Inhibition of platelet-derived growth factor receptor phosphorylation by STI571 (Gleevec) reduces growth and metastasis of human pancreatic carcinoma in an orthotopic nude mouse model.
Inhibition of platelet-derived growth factor receptor phosphorylation by STI571 (Gleevec) reduces growth and metastasis of human pancreatic carcinoma in an orthotopic nude mouse model.
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发表时间：
2003-12
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通讯作者：
R. Hwang;K. Yokoi;C. Bucana;R. Tsan;J. Killion;Douglas B. Evans;I. Fidler
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作者：
R. Hwang;K. Yokoi;C. Bucana;R. Tsan;J. Killion;Douglas B. Evans;I. Fidler
目的研究血小板衍生生长因子（PDGF）配体和受体在人胰腺腺癌临床标本中的表达，并测定PDGF受体蛋白酪氨酸激酶抑制剂STI571 （Gleevec）对裸鼠胰腺和肝脏中生长的人胰腺癌细胞的治疗作用。实验设计对31例人胰腺癌和L3.6pl人胰腺腺癌细胞进行PDGF-AA和-BB配体、pdgfr - α和- β、磷酸化pdgfr - α和- β的免疫组化染色。为了确定STI571在体内的作用，7天后将裸小鼠胰腺注射L3.6pl细胞，随机接受无菌水p.o（对照）、STI571、吉西他滨或STI571和吉西他滨的联合治疗。结果在31例人类胰腺腺癌临床标本中，29例肿瘤细胞和肿瘤相关内皮细胞均表达磷酸化的pdgfr - α和- β。培养液中生长的L3.6pl细胞表达适度的PDGF- aa，很少或不表达pdgfr - α或- β，而裸小鼠胰腺中生长的L3.6pl细胞表达高水平的PDGF和受体。共定位免疫组织化学分析表明，胰腺和肝脏转移灶中肿瘤相关内皮细胞表达活化的pdgfr - β。用STI571（每天50 mg/kg或100 mg/kg）治疗4周的小鼠肿瘤略小于对照组。与对照组相比，吉西他滨和STI571 （50 mg/kg）联合治疗的小鼠肿瘤体积小约70%，比仅用吉西他滨治疗的小鼠肿瘤体积小36% （P < 0.0002和P < 0.04）。联合治疗也能抑制自发性肝转移。用STI571和吉西他滨处理小鼠肿瘤后，活化（磷酸化）pdgfr - α和- β的表达降低，平均血管密度降低，细胞增殖减少，肿瘤细胞凋亡增加。综上所述，这些数据表明，激活肿瘤细胞和肿瘤内皮细胞的PDGFR可能是胰腺癌治疗的新靶点。
PURPOSE We evaluated the expression of platelet-derived growth factor (PDGF) ligands and receptors in clinical specimens of human pancreatic adenocarcinomas and determined the therapeutic effect of STI571 (Gleevec), a protein tyrosine kinase inhibitor of PDGF receptor (PDGFR), on human pancreatic carcinoma cells growing in the pancreas and liver of nude mice. EXPERIMENTAL DESIGN Immunohistochemical staining for PDGF-AA and -BB ligands, PDGFR-alpha and -beta, and phosphorylated PDGFR-alpha and -beta was performed on 31 specimens of human pancreatic cancer and L3.6pl human pancreatic adenocarcinoma cell line. To determine the in vivo effects of STI571, nude mice with L3.6pl cells injected into the pancreas were randomized 7 days later to receive one of the following treatments: sterile water p.o. (control), STI571, gemcitabine, or a combination of STI571 and gemcitabine. RESULTS In 29 of 31 clinical specimens of human pancreatic adenocarcinoma, both tumor cells and tumor-associated endothelial cells expressed phosphorylated PDGFR-alpha and -beta. L3.6pl cells growing in culture expressed moderate amounts of PDGF-AA and little to no PDGFR-alpha or -beta, whereas L3.6pl cells growing in the pancreas of nude mice expressed a high level of PDGF and receptors. Colocalization immunohistochemical analysis demonstrated expression of activated PDGFR-beta by tumor-associated endothelial cells in both the pancreas and in liver metastases. Tumors of mice treated for 4 weeks with STI571 (50 mg/kg or 100 mg/kg p.o. daily) were slightly smaller than controls. Tumors treated with gemcitabine and STI571 (50 mg/kg) were >70% smaller than tumors in control mice and 36% smaller than those in mice treated with gemcitabine only (P < 0.0002 and P < 0.04, respectively). Combination therapy also inhibited spontaneous metastasis to the liver. Tumors from mice treated with both STI571 and gemcitabine had decreased expression of activated (phosphorylated) PDGFR-alpha and -beta, decreased mean vessel density, decreased cell proliferation, and increased apoptosis of tumor cells. CONCLUSIONS Collectively, these data show that activated PDGFR on tumor cells and tumor-endothelial cells can be a novel target for therapy of pancreatic carcinoma.