Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis.
Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis.
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DOI：
10.1158/0008-5472.can-15-1793
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发表时间：
2016-03-15
期刊：
影响因子：
11.2
通讯作者：
Raz A
中科院分区：
文献类型：
--
作者：
Nakajima K;Kho DH;Yanagawa T;Harazono Y;Hogan V;Chen W;Ali-Fehmi R;Mehra R;Raz A
骨转移的管理在临床上仍然具有挑战性，并且需要鉴定可以在治疗上利用以改善患者结果的新分子靶标。半乳糖凝集素-3（Gal-3）被认为是一种改变骨肿瘤微环境的分泌因子。Gal-3的蛋白水解裂解也可能导致恶性细胞行为，但尚未在癌症转移中得到解决。在这里，我们报告说，半乳糖苷-3调节溶骨性骨肿瘤微环境的RANKL的存在。Gal-3定位于破骨细胞表面，通过RNAi或特异性拮抗剂对其进行抑制可显著抑制破骨细胞分化标志物，包括TRAP，并减少成熟破骨细胞的数量。在结构上，Gal-3的碳水化合物识别结构域（CRD）中的158-175个氨基酸序列负责增强破骨细胞生成。在破骨细胞成熟过程中，Gal-3与肌球蛋白-2A相互作用并共定位于细胞-细胞融合的表面沿着。在病理学上，骨转移癌表达并释放主要在乳腺癌骨转移中检测到的完整形式的Gal-3，以及在前列腺癌骨转移中更丰富的裂解形式。分泌的完整半乳糖苷-3与肌球蛋白-2A相互作用，导致破骨细胞生成，而裂解半乳糖苷-3的转变减弱了破骨细胞分化的增强。因此，我们的研究表明，Gal-3通过取决于其裂解状态的不同作用来塑造骨肿瘤微环境，并强调通过CRD靶向Gal-3作为减轻转移性小生境中溶骨性骨重建的潜在治疗策略。
Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone tumor microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including TRAP, and reduced the number of mature osteoclasts. Structurally, the 158–175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and co-localized with myosin-2A along the surface of cell-cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche.