Molecular pathway for cancer metastasis to bone
Molecular pathway for cancer metastasis to bone
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DOI：
10.1074/jbc.m304494200
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发表时间：
2003-10-03
影响因子：
4.8
通讯作者：
Byzova, TV
中科院分区：
文献类型：
--
作者：
De, S;Chen, JH;Byzova, TV
导致癌症骨转移的分子机制知之甚少，但仍决定预后和治疗。在这里，我们定义了一个新的分子途径，可能占前列腺癌的非常高的向骨性。通过使用分泌蛋白（分泌蛋白，酸性和富含半胱氨酸）缺陷型小鼠和重组人前列腺癌，我们证明，相对于转移性较低的前列腺癌细胞系，分泌蛋白选择性地支持高转移性前列腺癌细胞系向骨的迁移。增加的迁移到肿瘤细胞可以追溯到肿瘤细胞上整合素α V β 3和α V β 5的活化。这种激活由肿瘤细胞上的自分泌血管内皮生长因子（VEGF）/VEGF受体（VEGFR）-2环诱导，其也支持前列腺癌细胞的生长和增殖。α V β 5识别VEGF的结果是VEGF的产生增强。因此，表达VEGF/VEGFR-2的前列腺癌细胞将激活其表面上的α V β 3和α V β 5，并利用这些整合素向骨中的骨转移。在骨环境中，这些整合素的协同作用将刺激肿瘤的生长并进一步产生VEGF以支持新血管生成，从而有利于转移性肿瘤的发展。支持这一模型，活化的整合素被发现与VEGFR-2共定位在患者转移性前列腺肿瘤的组织样品中。
The molecular mechanism leading to the cancer metastasis to bone is poorly understood but yet determines prognosis and therapy. Here, we define a new molecular pathway that may account for the extraordinarily high osteotropism of prostate cancer. By using SPARC (secreted protein, acidic and rich in cysteine)-deficient mice and recombinant SPARC, we demonstrated that SPARC selectively supports the migration of highly metastatic relative to less metastatic prostate cancer cell lines to bone. Increased migration to SPARC can be traced to the activation of integrins alphaVbeta3 and alphaVbeta5 on tumor cells. Such activation is induced by an autocrine vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-2 loop on the tumor cells, which also supports the growth and proliferation of prostate cancer cells. A consequence of SPARC recognition by alphaVbeta5 is enhanced VEGF production. Thus, prostate cancer cells expressing VEGF/VEGFR-2 will activate alphaVbeta3 and alphaVbeta5 on their surface and use these integrins to migrate toward SPARC in bone. Within the bone environment, SPARC engagement of these integrins will stimulate growth of the tumor and further production of VEGF to support neoangiogenesis, thereby favoring the development of the metastatic tumor. Supporting this model, activated integrins were found to colocalize with VEGFR-2 in tissue samples of metastatic prostate tumors from patients.