Cancer Synthesis Essay

The last few decades there is seen a strong increase in the number of people who are overweighed or have obesity in developed countries as well as in less developed countries (1). The World Health Organization has published that in 2014 approximately 40% of the people above eighteen years old are overweighed (2). It is known that an high body mass index (BMI) is associated with a higher risk on the development of many diseases, including several kinds of cancer (3-5). Recent studies have been shown that people with a BMI above 25 kg/m² have an increased incidence of developing endometrial, colorectal and postmenopausal breast cancer. In addition, people with a BMI above 30 kg/m² has also an increased incidence of developing esophageal, thyroid, renal, gallbladder, pancreatic and ovarian cancer as well as multiple myeloma, non-Hodgkin
lymphoma, leukemia and many more (6). Statistics shows that next to these types of cancer also lung cancer is one of the most common forms of cancer in men and women and also is the main cancer type where the most deaths have been observed (7). Although a high BMI will induce the development of several kinds of cancer, lung cancer is not included. In literature of previous epidemiological studies an inverse association is seen between BMI and the development of lung cancer (8, 9). Lung cancer is worldwide the leading cause of death, while the incidence can be lower than other cancer cases. Lung cancer is seen more in less developed countries compared to more developed countries. This differences is caused by the fact that in less developed countries most homes keep warm by wood fires. Besides that, lung cancer is also seen more in males, approximately 68% of total lung cancer cases, than in females, which are only 32% of the total lung cancer cases (10). Around 87% of the lung cancer cases are caused by cigarette smoking (11).
Exposure to radon gas, that is released from soil and building materials, is the second leading cause of lung cancer in well-developed regions as Europe and North America. Other risk factors for lung cancer are secondhand smoke exposure, asbestos, certain metals, exhaust gases and other organic chemicals, radiation or air pollution (12). When looked at a molecular level of cigarette smoke and other risk factors that causes lung cancer, all these smokes and gases contain several carcinogenic components. The most carcinogenic components in cigarette smoke are benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon, and nitrosamine (10). BaP is activated by the phase I enzymes that are responsible for the metabolism of xenobiotics, the cytochrome P450 enzymes (CYPs) (13). CYPs detoxify a wide variety of xenobiotics but also is an enzyme that provides bio activation of carcinogenic compounds, such as BaP, that can bind to DNA after it is metabolized to form DNA-adducts. The primary CYPs that are involved in especially the metabolism of BaP are CYP1A1 and CYP1B1
(14). In addition, BaP by itself is involved in the expression of these CYPs via the aryl hydrocarbon receptor (AhR), since BaP and other polycyclic aromatic hydrocarbons (PAHs) are ligands for this receptor (15). Activity of the enzyme CYP1A1 is induced by cigarette smoking (16). It is seen that the induction of the enzyme CYP1A1 expression, which is involved in metabolism of BaP, is due to the loss of methylation of the CYP1A1 promotor. The gene promotor of CYP1A1 is methylated for 33% in heavy smokers, for 71% in light smokers and for 98% in non-smokers or ex-smokers. This suggests that the rate of methylation is proportional to the expression of the enzyme. The more the promoter is methylated, the more inactive is the enzyme. Compared to non-smokers, smokers have an upregulation of the CYP1A1 genes in lung tissue (17).