Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases
Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases
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DOI：
10.1093/jnci/95.6.458
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发表时间：
2003-03-19
期刊：
影响因子：
--
通讯作者：
Fidler, IJ
中科院分区：
文献类型：
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作者：
Uehara, H;Kim, SJ;Fidler, IJ
背景：血小板衍生生长因子(PDGF)的表达及其受体(PDGF-R)的激活(通过自身磷酸化)是一种酪氨酸激酶，与骨实质中转移性前列腺癌细胞的生长有关。酪氨酸激酶抑制剂STI571通过抑制PDGF-R的自磷酸化来阻断PDGF信号通路。我们研究了STI571单独给药或与紫杉醇(紫杉醇)合用对前列腺癌转移小鼠模型肿瘤生长的影响。方法：将人前列腺癌PC-3MM2细胞接种于雄性裸鼠胫骨内。3天后，小鼠(每组20只)随机分为5周，分别给予口服和注射水(对照组)、每日口服STI571、每周注射紫杉醇或STI571加紫杉醇治疗。然后取骨和周围肌肉的病变进行组织学、Western blotting(PDGF-R磷酸化)、免疫组织化学(促血管生成分子的表达)和双重免疫荧光(以识别内皮细胞和凋亡的肿瘤细胞)分析。用数字X线片监测病变的生长情况。对照组小鼠骨损伤建立短期细胞培养，用于分析PDGF-R的磷酸化。所有的统计检验都是双面的。结果：体外培养的PC-3MM2细胞经STI571处理后，其PDGF-R的磷酸化程度低于未经处理的PC-3MM2细胞。在对照组小鼠中，骨损伤表达高水平的PDGF并激活(即磷酸化)PDGF-R，而邻近肌肉组织的损伤则不表达。活化的PDGF-R存在于骨损伤内皮细胞的表面，而不存在于未注射的骨内皮细胞。与水或紫杉醇单独治疗的小鼠相比，STI571或STI571加紫杉醇治疗的小鼠肿瘤发生率更低，肿瘤更小，骨溶解和淋巴结转移更少(均P<；.001)。与对照组相比，接受STI571或STI571加紫杉醇治疗的小鼠肿瘤细胞和肿瘤相关内皮细胞上的PDGF-R磷酸化较少，肿瘤细胞增殖较少，肿瘤细胞凋亡显著增多(均P<0.01)，肿瘤相关内皮细胞较少(P<0.01)。结论：当内皮细胞暴露于表达PDGF的肿瘤细胞时，它们似乎表达磷酸化的PDGF-R。使用STI571抑制PDGF-R的磷酸化，特别是与紫杉醇联合使用，可能会对前列腺癌的骨转移产生实质性的治疗效果。
Background: Expression of platelet-derived growth factor (PDGF) and activation (by autophosphorylation) of its receptor (PDGF-R), a tyrosine kinase, are associated with the growth of metastatic prostate tumor cells in the bone parenchyma. The tyrosine kinase inhibitor STI571 blocks the PDGF signaling pathway by inhibiting PDGF-R autophosphorylation. We examined the effects of STI571, given alone or with paclitaxel (Taxol), on tumor growth in a mouse model of prostate cancer metastasis. Methods: Human prostate cancer PC-3MM2 cells were injected into the tibias of male nude mice. Three days later the mice (20 per group) were randomly assigned to 5 weeks of treatment with oral and injected water (control), daily oral STI571, weekly injected paclitaxel, or STI571 plus paclitaxel. Lesions in bone and the surrounding muscles were then harvested and analyzed by histology, western blotting (for PDGF-R phosphorylation),immunohistochemistry (for expression of proangiogenic molecules), and double immunofluorescence (to identify endothelial cells and apoptotic tumor cells). Growth of bone lesions was monitored by digital radiography. Bone lesions from control mice were used to establish short-term cell cultures for analysis of PDGF-R phosphorylation. All statistical tests were two-sided. Results: PC-3MM2 cells cultured from bone lesions and treated in vitro with STI571 had less phosphorylated PDGF-R than untreated cells. In control mice, bone lesions expressed high levels of PDGF and activated (i.e., phosphorylated) PDGF-R, whereas lesions in the adjacent musculature did not. Activated PDGF-R was present on the surface of endothelial cells within the bone lesions but not in endothelial cells of uninjected bone. Mice treated with STI571 or STI571 plus paclitaxel had a lower tumor incidence, smaller tumors, and less bone lysis and lymph node metastasis than mice treated with water or paclitaxel alone (P < .001 for all). Mice treated with STI571 or STI571 plus paclitaxel had less phosphorylated PDGF-R on tumor cells and tumor-associated endothelial cells, less tumor cell proliferation, statistically significantly more apoptotic tumor cells (all P < .001), and fewer tumor-associated endothelial cells (P < .001) than control mice. Conclusions: Endothelial cells appear to express phosphorylated PDGF-R when they are exposed to tumor cells that express PDGF. Using STI571 to inhibit PDGF-R phosphorylation may, especially in combination with paclitaxel, produce substantial therapeutic effects against prostate cancer bone metastasis.