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.
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