EFFECTS OF TOBACCO-INDUCED EPITHELIAL CANCERS MEDIATED BY STROMAL FIBROBLASTS

间质成纤维细胞介导的烟草诱发上皮癌的影响

• 批准号: 7365639
• 负责人: CHUNG-HO SUN
• 金额: $ 0.96万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7365639
• 关键词: EFFECTS; TOBACCO; INDUCED; EPITHELIAL; CANCERS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tobacco use increases the risk of developing cancers of the oral cavity and respiratory tract. Although cigarette smoke and smokeless tobacco extract contain multiple compounds that can induce potentially oncogenic mutations, little is known about the mechanisms by which tumors develop in chronic tobacco users. Here, we examine the effects of smokeless tobacco extracts (STE) on human skin and oral fibroblasts. We show that STE elevated the levels of intracellular reactive oxygen, oxidative DNA damage and DNA double-strand breaks in a dose-dependent manner. Extended exposure to STE induced fibroblasts to undergo a senescence-like growth arrest, with striking accompanying changes in the secretory phenotype. Using co-cultures of STE-exposed fibroblasts and immortalized but non-tumorigenic keratinocytes (partially transformed epithelial cells), we further show that factors secreted by STE-modified fibroblasts alter the proliferation and invasiveness of partially transformed epithelial cells, but not their normal counterparts. In addition, STE-exposed fibroblasts caused partially transformed epithelial cells to lose expression of E-cadherin and ZO-1 (markers of cell polarization), as well as of involucrin (marker of keratinization), changes that are indicative of compromised epithelial function and commonly associated with malignant transformation. Together, our results suggest that fibroblasts may contribute to tobacco-induced carcinogenesis indirectly by promoting malignant transformation of epithelial cells. Thus, tobacco may not only initiate mutagenic changes, but also promote growth of mutant cells by creating procarcinogenic tissue microenvironment mediated by the stroma.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。吸烟会增加患口腔癌和呼吸道癌的风险。虽然香烟烟雾和无烟烟草提取物含有多种可诱导潜在致癌突变的化合物，但对慢性烟草使用者中肿瘤发生的机制知之甚少。在这里，我们研究了无烟烟草提取物（STE）对人类皮肤和口腔成纤维细胞的影响。我们发现，STE升高细胞内活性氧，氧化DNA损伤和DNA双链断裂的水平在剂量依赖性的方式。延长暴露于STE诱导成纤维细胞经历衰老样生长停滞，伴随着分泌表型的显著变化。使用共培养的ST暴露的成纤维细胞和永生化的，但非致瘤性角质形成细胞（部分转化的上皮细胞），我们进一步表明，由ST修饰的成纤维细胞分泌的因子改变部分转化的上皮细胞的增殖和侵袭性，但不是他们的正常对应物。此外，ST暴露的成纤维细胞导致部分转化的上皮细胞失去E-钙粘蛋白和ZO-1（细胞极化的标志物）以及外皮蛋白（角化的标志物）的表达，这些变化表明上皮功能受损，通常与恶性转化相关。总之，我们的研究结果表明，成纤维细胞可能有助于烟草诱导的癌间接促进上皮细胞的恶性转化。因此，烟草不仅可以引发突变变化，而且可以通过基质介导的前致癌组织微环境来促进突变细胞的生长。