Natural mechanisms protecting against cancer
Introduction
Natural defense mechanisms protecting against infection or against cancer can be categorized into non-immune and immune with the latter belonging either to innate or adaptive immunity.
Our concepts of the role of the immune system in the protection against cancer usually belong to two extreme attitudes that either exaggerate or negate the importance of immunity in this defense. On the one hand, Burnet suggested that immunosurveillance is responsible for detecting and eliminating tumor cells being a central mechanism by which tumor development is kept in check [1]. Based on this hypothesis, it could be assumed that arising tumor cells are destroyed by the immune system in the majority of cases, probably hundreds or thousands times during our life, and only rarely they evade this defense giving rise to malignant tumors. On the other hand, immune stimulation hypothesis predicts that low immune reactivity against tumors, as it is usually observed in cancer patients, is stimulating rather than inhibiting tumor cells [2]. As it often happens with extreme attitudes neither of the above theories seems to be correct. Immune defense mechanisms form the last barrier in our natural mechanisms of protection against cancer and are probably less effective as compared with some other mechanisms operating at earlier stages of malignant tumor formation.
The immune mechanisms that protect against infectious microorganisms, operating during the entire lifespan of individuals including their reproductive periods, have undergone positive selection and thus became perfected during human evolution under selective pressure of attacking microbes and diseases they produce. Non-immune mechanisms protecting against cancer, as they are active at early stages of the multistep process of carcinogenesis, had similar chance for positive selection and perfection. It should be kept in mind that genetic selection acts on the individual phenotypes and either favors or hinders reproduction and thus the propagation of that individual’s genotype [3]. Thus, selection may operate at any time from conception to the end of the reproductive period but not beyond that time [4]. Since the multistage process of carcinogenesis and full development of cancer lasts for up to several decades [5] and cancer incidence grows exponentially with age, it can be hypothesized that immune anti-tumor mechanisms operating usually in elderly population did not have such an opportunity for positive selection and improvement in our evolution. Some observations seem to support indirectly this hypothesis suggesting more important role of non-immune anti-carcinogenic mechanisms operating early as compared with anti-tumor immunity operating later. Nucleotide-excision repair (NER), which is only one of the DNA repair mechanisms, protects against cancer at early stage of carcinogenesis. Impairment of NER observed in the human recessive hereditary disease xeroderma pigmentosum, causes a 5000-fold increase in the incidence of squamous and basal cell carcinoma and a 2000-fold increase in the incidence of melanoma [6]. On the other hand, prolonged treatment with immunosuppressive drugs in allograft recipients effectively impairs adaptive immunity but increases the risk of squamous and basal cell carcinoma “only” 65-fold according to one of the reports [7] although skin cancers are among the most frequent neoplasms in allograft recipients [8]. In another report, incidence of cancer of the lip, skin (non-melanotic), kidney, endocrine glands, and cervix of uterus, was increased 10–30 times in renal transplant patients [9].
Our knowledge on the natural defense against cancer is far from being complete and is full of paradoxes and misconceptions. A good example of this unawareness was our conviction that supplementation of human diet with β carotene should diminish the incidence of cancer (see below).
Section snippets
The multistage process of carcinogenesis
Based on the experimental studies in rodents, the multistage process of carcinogenesis has been traditionally divided into initiation, promotion and progression [10], [11] (Fig. 1).
Initiation begins with DNA damage in a cell population exposed to chemical, physical or microbial (mostly viral) carcinogens. If not repaired, DNA damage could produce genetic mutations. The majority of these DNA alterations is irrelevant to the life of the cell and is completely innocent from the point of view of
Anti-carcinogenic substances present in the human diet
It is considered that 80–90% of all human cancers are environmentally induced [13] and 30–40% of them by carcinogens present in our diet [14]. Almost all plants including those forming human diet, seem to produce some kind of toxic substances called natural pesticides, defending them against fungi, insects and/or animals feeding on them [15], [16], [17]. Many of both synthetic and natural pesticides are carcinogenic at appropriate doses [18]. Although our fears are mainly concentrated on
The concept of tumor immunosurveillance
The tumor immunosurveillance hypothesis, first raised by Paul Ehrlich in 1909 and then refined by Burnet and Thomas, postulated that the immune system constantly surveys the newly developing tumors and, as long as it is effective, prevents the development of neoplastic disease. It was assumed that clinically evident tumors represent exceptions that slipped through the immunological net.
The increased incidence of tumors in immunosuppressed recipients following organ transplantation, and in
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