Selective clonal expansion and microenvironmental permissiveness in tobacco carcinogenesis

Abstract

Historically our knowledge about the direct carcinogenic activity of cigarette smoke and its constituents grew from painting experiments on the skin of mice to produce papillomas and carcinomas. The neutral fraction of cigarette smoke condensate had most of the carcinogenic activity in this test and was rich in carcinogenic polycyclic aromatic hydrocarbons (PAHs), the most abundant by far being BP. However, the concentration of BP in the condensate was only about 2% the amount of pure BP required to cause skin tumors. In other fractions there were non-carcinogenic constituents that promoted tumor formation when applied repeatedly to mouse skin that had been initiated by a single subcarcinogenic application of BP. There were also constituents of cigarette smoke that acted as cocarcinogens when applied simultaneously with repeated applications of BP. BP was effective as an initiator at lower concentrations than as a complete carcinogen, and some non-carcinogenic PAHs in the condensate were also active initiators. It was concluded from these studies that cigarette smoke condensate is primarily a tumorpromoting and co-carcinogenic agent with weak activity as a complete carcinogen. A major effect of promoters, and possibly of co-carcinogens, is a diffuse hyperplasia which includes selective expansion of clones carrying endogenous mutations and/or mutations induced by PAHs and other carcinogens such as NNK. The induced mutations as well as damaged cells would occur throughout the exposed region and, along with the hyperplasia, increase the permissiveness of the cellular microenvironment for neoplastic expression of any potential tumor cell in its midst. Since neither the promoters nor co-carcinogens in tobacco smoke are known to interact directly with DNA, their effects can be considered epigenetic processes that act upon genetically altered cells. Examples are cited from studies of experimental skin carcinogenesis, smoking-induced histopathological changes in human lung and spontaneous transformation in cell culture to illustrate the genetic and epigenetic interactions of neoplastic development in general and their significance for smoking-induced lung cancer in particular. Certain dietary modifications that appear to be effective in moderating the promotional phase of animal and human carcinogenesis are suggested for trial in managing lung cancer.

Cigarette smoke components inhibited intercellular communication and differentiation in human pancreatic ductal epithelial cells

“…This observation is significant considering that cigarette smoke contributes more to the promoting than the initiating phase of cancer. 11 Our results do not explain the entire carcinogenic nature of the complex mixtures found in cigarette smoke, however, these in vitro studies do indicate that a much overlooked class of compounds found in cigarette smoke that can induce molecular events consistent with the tumor promoting phase of cancer.…”

“…DH, the heat-inactivated control. (BaP), 46 and that cigarette smoke is a strong promoter and weak complete carcinogen 11,[47][48][49] suggest that this fraction could significantly contribute to cancer. Ten to 15 years after giving up smoking, the exsmoker faces the same low risk of developing cancer of the upper digestive tract, the lung, the pancreas, and the urinary tract as the nonsmoker.…”

“…This is important, particularly when numerous studies have shown that cigarette smoke contributes more to the promoting than the initiating phase of cancer. 11 A recent review article strongly suggested that point mutations contributing to cancer arise primarily as errors during turnover of undamaged DNA and environmental conditions, including cigarette smoke, select rather than induce oncomutations. 12 The strong promoting and cocarcinogenic activity of cigarette smoke and its weak activity as a complete carcinogen 11 is consistent with the observations that the risk of pancreatic cancer of former smokers approaches the risk of ''never'' smokers within a few years subsequent to quitting.…”

Cigarette smoke condensate-induced transformation of normal human breast epithelial cells in vitro

“…One may think that the decreased cell growth may prevent breast carcinogenesis after cigarette smoking. However, consistent with the selective 'clonal' expansion and microenvironment permissiveness in tobacco-mediated lung carcinogenesis (Rubin, 2002), a single transformed normal breast epithelial cell can give rise to a tumor. Thus, the main focus of our study was to examine the underlying mechanisms involved in the transformation of normal breast epithelial cells by CSC.…”

AKR1C1 as a Biomarker for Differentiating the Biological Effects of Combustible from Non-Combustible Tobacco Products

“…Cigarette smoke is primarily considered to be a tumor-promoting and co-carcinogenic agent and only a weak complete carcinogen [4][5][6]. Cigarette smoke or its components cause DNA mutations and chromosomal damage, protein modifications, and expression changes of genes involved in cell death, inflammation, DNA repair and cell cycle regulation [4,[7][8][9][10][11]. In addition, the molecular response to cigarette smoke exposure is cell-and tissue-specific and varies with the type of exposed target organ and tobacco product [7,12,13].…”