Buffering capacity of the smoke of different tobaccos in relation to lung cancer risks.

A method of assessing "buffering capacity" is described for comparison of the degree of acidity of alkalinity of the smoke of different tobaccos as presented to the oral and respiratory tracts of the smoker. Nicotine is more readily absorbed from an alkaline than from an acid smoke. The smoker of tobaccos giving a smoke of acid buffering capacity, in order to achieve full nicotine satisfaction, tends to smoke more and to inhale more, thus increasing lung cancer risks, than the smoker of tobaccos giving smoke of less acid or of alkaline buffering capacity.     

Strain-dependent differences in susceptibility to lung cancer in inbred mice exposed to mainstream cigarette smoke

It is becoming increasingly clear that genetic susceptibility is an important host factor determining the effects of exposure to a number of airborne particles and gases. Although numerous studies have identified a genetic component for spontaneous pulmonary tumor development and for chemically induced lung cancer (e.g., urethane) in mice, a systematic examination of murine inter-strain differences in response to cigarette smoke inhalation has not been conducted. We addressed this research gap by examining the strain distribution pattern of lung cancer in nine inbred strains of mice exposed to 258 mg/m³ mainstream cigarette smoke for 5 months followed by 4 months of rest. Lung tumors were enumerated on fixed lungs visualized at low magnification and on serial step sections examined microscopically. With the low magnification examination, we observed statistically significant increases in the number of lung tumors in cigarette smoke-exposed A/J and the genetically-related A/HeJ mice (p < 0.05). While fewer tumors were identified by the microscopic enumeration method, it confirmed that significant increases in lung tumors occurred only in A/J and A/HeJ mice exposed to cigarette smoke (p < 0.05). Thus, as predicted by epidemiologic studies and animal experiments using chemically induced lung cancer models, these findings suggest that genetic host factors play a significant role in the pulmonary tumorigenic response of mice to mainstream cigarette smoke.     

Cigarette,cigar and pipe smoking,passive smoke exposure,and risk of pancreatic cancer: a population-based study in the San Francisco Bay Area

Background  

To examine the influence of cigarette, cigar and pipe smoking, cessation of cigarette smoking and passive smoke exposure on the risk of pancreatic cancer.     

Risk of lung cancer among cigarette and pipe smokers in southern China.

Studies in Shanghai and in north-east China indicate that cigarette smoking is a major contributor to the high rates of lung cancer in those areas, but doubts persist regarding the influence of cigarette use on lung cancer rates in other areas of China. In addition, the risk of lung cancer associated with other methods of tobacco consumption--in particular, the use of bamboo water-pipes and long-stem pipes--is uncertain. A population-based case-control study of 427 male lung cancer patients residing in a mining area of Southern China and 1,011 controls was carried out to address this and other issues. Of these patients, 63% smoked cigarettes and (water and long-stem) pipes; 17% and 14% smoked only cigarettes or pipes, respectively; and 6% did not smoke. Compared to non-smokers, smokers of cigarettes only, smokers of pipes only and mixed smokers were at increased risk; OR = 2.6 (95% CI 1.1-6.2), 1.8 (95% CI 0.8-4.2) and 4.1 (95% CI 2.3-9.2), respectively. Risk increased with duration of tobacco use; however, the rate of increase with years of cigarette use was significantly greater than for years of pipe use (p = 0.03). In addition, risks increased 8-fold in the highest quartile of number of cigarettes per day compared to non-cigarette smokers vs. 2.3-fold for the highest quartile of number of liang (50 g) smoked per month compared to non-pipe-smokers; the trends in the ORs differed significantly (p less than 0.001). Results suggest that, in this area of China, tobacco use is an important cause of lung cancer, and that smoking cigarettes may be more deleterious than smoking pipes (primarily water pipes).     

Bladder cancer in relation to cigarette smoking

The importance of smoking-related variables in the development of bladder cancer was examined in data from a hospital-based case-control study of 1316 male and 505 female cases, and 3940 male and 1504 female age-matched controls interviewed in 20 hospitals from 9 United States cities between 1969 and 1984. For male current smokers, odds ratios for number of cigarettes smoked per day (cpd) increased to approximately 2.5 for smokers of more than 20 cpd, after adjustment for duration and nonsmoking-related covariates. Above 20 cpd, no further increase in odds ratio was observed. In females, the adjusted odds ratios showed no significant effect of increasing cpd level. In males, the odds ratios for duration increased from 1.18 (0.52-2.72) in those who smoke for less than 20 years to 2.31 (1.65-3.24) in those who smoked for greater than 40 years. In females, the corresponding odds ratios were 0.97 (0.27-3.44) and 1.62 (1.00-2.62). The results did not suggest an increased risk with early age at start of smoking in either sex. Ex-cigarette smokers, as a whole, had reduced odds ratios for bladder cancer, but the extent of the reduction was similar in short-term and longer-term quitters. The findings of this investigations support an association between smoking and bladder cancer. The pattern of risk associated with cpd and duration among current smokers and the early decline in risk associated with quitting are discussed in relation to possible mechanisms of bladder carcinogenesis.     

The biologic effects of cigarette smoke on cancer cells

Smoking is one of the largest preventable risk factors for developing cancer, and continued smoking by cancer patients is associated with increased toxicity, recurrence, risk of second primary cancer, and mortality. Cigarette smoke (CS) contains thousands of chemicals, including many known carcinogens. The carcinogenic effects of CS are well established, but relatively little work has been done to evaluate the effects of CS on cancer cells. In this review of the literature, the authors demonstrate that CS induces a more malignant tumor phenotype by increasing proliferation, migration, invasion, and angiogenesis and by activating prosurvival cellular pathways. Significant work is needed to understand the biologic effect of CS on cancer biology, including the development of model systems and the identification of critical biologic mediators of CS‐induced changes in cancer cell physiology. Cancer 2014;120:3617–3626 . © 2014 American Cancer Society.     

Autophagy in fibroblasts induced by cigarette smoke extract promotes invasion in lung cancer cells

We investigated the effects of cigarette smoke extract (CSE) on lung fibroblasts and found that the invasiveness of lung cancer cells was facilitated by the conditioned medium from CSE-treated fibroblasts. CSE induced autophagy in fibroblasts and increased the expression of autophagy-related proteins, including optineurin and Ras-related protein Rab1B. Afterward, the fibroblasts produced high levels of interleukin-8 (IL-8), which promoted cancer cell invasion. The inhibition of either optineurin or Rab1B abrogated a rise in microtubule-associated protein 1 light chain 3 β and a decrease in p62 protein, as well as the production of IL-8, in CSE-treated fibroblasts. A three-dimensional invasion assay using cancer cell spheroids revealed that the invasion of cancer cells alone and the fibroblast-led cancer cell invasion were both enhanced by the conditioned media from CSE-treated fibroblasts. These results suggest that cigarette smoke may induce autophagy and IL-8 secretion in lung fibroblasts and modify the microenvironment to favor invasion of lung cancer cells.     

Gene expression in the lung of p53 mutant mice exposed to cigarette smoke

We showed previously that p53 mutations play a role in cigarette smoke-related carcinogenesis not only in humans but also in A/J mice. In fact, (UL53-3 x A/J)F(1) mice, carrying a dominant-negative germ-line p53 mutation, responded to exposure to environmental cigarette smoke more efficiently than their wild-type (wt) littermate controls in terms of molecular alterations, cytogenetic damage, and lung tumor yield. To clarify the mechanisms involved, we analyzed by cDNA array the expression of 1,185 cancer-related genes in the lung of the same mice. Neither environmental cigarette smoke nor the p53 status affected the expression of the p53 gene, but the p53 mutation strikingly increased the basal levels of p53 nuclear protein in the lung. Environmental cigarette smoke increased p53 protein levels in wt mice only. The p53 mutation enhanced the expression of positive cell cycle regulators in sham-exposed mice, which suggests a physiologic protective role of p53. In environmental cigarette smoke-exposed mice, the p53 mutation resulted in a lack of induction of proapoptotic genes and in overexpression of genes involved in cell proliferation, signal transduction, angiogenesis, inflammation, and immune response. Mutant mice and wt mice reacted to environmental cigarette smoke in a similar manner regarding genes involved in metabolism of xenobiotics, multidrug resistance, and protein repair. Irrespective of the p53 status, environmental cigarette smoke poorly affected the expression of oncogenes, tumor suppressor genes, and DNA repair genes. Taken together, these findings may explain the increased susceptibility of p53 mutant mice to smoke-related alterations of intermediate biomarkers and lung carcinogenesis.     

The concentrations of five tumor markers in both BAL fractions in lung cancer patients in relation to cigarette smoking

BACKGROUND: Lung cancer is the leading cause of death from cancer. Tobacco is related to the development of this type of tumor due to genetic alterations and to the secretion of certain biological markers. Bronchogenic carcinomas secrete a series of biological substances known as tumor markers. Some of these markers, such as carcinoembryonic antigen, neuron-specific enolase, tissue polypeptide antigen (TPA), tissue polypeptide-specific antigen (TPS) and CYFRA 21.1, possess clear clinical value when analyzed in bronchoalveolar lavage (BAL) of patients with lung malignancies, particularly when they are analyzed in the two BAL fractions, bronchial (BF) and alveolar (AF), being more increased in the BF. For this reason, we intend to demonstrate that smokers with cancer secrete more biological substances in the BF and that the concentrations of these markers are higher in the BAL of smokers than in that of non-smokers. METHODS: The five aforementioned tumor markers were studied in the two BAL fractions of 52 lung cancer patients (46 smokers and 6 non-smokers). We performed BAL using 150 ml of 0.9% saline solution divided in three aliquots of 50 ml. The fluid obtained from the first 50 ml was the BF. The liquid from the other two aliquots was the AF. The five tumor marker concentrations were calculated in accord with the indications of the laboratory. RESULTS: The TPA and TPS levels in the BAL of lung cancer patients were more increased in the BF than in the AF, even when the patients were divided into smokers and non-smokers. When we compared smokers with non-smokers, the smokers had higher levels of TPS in the BF and of TPA in the AF. CONCLUSIONS: Thus, we believe that the cellular alterations produced by tobacco are responsible for the secretion of these tumor markers.     

Urinary pH, cigarette smoking and bladder cancer risk

Glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolite can be rapidly hydrolyzed in acidic urine to undergo further metabolic activation and form DNA adducts in the urothelium. We conducted a large multicenter case-control study in Spain to explore the etiology of bladder cancer and evaluated the association between urine pH and bladder cancer risk, alone and in combination with cigarette smoking. In total, 712 incident urothelial cell carcinoma cases and 611 hospital controls directly measured their urine pH with dipsticks twice a day (first void in the morning and early in the evening) during four consecutive days 2 weeks after hospital discharge. We found that a consistently acidic urine pH ≤6.0 was associated with an increased risk of bladder cancer [odds ratio (OR) = 1.5, 95% confidence interval (CI): 1.2-1.9] compared with all other subjects. Furthermore, risk estimates for smoking intensity and risk of bladder cancer among current smokers tended to be higher for those with a consistently acidic urine (OR = 8.8, 11.5 and 23.8) compared with those without (OR = 4.3, 7.7 and 5.8, respectively, for 1-19, 20-29 and 30+ cigarettes per day; P(interaction) for 30+ cigarettes per day = 0.024). These results suggest that urine pH, which is determined primarily by diet and body surface area, may be an important modifier of smoking and risk of bladder cancer.     

The effect of cigarette smoke on aryl hydrocarbon hydroxylase activity and cytochrome P450 content in rat liver and lung microsomes.

Levels of activity of the enzyme aryl hydrocarbon hydroxylase and cytochrome P450 have been estimated in lung and liver of rats exposed to graded doses of cigarette smoke and in human bronchial mucosa of smokers, non-smokers and patients with lung cancer. Exposure of rats to smoke of four cigarettes increased both hepatic and pulmonary aryl hydrocarbon hydroxylase activity. Exposure to smoke of four cigarettes daily for seven and 14 days did not result in higher aryl hydrocarbon hydroxylase levels in the liver than one day's exposure, but in the lung longer exposures caused greater increases in enzyme activity. Injection of benzo(a)pyrene at two dose levels caused a much greater increase in both liver and lung aryl hydrocarbon hydroxylase than smoking. The lower dose maximally stimulated the enzyme in both organs. The changes in aryl hydrocarbon hydroxylase activity were accompanied by significant increases in both liver weight and the cytochrome P450 content of liver microsomes but the increase in cytochrome P450 did not parallel those in aryl hydrocarbon hydroxylase activity. Of 40 surgical and autopsy specimens of human lung and tracheal mucosa from smokers, non-smokers and cancer patients, only one was found to have detectable aryl hydrocarbon hydroxylase activity. The relationship between aryl hydrocarbon hydroxylase induction by cigarette smoke in human tissues and the development of bronchogenic carcinoma in smokers remains unclear.     

Molecular alterations and lung tumors in p53 mutant mice exposed to cigarette smoke

Mutations and deletions in p53 are the most common genetic lesions in human cancer,and an extraordinarily high incidence of lung cancer occurs in smokers suffering from Li-Fraumeni syndrome, which is characterized by germ-line inactivation of one p53 allele. In contrast, p53 mutations are infrequent in lung tumors formed in A/J mice. Moreover, despite the dominant role of cigarette smoke in the epidemiology of human lung cancer, it is very difficult to reproduce the lung tumorigenicity of this complex mixture in animal models. We used a transgenic mouse with a dominant-negative p53 mutation to examine the effects of a mutant p53 on smoke-induced lung carcinogenesis in mice. p53 mutant (UL53-3 x A/J)F(1) mice of both genders and their wild-type (wt) littermate controls were exposed whole-body to environmental cigarette smoke (ECS) for up to 9.5 months. Untreated mutant mice of both genders underwent an early stimulus of bronchial cell proliferation, and an age-related formation of DNA adducts in lung and heart. In males, there was an age-related increase of micronucleated normochromatic erythrocytes in peripheral blood and an impairment of body weight gain. These findings underscore a physiological protective role of p53 in wt A/J mice. The response of wt and mutant mice to ECS was similar in terms of oxidative DNA damage in lung and heart, proliferation of the bronchial epithelium, and levels of p53 oncoprotein, as assessed after exposure for 28 days. In contrast, ECS-exposed mutant mice underwent a lower induction of apoptosis in bronchial epithelium, a greater formation of DNA adducts in lung and heart, and a more intense cytogenetic damage, shown by a higher frequency of micronuclei in pulmonary alveolar macrophages and in peripheral blood normochromatic erythrocytes. Interestingly, at the end of the experiment, DNA adducts were not repaired in either wt or mutant mice after discontinuing exposure to ECS for 1 week. A weak but significant increase of lung tumor incidence and multiplicity was induced in p53 mutant (UL53-3 x A/J)F(1) mice after exposure to ECS for either 5 months, followed by recovery in air for 4.5 months, or 9.5 continuative months. Conversely, no tumorigenic effect was observed in their wt littermate controls, carrying a 99.9% A/J background and 5% FVB genome. This contrasts with the weakly positive results obtained in previous studies using wt A/J mice. Thus, in agreement with the results of previous lung tumorigenicity studies performed with the smoke carcinogens benzo(a)pyrene and 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone, (UL53-3 x A/J)F(1) mice carrying a mutant p53 transgene appear to be more sensitive to ECS than the corresponding wt littermate controls. These findings provide evidence that p53 mutations play a role in smoke-related carcinogenesis not only in humans but also in A/J mice.     

Lung cancer type in relation to cigarette dosage.

In a retrospective study of 1,228 white males with histologically confirmed bronchogenic carcinoma, the proportion of squamous cell carcinoma increased with increasing age at diagnosis. Since the distribution of cell types was much the same in the 73% of cases aged 50-69, the relationship of cancer type to daily cigarette dosage was studied in this group. Squamous cell carcinoma increased from 48% of those men who smoked less than 20 cigarettes per day to 61% of those who smoked 40 or more cigarettes per day. Comparison with other studies showed conflicting results.     

The relation of passive smoking to lung cancer

To evaluate the role of passive smoking in the development of lung cancer among nonsmokers, data were pooled from three large incident case-control interview studies. Ninety-nine lung cancer cases and 736 controls never used any form of tobacco. Overall the adjusted odds ratio for lung cancer among nonsmokers ever living with a smoker was 0.8 (95% confidence interval, 0.5-1.3) rising to 1.2 among those exposed for 40 or more years. Persons living with a spouse who smoked cigarettes were at increased risk (adjusted odds ratio, 1.5; 95% confidence interval, 0.8-2.8). When adjusted for age and gender, there was a significant trend in risk with increasing amounts smoked per week by the spouse (P = 0.05) and with cumulative pack-years of exposure (P = 0.03). This effect was limited to females, especially older women whose husbands were heavy smokers. The elevated risk associated with spouse smoking was restricted to squamous and small cell carcinomas (odds ratio, 2.9; 95% confidence interval, 0.9-9.3), which provides additional evidence linking passive smoking to lung cancer.