Targeting the expression of platelet-derived growth factor receptor by reactive stroma inhibits growth and metastasis of human colon carcinoma
Targeting the expression of platelet-derived growth factor receptor by reactive stroma inhibits growth and metastasis of human colon carcinoma
复制标题
DOI：
10.2353/ajpath.2006.060653
复制
发表时间：
2006-12-01
影响因子：
6
通讯作者：
Fidler, Isaiah J.
中科院分区：
文献类型：
--
作者：
Kitadai, Yasuhiko;Sasaki, Takamitsu;Fidler, Isaiah J.
结肠癌中的基质细胞表达高水平的血小板衍生生长因子受体（PDGF-R），而结肠癌细胞不表达。在这里，我们研究了阻断PDGF-R是否可以抑制体内结肠癌的生长。将KM 12 SM人结肠癌细胞皮下注射（异位植入）到裸鼠的盲肠壁（原位植入）或脾脏（实验性肝转移）中。在结肠和肝脏中，肿瘤诱导活跃的间质反应，而在皮下组织中，间质反应是最小的。小鼠组（n = 10）接受生理盐水（对照）、酪氨酸激酶抑制剂伊马替尼、伊立替康或伊马替尼和伊立替康的组合。伊马替尼和伊立替康治疗4周可显著抑制盲肠中的肿瘤生长（相对于对照或单药治疗）。和肝脏但皮下组织没有联合治疗可完全抑制淋巴结转移。伊马替尼单独或与伊立替康联合可抑制肿瘤相关基质细胞和周细胞的PDGF-R β磷酸化。联合治疗也显着减少基质。反应、肿瘤细胞增殖和肿瘤微血管的周细胞覆盖以及肿瘤细胞和肿瘤相关基质细胞的凋亡增加。这些数据表明，阻断肿瘤相关基质细胞和周细胞中的PDGF-R信号传导途径可抑制结肠癌细胞的进行性生长和转移。
The stromal cells within colon carcinoma express high levels of the platelet-derived growth factor receptor (PDGF-R), whereas colon cancer cells do not. Here, we examined whether blocking PDGF-R could inhibit colon cancer growth in vivo. KM12SM human colon cancer cells were injected subcutaneously (ectopic implantation) into the cecal wall (orthotopic implantation) or into the spleen (experimental liver metastasis) of nude mice. in the colon and liver, the tumors induced active stromal reaction, whereas in the subcutis, the stromal reaction was minimal. Groups of mice (n = 10) received saline (control), the tyrosine kinase inhibitor imatinib, irinotecan, or a combination of imatinib and irinotecan. Four weeks of treatment with imatinib and irinotecan significantly inhibited tumor growth (relative to control or single-agent therapy) in the cecum. and liver but not in the subcutis. The combination therapy completely inhibited lymph node metastasis. Imatinib alone or in combination with irinotecan inhibited phosphorylation of PDGF-R beta of tumor-associated stromal cells and pericytes. Combination therapy also significantly decreased stromal. reaction, tumor cell proliferation, and pericyte coverage of tumor microvessels and increased apoptosis of tumor cells and tumor-associated stromal cells. These data demonstrate that blockade of PDGF-R signaling pathways in tumor-associated stromal cells and pericytes inhibits the progressive growth and metastasis of colon cancer-cells.