the primacy of β1 integrin activation in the metastatic cascade至高无上的β1整合素转移级联激活.pdfVIP

The Primacy of b1 Integrin Activation in the Metastatic Cascade 1 1 1 2,3 4 1,2 Hisashi Kato , Zhongji Liao , John V. Mitsios , Huan-You Wang , Elena I. Deryugina , Judith A. Varner , James P. Quigley4, Sanford J. Shattil1,2* 1 Department of Medicine, University of California San Diego, La Jolla, California, United States of America, 2 Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, United States of America, 3 Department of Pathology, Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, United States of America, 4 Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America Abstract After neoplastic cells leave the primary tumor and circulate, they may extravasate from the vasculature and colonize tissues to form metastases. b1 integrins play diverse roles in tumorigenesis and tumor progression, including extravasation. In blood cells, activation of b1 integrins can be regulated by ‘‘inside-out’’ signals leading to extravasation from the circulation into tissues. However, a role for inside-out b1 activation in tumor cell metastasis is uncertain. Here we show that b1 integrin activation promotes tumor metastasis and that activated b1 integrin may serve as a biomarker of metastatic human melanoma. To determine whether b1 integrin activation can influence tumor cell metastasis, the b1 integrin subunit in melanoma and breast cancer cell lines was stably knocked down with shRNA and replaced with wild-type or constitutively- active b1. When tumor cells expressing constitutively-active b1 integrins were injected intravenously into chick