A role for fibroblasts in mediating the effects of tobacco-induced epithelial cell growth and invasion.
A role for fibroblasts in mediating the effects of tobacco-induced epithelial cell growth and invasion.
复制标题
成纤维细胞在介导烟草诱导的上皮细胞生长和侵袭的作用中的作用。
DOI：
10.1158/1541-7786.mcr-08-0062
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发表时间：
2008-07
期刊：
影响因子：
--
通讯作者：
Krtolica A
中科院分区：
文献类型：
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作者：
Coppe JP;Boysen M;Sun CH;Wong BJ;Kang MK;Park NH;Desprez PY;Campisi J;Krtolica A
香烟烟雾和无烟烟草提取物含有多种致癌化合物，但对慢性暴露于致癌物（如烟草制品中存在的致癌物）后肿瘤发生和发展的机制知之甚少。在这里，我们研究了无烟烟草提取物对人口腔成纤维细胞的影响。我们发现，无烟烟草提取物以剂量依赖的方式提高了细胞内活性氧、氧化性DNA损伤和DNA双链断裂的水平。长时间暴露于提取物诱导成纤维细胞进行衰老样生长停滞，伴随着分泌表型的显著变化。使用无烟烟草提取物暴露的成纤维细胞和永生化但非致瘤性角质形成细胞的共培养物，我们进一步表明，提取物修饰的成纤维细胞分泌的因子增加部分转化的上皮细胞的增殖和侵袭力，但不是它们的正常对应物。此外，暴露于无烟烟草提取物的成纤维细胞导致部分转化的角质形成细胞失去E-钙粘蛋白和ZO-1以及外皮蛋白的表达，这些变化表明上皮功能受损，通常与恶性进展相关。总之，我们的研究结果表明，成纤维细胞可能有助于间接增加上皮细胞的侵略性肿瘤的发生。因此，烟草不仅可以在上皮细胞中引发突变变化，而且还可以通过创造前致癌基质环境来促进突变细胞的生长和侵袭。
Cigarette smoke and smokeless tobacco extracts contain multiple carcinogenic compounds, but little is known about the mechanisms by which tumors develop and progress upon chronic exposure to carcinogens such as those present in tobacco products. Here, we examine the effects of smokeless tobacco extracts on human oral fibroblasts. We show that smokeless tobacco extracts elevated the levels of intracellular reactive oxygen, oxidative DNA damage, and DNA double-strand breaks in a dose-dependent manner. Extended exposure to extracts induced fibroblasts to undergo a senescence-like growth arrest, with striking accompanying changes in the secretory phenotype. Using cocultures of smokeless tobacco extracts–exposed fibroblasts and immortalized but nontumorigenic keratinocytes, we further show that factors secreted by extracts-modified fibroblasts increase the proliferation and invasiveness of partially transformed epithelial cells, but not their normal counterparts. In addition, smokeless tobacco extracts–exposed fibroblasts caused partially transformed keratinocytes to lose the expression of E-cadherin and ZO-1, as well as involucrin, changes that are indicative of compromised epithelial function and commonly associated with malignant progression. Together, our results suggest that fibroblasts may contribute to tumorigenesis indirectly by increasing epithelial cell aggressiveness. Thus, tobacco may not only initiate mutagenic changes in epithelial cells but also promote the growth and invasion of mutant cells by creating a procarcinogenic stromal environment.