Renal cell carcinoma (RCC) accounts for 3% of adult deaths from cancer. The risk factors for its development are still under intense investigation. Although tobacco smoke is a risk factor, the data are inconsistent and the extent of the increased risk is unclear. Estimates from 19 case-control and 5 cohort studies were used. The case-control reports included 8,032 cases and 13,800 controls; the cohort estimates were based on 1,457,754 participants with 1,326 cases of RCC. The relative risk (RR) for RCC for ever smokers as compared to lifetime never smokers was 1.38 (95% confidence interval [CI] = 1.27-1.50). The RR for male smokers was 1.54 (95% CI = 1.42-1.68) and for female smokers was 1.22 (95% CI = 1.09-1.36). For men and women there was a strong dose-dependent increase in risk. Ever smoker men who had smoked 1-9, 10-20 or 21 or more cigarettes/day had a RR of 1.60 (95% CI = 1.21-2.12), 1.83 (95% CI = 1.30-2.57), or 2.03 (95% CI = 1.51-2.74), respectively. For women, the relative risks were 0.98 (95% CI = 0.71-1.35), 1.38 (95% CI = 0.90-2.11), or 1.58 (95% CI = 1.14-2.20), respectively. The advantages of smoking cessation were confirmed by a reduction in RR for those who had quit smoking for >10 years as compared to those who had quit for 1-10 years. Inhaled tobacco smoke is clearly implicated in the etiology of RCC, with a strong dose-dependent increase in risk associated with numbers of cigarettes smoked per day and a substantial reduction in risk for long-term former smokers.

TP53 mutations are common in lung cancers of smokers, with high prevalence of G:C-to-T:A transversions generally interpreted as mutagen fingerprints of tobacco smoke. In this study, TP53 (exons 5-9) and KRAS (codon 12) were analyzed in primary lung tumors of never (n = 40), former (n = 27), and current smokers (n = 64; mainly heavy smokers). Expression of p53, cyclooxygenase-2 (Cox-2), and nitrotyrosine (N-Tyr), a marker of protein damage by nitric oxide, were analyzed by immunohistochemistry. TP53 mutations were detected in 47.5% never, 55.6% former, and 77.4% current smokers. The relative risk for mutation increased with tobacco consumption (P linear trend < 0.0001). G:C-to-T:A transversions (P = 0.06, current versus never smokers) and A:T-to-G:C transitions (P = 0.03, former versus never smokers) were consistently associated with smoking. In contrast, G:C-to-A:T transitions were associated with never smoking (P = 0.02). About half of mutations in current smokers fell within a particular domain of p53 protein, suggesting a common structural effect. KRAS mutations, detected in 20 of 131 (15.3%) cases, were rare in squamous cell carcinoma compared with adenocarcinoma [relative risk (RR), 0.2; 95% confidence interval (95% CI), 0.07-1] and were more frequent in former smokers than in other categories. No significant differences in Cox-2 expression were found between ever and never smokers. However, high levels of N-Tyr were more common in never than ever smokers (RR, 10; 95% CI, 1.6-50). These results support the notion that lung tumorigenesis proceeds through different molecular mechanisms according to smoking status. In never smokers, accumulation of N-Tyr suggests an etiology involving severe inflammation. (Cancer Res 2005; 65(12): 5076-83)

Platelet-activating factor (PAF) is a potent proinflammatory phospholipid with multiple pathological and physiological effects. We have shown that basic fibroblast growth factor (bFGF) supplementation induces rapid proliferation of human umbilical vein endothelial cells (HUVEC), which is reduced upon removal of bFGF or by bFGF immunoneutralization. The PAF receptor antagonist LAU-8080 inhibited bFGF-stimulated HUVEC proliferation, indicating the involvement of PAF in the bFGF-mediated signaling of HUVEC. Although FGF receptor phosphorylation was not affected by LAU-8080, the bFGF-mediated prolonged phosphorylation, and activation of Erk-1 and -2 were attenuated. Phosphorylation of STAT-3 was observed in the presence of PAF or bFGF, which was attenuated by PAFR antagonists. PAF-induced STAT-3 phosphorylation observed in HUVEC pretreated with either Src inhibitor PP1 or JAK-2 inhibitor AG-490 indicated (i) immediate (1 min) phosphorylation of STAT-3 is dependent on Src, (ii) JAK-2-dependent STAT-3 phosphorylation occurs after the delayed (30 min) PAF exposure, and (iii) prolonged (60 min) STAT-3 phosphorylation may be either through Src and/or JAK-2. Attenuation of the STAT-3 phosphorylation by the PAFR antagonists indicated signaling through the PAF receptor. Taken together, these findings suggest the production of PAF is important for bFGF-mediated signaling and that a dual kinase mechanism is involved in the PAF-mediated signal transduction cascade.is an ether phospholipid second messenger that mediates a number of biological responses, including inflammatory and immune responses, shock, embryogenesis, and cell differentiation (for review, see Ref. 1). PAF is also a potent mediator of pathological angiogenesis associated with tumor expansion and metastasis (2, 3). Hepatocyte growth factor, tumor necrosis factor-␣, and thrombopoietin have been shown to induce angiogenesis through a mechanism involving PAF (4, 5). Many cells produce PAF, including monocytes, endothelial cells, neutrophils, and lymphocytes, and these cell types can themselves become targets of PAF bioactions (6). PAF acts through a specific Gprotein-linked receptor containing seven ␣-helical domains that span the plasma membrane (7) and has been localized to the plasmalemma (8) and a large endosomal compartment on human umbilical vein endothelial cells (HUVEC) (9). PAF also up-regulates the expression of its own receptor in several cell types including human alveolar macrophages (10) and rat epithelial cells (11), thus potentially providing a positive feedback loop for PAF action.Of the 20 members of the FGF family of growth factors, only acidic FGF and basic FGF (bFGF) have been shown to regulate proliferation and migration of capillary endothelial cells (for review, see Refs. 12 and 13). Although bFGF does not contain a traditional signal sequence, it is now clear that it is secreted via a tightly regulated non-conventional secretory pathway and is localized in the basement membrane and extracellular matrix of numerous tissues (14). bFGF binds t...

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