Chinni Sreenivasa R, Yamamoto Hamilto, Dong Zhong, Sabbota Aaron, Bonfil R Daniel, Cher Michael L
Department of Urology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Mol Cancer Res. 2008 Mar;6(3):446-57. doi: 10.1158/1541-7786.MCR-07-0117.
Chemokines and their receptors function in migration and homing of cells to target tissues. Recent evidence suggests that cancer cells use a chemokine receptor axis for metastasis formation at secondary sites. Previously, we showed that binding of the chemokine CXCL12 to its receptor CXCR4 mediated signaling events resulting in matrix metalloproteinase-9 expression in prostate cancer bone metastasis. A variety of methods, including lipid raft isolation, stable overexpression of CXCR4, cellular adhesion, invasion assays, and the severe combined immunodeficient-human bone tumor growth model were used. We found that (a) CXCR4 and HER2 coexist in lipid rafts of prostate cancer cells; (b) the CXCL12/CXCR4 axis results in transactivation of the HER2 receptor in lipid rafts of prostate cancer cells; (c) Src kinase mediates CXCL12/CXCR4 transactivation of HER2 in prostate cancer cells; (d) a pan-HER inhibitor desensitizes CXCR4-induced transactivation and subsequent matrix metalloproteinase-9 secretion and invasion; (e) lipid raft-disrupting agents inhibited raft-associated CXCL12/CXCR4 transactivation of the HER2 and cellular invasion; (f) overexpression of CXCR4 in prostate cancer cells leads to increased HER2 phosphorylation and migratory properties of prostate cancer cells; and (g) CXCR4 overexpression enhances bone tumor growth and osteolysis. These data suggest that lipid rafts on the cell membrane are the key site for CXCL12/CXCR4-induced HER2 receptor transactivation. This transactivation contributes to enhanced invasive signals and metastatic growth in the bone microenvironment.
趋化因子及其受体在细胞向靶组织的迁移和归巢过程中发挥作用。最近的证据表明，癌细胞利用趋化因子受体轴在继发部位形成转移。此前，我们发现趋化因子CXCL12与其受体CXCR4的结合介导了信号转导事件，导致前列腺癌骨转移中基质金属蛋白酶-9的表达。我们采用了多种方法，包括脂筏分离、CXCR4的稳定过表达、细胞黏附、侵袭实验以及严重联合免疫缺陷-人骨肿瘤生长模型。我们发现：（a）CXCR4和HER2共存于前列腺癌细胞的脂筏中；（b）CXCL12/CXCR4轴导致前列腺癌细胞脂筏中HER2受体的反式激活；（c）Src激酶介导前列腺癌细胞中CXCL12/CXCR4对HER2的反式激活；（d）一种泛HER抑制剂可使CXCR4诱导的反式激活以及随后的基质金属蛋白酶-9分泌和侵袭脱敏；（e）破坏脂筏的试剂抑制了与脂筏相关的CXCL12/CXCR4对HER2的反式激活和细胞侵袭；（f）前列腺癌细胞中CXCR4的过表达导致HER2磷酸化增加以及前列腺癌细胞迁移特性增强；（g）CXCR4过表达增强骨肿瘤生长和骨溶解。这些数据表明，细胞膜上的脂筏是CXCL12/CXCR4诱导HER2受体反式激活的关键位点。这种反式激活有助于增强骨微环境中的侵袭信号和转移生长。
