title: A role for fibroblasts in mediating the effects of tobacco-induced epithelial cell growth and invasion.
abstract: 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.
authors.affiliation: California Pacific Medical Center, Research Institute, San Francisco, CA 94107, USA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Coppe
authors.forename: Megan
authors.initials: M
authors.lastname: Boysen
authors.forename: Chung Ho
authors.initials: CH
authors.lastname: Sun
authors.forename: Brian J F
authors.initials: BJ
authors.lastname: Wong
authors.forename: Mo K
authors.initials: MK
authors.lastname: Kang
authors.forename: No-Hee
authors.initials: NH
authors.lastname: Park
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Desprez
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
authors.forename: Ana
authors.initials: A
authors.lastname: Krtolica
mesh_terms: D001485:Basement Membrane / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002450:Cell Communication; D016764:Cell Polarity; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D004249:DNA Damage; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D007633:Keratins / Q000378:metabolism; D009055:Mouth / Q000166:cytology; D018384:Oxidative Stress; D010641:Phenotype; D040081:Protein Array Analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000166:cytology; D012995:Solubility
chemical_list: D015415:Biomarkers; D017077:Culture Media, Conditioned; C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species; D007633:Keratins