. Specifically, WISP1 was secreted by cancer cells, bound to type I collagen (Col I), and linearized Col I via its cysteine-rich C-terminal (CT) domain. In contrast, WISP2, which lacks a CT domain, inhibited Col I linearization by preventing WISP1-Col I binding. Analysis of patient data revealed that expression is lower in most solid tumors, in comparison with normal tissues. Consequently, genetic or pharmacologic restoration of higher WISP2 levels impaired collagen linearization and prevented tumor cell invasion and metastasis in models of human and murine breast cancer. Thus, this study uncovers WISP2 as the first inhibitor of collagen linearization ever identified and reveals that collagen architecture can be normalized and metastasis inhibited by therapeutically restoring a high WISP2:WISP1 ratio. SIGNIFICANCE: Two secreted factors, WISP1 and WISP2, antagonistically regulate collagen linearization, and therapeutically increasing the WISP2:WISP1 ratio in tumors limits collagen linearization and inhibits metastasis..
胶原重塑参与了许多生理和病理过程。在原发性肿瘤中，胶原纤维的线性化促进了癌细胞的侵袭和转移，预示着预后不良。然而，目前尚不清楚是否存在可以被治疗利用的胶原线性化的内源性抑制剂。在这里，我们发现胶原线性化受到两种具有拮抗作用的分泌细胞外基质蛋白的控制。具体来说，WISP1 由癌细胞分泌，与 I 型胶原（Col I）结合，并通过其富含半胱氨酸的 C 端（CT）结构域线性化 Col I。相比之下，缺乏 CT 结构域的 WISP2 通过阻止 WISP1-Col I 结合来抑制 Col I 线性化。对患者数据的分析表明，与正常组织相比，大多数实体瘤中 的表达水平较低。因此，通过遗传或药理学方法恢复较高的 WISP2 水平会损害胶原线性化，并在人类和鼠类乳腺癌模型中阻止肿瘤细胞侵袭和转移。因此，这项研究揭示了 WISP2 作为首个被鉴定出的胶原线性化抑制剂，并表明通过治疗性地恢复高 WISP2:WISP1 比值，可以使胶原结构正常化并抑制转移。意义：两种分泌因子 WISP1 和 WISP2 拮抗地调节胶原线性化，在肿瘤中治疗性地增加 WISP2:WISP1 比值可以限制胶原线性化并抑制转移。
