Search

Smoking is the most important known risk factor for the development of lung cancer. Tobacco exposure results in chronic inflammation, tissue injury, and repair. A recent hypothesis argues for a stem/progenitor cell involved in airway epithelial repair that may be a tumor-initiating cell in lung cancer and which may be associated with recurrence and metastasis. We used immunostaining, quantitative real-time PCR, Western blots, and lung cancer tissue microarrays to identify subpopulations of airway epithelial stem/progenitor cells under steady-state conditions, normal repair, aberrant repair with premalignant lesions and lung cancer, and their correlation with injury and prognosis. We identified a population of keratin 14 (K14)-expressing progenitor epithelial cells that was involved in repair after injury. Dysregulated repair resulted in the persistence of K14+ cells in the airway epithelium in potentially premalignant lesions. The presence of K14+ progenitor airway epithelial cells in NSCLC predicted a poor prognosis, and this predictive value was strongest in smokers, in which it also correlated with metastasis. This suggests that reparative K14+ progenitor cells may be tumor-initiating cells in this subgroup of smokers with NSCLC., ((c)2010 AACR.)

The inducible form of cyclooxygenase (COX), COX-2, is up-regulated in many epithelial cancers and its prostaglandin products increase proliferation, enhance angiogenesis, and inhibit apoptosis in several tissues. Pharmacologic inhibition and genetic deletion studies showed a marked reduction of tumor development in colon and skin. COX-2 has also been strongly implicated in urinary bladder cancer primarily by studies with nonselective COX- and COX-2-selective inhibitors. We now show that forced expression of COX-2, under the control of a keratin 5 promoter, is sufficient to cause transitional cell hyperplasia (TCH) in 17% and 75% of the heterozygous and homozygous transgenic lines, respectively, in an age-dependent manner. TCH was strongly associated with inflammation, primarily nodules of B lymphocytes; some T cells and macrophage infiltration were also observed. Additionally, transitional cell carcinoma was observed in approximately 10% of the K5.COX-2 transgenic mice; no TCH or transitional cell carcinoma was observed in wild-type bladders. Immunohistochemistry for vascular proliferation and vascular endothelial growth factor showed significant increases above that in wild-type urinary bladders. Our results suggest that overexpression of COX-2 is sufficient to cause hyperplasia and carcinomas in the urinary bladder. Therefore, inhibition of COX-2 should continue to be pursued as a potential chemopreventive and therapeutic strategy.

To directly evaluate the role of increased ornithine decarboxylase (ODC) and polyamines in mouse skin carcinogenesis, we used bovine keratin 5 (K5) and keratin 6 (K6) promoter elements to direct the expression of antizyme (AZ) to specific skin cell populations. AZ is a multifunctional regulator of polyamine metabolism that inhibits ODC activity, stimulates ODC degradation, and suppresses polyamine uptake. K5-AZ mice treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) at 0 and 24 h exhibit increases in epidermal and dermal ODC activity that are reduced in magnitude. K6-AZ mice treated similarly do not show any increased ODC activity or protein after a second application due to TPA-induced expression of AZ protein. Epidermal and dermal polyamine content, particularly spermidine, is reduced in untreated K5-AZ mice and TPA-treated K5-AZ and K6-AZ mice. Susceptibility to 7,12-dimethylbenz(a)anthracene/TPA carcinogenesis was also investigated for two K6-AZ transgenic lines [K6-AZ(52) and K6-AZ(18)] and a single K5-AZ line. K6-AZ(52) mice had a substantial delay in tumor onset and a >80% reduction in tumor multiplicity compared with normal littermates. K6-AZ(18) and K5-AZ mice also developed fewer papillomas than littermate controls (35% and 50%, respectively), and the combination of these lines to produce double transgenic animals yielded an additive decrease (70%) in tumor multiplicity. These mice demonstrate for the first time that AZ suppresses tumor growth in an animal cancer model and provide a valuable model system to evaluate the role of ODC and polyamines in skin tumorigenesis.