Natural mechanisms protecting against cancer

Abstract

Carcinogenesis is a multistage process. At each step of this process, there are natural mechanisms protecting against development of cancer. The majority of cancers in humans is induced by carcinogenic factors present in our environment including our food. However, some natural substances present in our diet or synthesized in our cells are able to block, trap or decompose reactive oxygen species (ROS) participating in carcinogenesis. Carcinogens can also be removed from our cells. If DNA damage occurs, it is repaired in most of the cases. Unrepaired DNA alterations can be fixed as mutations in proliferating cells only and mutations of very few strategic genes can induce tumor formation, the most relevant are those activating proto-oncogenes and inactivating tumor suppressor genes. A series of mutations and/or epigenetic changes is required to drive transformation of a normal cell into malignant tumor. The apparently unrestricted growth has to be accompanied by a mechanism preserving telomeres which otherwise shorten with succeeding cell divisions leading to growth arrest. Tumor can not develop beyond the size of 1–2 mm in diameter without the induction of angiogenesis which is regulated by natural inhibitors. To invade the surrounding tissues epithelial tumor cells have to lose some adhesion molecules keeping them attached to each other and to produce enzymes able to dissolve the elements of the basement membrane. On the other hand, acquisition of other adhesion molecules enables interaction of circulating tumor cells with endothelial cells facilitating extravasation and metastasis. One of the last barriers protecting against cancer is the activity of the immune system. Both innate and adaptive immunity participates in anti-tumor effects including the activity of natural killer (NK) cells, natural killer T cells, macrophages, neutrophils and eosinophils, complement, various cytokines, specific antibodies, and specific T cytotoxic cells. Upon activation neutrophils and macrophages are able to kill tumor cells but they can also release ROS, angiogenic and immunosuppressive substances. Many cytokines belonging to different families display anti-tumor activity but their role in natural anti-tumor defense remains largely to be established.

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).