ReviewGenetic and environmental factors in cancer and neurodegenerative diseases
Introduction
An increasingly important health problem in the world is the rising incidence of age-related neurodegenerative diseases. Ironically, this is partly due to the increasing longevity of the populations, which results from better living and working conditions. Even if the aetiology of neurodegeneration is not completely understood, the irregular inheritance pattern found in many neurodegenerative diseases is likely to be the result from the interaction of genetic and environmental factors. Neurodegenerative diseases, including many types of dementia, fall into many groups, ranging from diseases with a clear genetic aetiology (Huntington’s disease) to diseases which are believed to be the result of chronic environmental exposure (Guam Parkinson-dementia syndrome), including also inheritable as well as transmissible prion diseases (Kuru, Creutzfeld–Jacob disease), and those whose aetiology is unknown but have a genetic component in at least some cases (Parkinson’s disease, Alzheimer’s disease) [1]. The role of environmental and occupational exposures to neurotoxicants in the pathogenesis of neurodegenerative diseases has not been fully elucidated, but many chemicals can affect the nervous system and some of them require metabolic activation to induce their toxic effects, so that genetic polymorphisms that encode for defective forms of the detoxifying enzymes can further increase the risk of effects from exposure to neurotoxicants [2]. To improve human health and the quality of life, it will be essential to obtain a better understanding of the key biochemical mechanisms and risk factors underlying neurodegeneration. Cancer is now considered a progressive disease characterised by the accumulation of defects in different genes. Cancer-related genes are classified mainly as either oncogenes or tumor suppressor genes. Mutated proto-oncogenes (i.e. oncogenes) contribute to tumor development by enhancing cell growth. Tumor suppressor genes usually inhibit cell growth and transformation, and their loss of function contributes to tumor development. In recent years other types of genes have been found that, if inactivated by mutations, can increase carcinogenesis, for example damaged DNA repair genes affect the carcinogenetic process by destroying the genetic stability of the cells, making them more prone to mutational alterations [3]. Until a few years ago, cancer predisposition was mainly attributed to the level of exposure to carcinogenic agents; at present it is clear that the long process that leads from exposure to a carcinogenic agent to cancer, sometimes more than 20 years later, is subjected to individual modulations: while rare alterations of oncogenes or tumor suppressor genes dramatically raise cancer risk for the single affected subjects, more common polymorphisms in genes encoding for metabolic enzymes are responsible for a small, but rather frequent increase of cancer risk at the population level, especially in people exposed to carcinogens [4].
Section snippets
Causative genes in carcinogenesis
Cancer genes may be involved in the cell division control or in the execution of apoptosis, may code for transcriptional regulators, may be genes involved in signal transduction pathways, may code for growth factors or growth factors receptors, may be genes whose products are important for the cellular adhesion (Table 1a). It is important to note that a function does not exclude another, for example a gene involved in the cell division cycle control may do it acting as a transcriptional
Environmental factors in carcinogenesis
Cancers may results from environmental exposure to exogenous agents; epidemiological data on populations indicate an association between many human cancers and lifestyle/diet, moreover detailed studies of mutational events in human cancers have provided evidence for a direct action of environmental carcinogens in the development of certain cancers (Table 2a): an excellent example is lung cancer which has been linked to tobacco smoke, making cigarette smoking one of the major causal factors for
Susceptibility factors in carcinogenesis
Several chemicals require metabolic activation to explain their toxic effect; for this reason differences in metabolic enzymes may account for an inter-individual susceptibility to them; one example is lung cancer: although cigarette smoking is the the predominant cause of lung cancer in US, only about 15% of cigarette smokers develop the disease. Therefore, among cigarette smokers, there exist individuals with high risk for lung cancer whereas others are resistant. The inter-individual
Oxidative stress in carcinogenesis
A wide variety of reactive oxygen species (ROS) can be found in biological systems, and a variety of critical biomolecules, including lipids, proteins and DNA, can be damaged by them. Under normal physiological conditions cells thereby cope with the flux of ROS. Oxidative stress describes a condition in which cellular antioxidant defences are insufficient to keep the levels of ROS below a toxic threshold. This may be either due to excessive production of ROS, loss of antioxidant defences or
Apoptosis in carcinogenesis
Apoptosis or programmed cell death (PCD) is a physiological process necessary for organ development, tissue homeostasis and elimination of defective or potentially dangerous cells without a concomitant inflammatory response in the surrounding tissues [86]. Three classic pathways of apoptotic signalling in mammalian cells are known, and they all require the activation of a family of cysteine proteases, called caspases. The first one is initiated by the withdrawal of growth factors and is
Aging in carcinogenesis
Although many hypotheses have been proposed over the years to explain the aging process, the exact mechanisms are not well defined. Most theories of aging are based on two fundamental concepts: aging is the result of genetic programs akin to those of development and morphogenesis; and aging is due to evolutionary non-adaptative homeostatic failures [97]. Cancer is an age-related disorder, and its frequency increases throughout almost the entire lifespan. The incidence of cancer peaked in the
Discussion and future prospects
Even if carcinogenesis and neurodegeneration are different pathologies, common factors can be identified in the generation and the progression of both the diseases. The current opinion is that cancer is a multi-step process in which the first mutation may derive from parents or may arise in the genome following the action by endogenous and/or exogenous factors. The successive divisions of the initiated cell generate a clone of cells each of one may be the target for subsequent mutations leading
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