Gioni Vassiliki, Karampinas Theodoros, Voutsinas Gerassimos, Roussidis Andreas E, Papadopoulos Savvas, Karamanos Nikos K, Kletsas Dimitris
Laboratory of Cell Proliferation and Ageing, Institute of Biology, National Center for Scientific Research "Demokritos," 153 10 Athens, Greece.
Mol Cancer Res. 2008 May;6(5):706-14. doi: 10.1158/1541-7786.MCR-07-0355.
Tumor stroma plays an important role in cancer development. In a variety of tumors, such as breast carcinomas, a desmoplastic response, characterized by stromal fibroblast and collagen accumulation, is observed having synergistic effects on tumor progression. However, the effect of known anticancer drugs on stromal cells has not been thoroughly investigated. Imatinib mesylate is a selective inhibitor of several protein tyrosine kinases, including the receptor of platelet-derived growth factor, an important mediator of desmoplasia. Recently, we have shown that imatinib inhibits the growth and invasiveness of human epithelial breast cancer cells. Here, we studied the effect of imatinib on the proliferation and collagen accumulation in breast stromal fibroblasts. We have shown that it blocks the activation of the extracellular signal-regulated kinase and Akt signaling pathways and up-regulates cyclin-dependent kinase inhibitor p21(WAF1), leading to the inhibition of fibroblast proliferation, by arresting them at the G(0)/G(1) phase of the cell cycle. Imatinib inhibits more potently the platelet-derived growth factor-mediated stimulation of breast fibroblast proliferation. By using specific inhibitors, we have found that this is due to the inhibition of the Akt pathway. In addition, imatinib inhibits fibroblast-mediated collagen accumulation. Conventional and quantitative PCR analysis, as well as gelatin zymography, indicates that this is due to the down-regulation of mRNA synthesis of collagen I and collagen III-the main collagen types in breast stroma-and not to the up-regulation or activation of collagenases matrix metalloproteinase 2 and matrix metalloproteinase 9. These data indicate that imatinib has an antifibrotic effect on human breast stromal fibroblasts that may inhibit desmoplastic reaction and thus tumor progression.
肿瘤基质在癌症发展过程中发挥着重要作用。在多种肿瘤中，如乳腺癌，会观察到一种以基质成纤维细胞和胶原蛋白积聚为特征的促纤维增生反应，该反应对肿瘤进展具有协同作用。然而，已知抗癌药物对基质细胞的影响尚未得到充分研究。甲磺酸伊马替尼是几种蛋白酪氨酸激酶的选择性抑制剂，包括血小板衍生生长因子受体，而血小板衍生生长因子是促纤维增生的重要介质。最近，我们发现伊马替尼可抑制人上皮性乳腺癌细胞的生长和侵袭能力。在此，我们研究了伊马替尼对乳腺基质成纤维细胞增殖和胶原蛋白积聚的影响。我们发现它可阻断细胞外信号调节激酶和Akt信号通路的激活，并上调细胞周期蛋白依赖性激酶抑制剂p21（WAF1），通过使成纤维细胞停滞于细胞周期的G(0)/G(1)期，从而抑制其增殖。伊马替尼更有效地抑制血小板衍生生长因子介导的乳腺成纤维细胞增殖刺激。通过使用特异性抑制剂，我们发现这是由于Akt信号通路受到抑制所致。此外，伊马替尼还可抑制成纤维细胞介导的胶原蛋白积聚。传统PCR和定量PCR分析以及明胶酶谱分析表明，这是由于乳腺基质中主要的胶原蛋白类型Ⅰ型胶原蛋白和Ⅲ型胶原蛋白的mRNA合成下调，而非由于基质金属蛋白酶2和基质金属蛋白酶9这两种胶原酶的上调或激活。这些数据表明，伊马替尼对人乳腺基质成纤维细胞具有抗纤维化作用，可能会抑制促纤维增生反应，进而抑制肿瘤进展。
