Our objective is to identify molecular factors which contribute to the increased risk of smokers for oral squamous cell carcinoma (OSCC). In the present study, we investigated the effects of cigarette smoke condensate (CSC) on gene expression profiles in different human oral cell phenotypes: normal epidermal keratinocytes (NHEK), oral dysplasia cell lines (Leuk1 and Leuk2), and a primary oral carcinoma cell line (101A). We determined differential gene expression patterns in CSC-exposed versus non-exposed cells using high-density microarray RNA expression profiling and validation by quantitative real-time RT-PCR. A set of 35 genes was specifically up- or down-regulated following CSC treatment (25microg/ml for 24h) by at least 2-fold in any one cell type. Notably, five genes of the cytochrome P450 (CYP1A1, CYP1B1) and aldo-keto reductase (AKR1C1, AKR1C3, AKR1B10) families were highly increased in expression, some of them 15- to 30-fold. The timing and extent of induction for these genes differed among the four cell phenotypes. A potential biological interaction network for the CSC response in oral cells was derived from these data, proposing novel putative response pathways. These CSC-responsive genes presumably participate in the prevention or repair of carcinogen-induced DNA damage in tobacco-related oral carcinogenesis, and may potentially be exploited for determining the severity of exposure and for correcting mutagenic damage in exposed tissues of the oral cavity.
Abstract. Solid tumors and hematological cancers contain small population of tumor cells that are believed to play a critical role in the development and progression of the disease. These cells, named Cancer Stem Cells (CSCs), have been found in leukemia, myeloma, breast, prostate, pancreas, colon, brain and lung cancers. It is also thought that CSCs drive the metastatic spread of cancer. The CSC compartment features a specific and phenotypically defined cell population characterized with self-renewal (through mutations), quiescence or slow cycling, overexpression of anti-apoptotic proteins, multidrug resistance and impaired differentiation. CSCs show resistance to a number of conventional therapies, and it is believed that this explains why it is difficult to completely eradicate the disease and why recurrence is an ever-present threat. A hierarchical phenomenological model is proposed based on eight compartments following the stem cell lineage at the normal and cancer cell levels. As an empirical test, the tumor grading and progression, typically collected in the pathologic lab, is used to correlate the outcome of this model with the tumor development stages. In addition, the model is able to quantitatively account for the temporal development of the population of observed cell types. Two types of therapeutic treatment models are considered, with dose-density chemotherapy (a pulsatile scenario) as well as continuous, metronomic delivery. The drug hit is considered at the stem cell progenitor and early differentiated specialized cell levels for both normal and cancer cells, while the quiescent stem cell and fully differentiated compartments are considered favorable outcome for cancer treatment. Circulating progenitors are neglected in this analysis. The model provides a number of experimentally testable predictions. The relative importance of the cell kill and survival is demonstrated through a deterministic parametric study. The significance of the stem cell compartment is underlined based on this simulation study. This predictive mathematical model for cancer stem cell hypothesis is used
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