Division of Hematology-Oncology, Tufts Medical Center, Boston, Massachusetts.
Mol Cancer Res. 2020 Jan;18(1):27-32. doi: 10.1158/1541-7786.MCR-19-0442. Epub 2019 Oct 21.
Fibronectin-binding integrins α5β1 and αv collaborate in prostate cancer-bone stromal interactions relevant to the colonization of the bone marrow microenvironment. Combinatorial inactivation of these integrins on prostate cancer cells was assessed. Monospecific antibodies to α5β1and αv integrins alone (MAb) and in combination (cMAb), and a bispecific antibody that simultaneously targets α5β1and αv integrins (BsAbα5β1/αv) were compared in assays of chemotaxis, clonogenic survival, and induction of endothelial migration. Cellular expression of integrins, their transcription, translation, and degradation fate was compared. The BsAbα5β1/αv was superior to MAbs and cMAbs in abrogating adhesion, migration, clonogenic survival, and induction of endothelial migration responses by prostate cancer cells. Integrin upregulation observed with MAbs or cMAbs was abrogated with the BsAbα5β1/αv. Loss of integrin expression was uniquely induced by the BsAbα5β1/αv and blocked by lysosomal inhibition. IMPLICATIONS: A novel and effective combinatorial strategy to target α5β1and αv integrins is defined for translational studies. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/1/27/F1.large.jpg.
纤连蛋白结合整合素 α5β1 和 αv 在与骨髓微环境定植相关的前列腺癌-骨基质相互作用中协同作用。评估了这些整合素在前列腺癌细胞上的组合失活。单独（MAb）和组合（cMAb）使用针对 α5β1 和 αv 整合素的单克隆抗体，以及同时针对 α5β1 和 αv 整合素的双特异性抗体（BsAbα5β1/αv）在趋化、集落存活和诱导内皮迁移测定中进行了比较。比较了整合素的细胞表达、转录、翻译和降解命运。BsAbα5β1/αv 在阻断前列腺癌细胞的粘附、迁移、集落存活和诱导内皮迁移反应方面优于 MAb 和 cMAb。MAb 或 cMAb 观察到的整合素上调被 BsAbα5β1/αv 阻断。整合素表达的丧失仅由 BsAbα5β1/αv 诱导，并被溶酶体抑制所阻断。意义：定义了一种针对 α5β1 和 αv 整合素的新型有效组合策略，用于转化研究。直观描述：http://mcr.aacrjournals.org/content/molcanres/18/1/27/F1.large.jpg。
