Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity
Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity
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DOI：
10.1158/0008-5472.can-05-1809
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发表时间：
2005-12-01
期刊：
影响因子：
11.2
通讯作者：
Keller, ET
中科院分区：
文献类型：
--
作者：
Kitagawa, Y;Dai, JL;Keller, ET
前列腺癌经常转移到骨，导致通过未知机制形成成骨细胞转移。血管内皮生长因子（VEGF）最近已被证明可以促进成骨细胞的活性。因此，我们测试了VEGF是否有助于前列腺癌诱导成骨细胞活性的能力。PC-3、LNCaP和C4-2B前列腺癌细胞系表达VEGF-165和VEGF-189 mRNA亚型和VEGF蛋白。前列腺癌细胞表达VEGF受体（VEGFR）神经纤毛蛋白-I的mRNA，但不表达VEGF受体FIT-1或KDR。相反，小鼠前成骨细胞（MC 3 T3-E1）表达FIT-1和神经纤毛蛋白-1 mRNA，但不表达KDR。PTK 787是一种VEGFR酪氨酸激酶抑制剂，在体外抑制人微血管内皮细胞的增殖，但不抑制前列腺癌的增殖。C4-2B条件培养基诱导成骨细胞分化，通过碱性磷酸酶和骨钙素的产生和MC 3 T3-E1的矿化来测量。PTK 787阻断C4-2B条件培养基诱导的成骨细胞活性。VEGF直接诱导碱性磷酸酶和骨钙素，但不诱导MC 3 T3-E1矿化。这些结果表明，VEGF诱导成骨细胞的初始分化，但需要其他因素，目前在C4-2B，诱导矿化。为了确定VEGF是否影响前列腺癌发展成骨细胞病变的能力，我们将C4-2B细胞注射到小鼠胫骨中，在肿瘤生长6周后，给予PTK 787 4周。通过骨矿物质密度和血清骨钙素测定，PTK 787可降低胫骨内肿瘤负荷和C4- 2B诱导的成骨细胞活性。这些结果表明，VEGF有助于前列腺癌诱导的成骨细胞活性在体内。
Prostate cancer frequently metastasizes to bone resulting in the formation of osteoblastic metastases through unknown mechanisms. Vascular endothelial growth factor (VEGF) has been shown recently to promote osteoblast activity. Accordingly, we tested if VEGF contributes to the ability of prostate cancer to induce osteoblast activity. PC-3, LNCaP, and C4-2B prostate cancer cell lines expressed both VEGF-165 and VEGF-189 mRNA isoforms and VEGF protein. Prostate cancer cells expressed the mRNA for VEGF receptor (VEGFR) neuropilin-I but not the VEGFRs FIt-1 or KDR. In contrast, mouse preosteoblastic cells (MC3T3-E1) expressed FIt-1 and neuropilin-l mRNA but not KDR. PTK787, a VEGFR tyrosine kinase inhibitor, inhibited the proliferation of human microvascular endothelial cells but not prostate cancer proliferation in vitro. C4-2B conditioned medium induced osteoblast differentiation as measured by production of alkaline phosphatase and osteocalcin and mineralization of MC3T3-E1. PTK787 blocked the C4-2B conditioned medium-induced osteoblastic activity. VEGF directly induced alkaline phosphatase and osteocalcin but not mineralization of MC3T3-E1. These results suggest that VEGF induces initial differentiation of osteoblasts but requires other factors, present in C4-2B, to induce mineralization. To determine if VEGF influences the ability of prostate cancer to develop osteoblastic lesions, we injected C4-2B cells into the tibia of mice and, after the tumors grew for 6 weeks, administered PTK787 for 4 weeks. PTK787 decreased both intratibial tumor burden and C4-2B-induced osteoblastic activity as measured by bone mineral density and serum osteocalcin. These results show that VEGF contributes to prostate cancer-induced osteoblastic activity in vivo.