Cancer Pathophysiology

Cancer describes a group of more than 150 disease processes characterized by uncontrolled growth and spread of cells. Cancer is not a singular, specific disease but a group of variable tissue responses that result in uncontrolled cell growth (McCance & Roberts, 1998; Fraumeni, 1982). Healthy tissues are composed of cells. Healthy cells have a specific size, structure, function and growth rate that best serves the needs of the tissues they compose. Cancer cells differ from normal cells in size, structure, function, and growth rate. These malignant cells lack the normal controls of growth seen in healthy cells, and grow uncontrollably. This uncontrolled growth allows the cancer cells to invade adjacent structures and then destroy surrounding tissues and organs. Malignant cells may also metastasize to other areas of the body through the cardiovascular or lymphatic systems. This uncontrolled growth and spread of cancer cells can eventually interfere with one or more of a person's vital organs or functions and possibly lead to death. The primary sites of cancer metastasis are the bone, the lymph nodes, the liver, the lungs, and the brain (McCance & Roberts, 1998).Malignant cells also lose their ability to differentiate or change like normal healthy cells. This inability to differentiate prevents cancer cells from performing the functions required by the tissues and results in a variety of other tissue changes in the body such as pain, cachexia, lowered immunity, anemia, leukopenia, and thrombocytopenia. Some of these changes, such as pain, can be benign but others denote a malignant or premalignant state. Benign neoplasms or tumor cells are made up of the same cell type as the original parent cell, but have abnormal growth rates. Benign cells do not metastasize or invade surrounding tissue. Benign cells can, however, pose a significant problem in the body when they grow too large and compress vital organs or organ systems. The following will describe both malignant and benign tissue changes that occur in the body from abnormal growth and differentiation (McCance & Roberts, 1998).Dysplasia is a general category that indicates a disorganization of cells. In Dysplasia, a cell varies from its normal parent cell in size, shape, or organization. Dysplasia is often the result of chronic irritation such as the changes seen in cervical tissues from long-standing irritation of the cervix. Metaplasia is the first level of dysplasia (early dysplasia). Metaplasia is a reversible, benign, but abnormal change seen when a cell changes from one type to another. The most common type of metaplasia is in the epithelium of the respiratory tract where columnar epithelial cells change into squamous epithelial cells. Although metaplasia usually gives rise to an orderly arrangement of cells, it may sometimes produce disordered cell patterns. Disorderly cell patterns result in cells of the wrong size, shape or orientation lining up together and may result in inappropriate or faulty tissue behaviors (McCance & Roberts, 1998). Anaplasia is the loss of cellular differentiation. Anaplasia is the most advanced form of metaplasia and is a defining characteristic of malignant cells.Hyperplasia refers to an increase in the number of cells in a tissue or in a part of a tissue. Hyperplasia, which results in increased tissue size or mass, can be a normal consequence of certain physiologic alterations or it can be a sign of malignancy. Examples of normal hyperplasia are seen in the tissue increases that occur during wound healing, callus formation following a bone fracture, or breast mass increases during pregnancy. An abnormal hyperplasia response is seen in "Neoplastic Hyperplasia," in which there is an increase in cell mass due to tumor formation (McCance & Roberts, 1998). There are also considerable differences in the growth rates of malignant tumors. Some tumors are very slow-growing, even in a malignant state, and are therefore removed easily. Other tumors may grow slowly at first and then undergo change and continue to grow at a rapid pace. Others tumor types may grow very rapidly throughout their entire existence. Factors that affect tumor growth and development include the status of an individual's immune system, the rate the tumor cells are growing, the number of tumor cells actively spreading, and the rate that the normal tissues are being destroyed by the tumor. Several factors affect normal immune function, including stress, malnutrition, advancing age, and chronic diseases. Cancer itself appears to suppress the immune system both early and late in the disease process (McCance & Roberts, 1998).As described above, uncontrolled cell growth is a characteristic of cancer. Cellular growth rates are regulated by proteins produced by the genetic material in cells. Genetic material can be altered or mutated by environmental factors, errors in genetic replication or repair processes, or by tumor viruses. Altered or mutated genes are called oncogenes, and it is these oncogenes that allow uncontrolled growth in cells (McCance & Roberts, 1998).- See more at: http://www.ncpad.org/163/1257/Cancer~and~Exercise#sthash.8faMpxL6.dpufCauses of Cancer

Understanding what causes cancer is a complex process. Cancer has been linked to many factors, such as environmental exposures, lifestyle practices, medical interventions, genetic traits, viruses, familial susceptibility, and aging. Cancer is most probably the result of interactions between repeated carcinogenic exposures and an individual's susceptibility status (Fraumeni, 1982).In 1941, Rous and Kidd described a possible mechanism for the development of cancer called the Initiation-Promotion-Progression Theory. This theory describes cancer development in terms of requiring multiple steps or events. In this theory, a single exposure, event, or trait would not be sufficient for the development of cancer. The first component of this theory is the Initiation Stage. The initiation stage of carcinogenesis occurs when DNA is damaged or altered. This alteration may occur through exposure to a carcinogen, or errors in DNA replication and repair. Examples of initiators include environmental hazards, such as ionizing and non-ionizing radiation, and biological factors, such as hormones and viruses. The damaged or initiated cell will not necessarily become cancerous unless it is subsequently exposed to one or more promoting agents during the Promotion Stage. Promoting agents cause the altered cells to grow, proliferate, and develop into tumors. Promoters include environmental pollutants, drugs, and hormones. Interestingly, even the biological changes of the promoters are reversible through lifestyle factors that include diet, hormones, and a healthy immune system (McCance & Roberts, 1998). The remainder of this section will discuss the primary risk factors that appear to be involved in the initiation or promotion of various cancers.Environmental exposures and lifestyle practices have been determined to be the major risk factors in the development of cancer (Lichtenstein, et al., 2000, Chlebowski, 2000, McCance & Roberts, 1998, Fraumeni, 1982). The major lifestyle factors that contribute to cancer include smoking, alcohol, diet, medical practices, and ultraviolet exposures. As smoking is a major risk factor for both heart disease and cancer, tobacco exposure is the single largest preventable cause of early death (American Cancer Society, 2000, ACSM, 1998, McCance & Roberts, 1998, Sternfeld, 1992). More than 30% of all cancer deaths are directly related to smoking (American Cancer Society, 2000). Although smoking is most commonly associated with lung cancer, it also causes a three-fold increase in urinary tract cancers and is an established cause in cancers of the bladder, pancreas, larynx, mouth, and esophagus (Zeegers, et al., 2000 Marcus, et al., 2000, McCance & Roberts, 1998).Alcohol consumption has been linked to increased rates of cancer in the upper respiratory tract, digestive tract, breast, colorectum, and liver (Corrao, et al, 1999). The mechanisms for increased rates of breast cancer from alcohol consumption are unclear but may be related to impairments in the immune function or the inability of the liver to clear the body of carcinogens, or from decreases in cell membrane permeability in the breast (Rohan & McMichael, 1988). For colorectal cancers, alcohol consumption has been shown to increase rectal cell proliferation or growth in the rat. This increase in the proliferation of rectal cells from alcohol exposure may be the mechanism involved in the promotion of colorectal cancers. Alcohol combined with tobacco usage has also been shown to contribute to increased rates of cancer in the mouth, pharynx, larynx, esophagus, and liver (McCance & Roberts, 1998, Fraumeni, 1982).Dietary practices and obesity have been linked to certain types of cancer. High consumption of dietary fat is being examined as a contributing factor to endometrial, breast, prostate, ovarian, and rectal cancers (McCance & Roberts, 1998). Not all of the mechanisms for these associations are clear. High consumption of dietary fat may increase bile acids and cholesterol metabolites that may increase carcinogens in the body that are associated with colorectal cancers. Diets low in fiber have also been linked to increased rates of colon cancer. Food additives and food preparation are also suspect as cancer-causing agents. Nitrates, salts, and saccharin have been investigated as possible carcinogenic substances. Saccharin has not been shown to increase cancer risk in humans; however, this is not the case for nitrates and salts. Nitrates and salts that are used to preserve foods appear to increase rates of glandular stomach cancers. There are high rates of stomach cancers in countries where large quantities of salted fish or similarly preserved foods are consumed (McCance & Roberts, 1998). Methods of food preparation may also increase cancer rates. Excessively smoked or broiled fish or meat, or repeatedly reused fats for frying foods release Benzo(a)pyrene and other polycyclic hydrocarbons that may potentially cause cancer (McCance & Roberts, 1998). Dietary guidelines associated with lowering the risk of cancer include increasing the use of fiber, fruit, and vegetables in the diet, limiting alcohol consumption, and limiting foods that contain preservatives, or foods that are grilled or blackened (American Cancer Society, 2000).Obesity caused by a sedentary lifestyle and/or a high consumption of dietary fat appears to contribute to an increased risk for cancers of the breast, the ovaries, and the endometrium in females (National Heart, Lung, and Blood Institute, 2000, Wu, et al., 1999). Obese females have higher numbers of fat cells, and fat cells produce estrogen. Since higher levels of estrogen have been associated with higher levels of endometrial, ovarian, and breast cancers, it has been suggested that higher levels of estrogen from increased numbers of fat cells in obese females may increase their cancer risk (McTiernan, 2000).Medical practices and drugs have also been linked to increases in cancer rates. Androgen -anabolic steroids used to promote athletic performance and prevent muscle wasting cause cancers in the liver, prostate, and breast (Conway, et al., 2000; Fraumeni, 1982). Estrogen replacement medications and steroid contraceptives may contribute to increased risk for developing cancers of the endometrium, vagina, ovaries, and breast (Coughlin, et al., 2000; Koukoulis, 2000; McCance & Roberts, 1998). Immunosuppressants, such as those used in transplant procedures, are linked to lymphomas, skin cancer, and soft tissue sarcomas. Interestingly, some chemotherapeutic drugs used to treat cancer, such as alkylating agents, are linked to cancers of the bladder and to leukemia (McCance & Roberts, 1998). In situations where long-term prognosis is a factor, the benefits must be weighed against the risks when choosing to use these drugs.Environmental factors that may increase cancer rates include air and ground pollution, occupational hazards, ultraviolet radiation, and radon gas. Air and ground pollution caused by industrial emissions and insecticides are associated with a variety of cancers (Ojajarvi, et al., 2000, McCance & Roberts, 1998, Fraumeni, 1982). Arsenic from pesticide applications, and from mining and smelting, contaminates groundwater and causes lung, skin, and liver cancers (Ojajarvi, et al., 2000). Industrial glues and varnish, as well as benzene byproducts from the petroleum industry, may contribute to increases in leukemia (McCance & Roberts, 1998; Fraumeni, 1982). Asbestos, mustard gas, heavy metals, aromatic hydrocarbons, and halogenated organic compounds from water chlorination are associated with increases in lung, bladder, liver, and pancreatic cancers (Ojajarvi, et al., 2000; McCance & Roberts, 1998). Radon gas trapped in houses contributes to an estimated 10% of lung and larynx cancers (Lubin et al., 1997; Tirmarche, 1997). Increases in ultraviolet exposures from tanning lamps and from diminished ozone levels contributes to increases in skin cancers and melanomas (Swerdlow, et al., 1998). Highway maintenance workers and roofers exposed to bitumen fumes and coal tar fumes from asphalt are at increased risk for cancers of the lung, stomach, and skin, as well as leukemia (Partanen & Boffetta, 1994).Although environmental factors are the major cause of cancer, age is the single best predictor of the risk of developing cancer (American Cancer Society, 2000). Rates for the development of cancer begin to increase at 40 years of age and then increase rapidly at 50 years of age (American Cancer Society, 2000; Pfalzer, 1994; Pfalzer, 1992). The increasing risk for developing cancer with aging may be related to the increased likelihood of cumulative effects from environmental exposures, the potential for long latency periods, and increased opportunities for multi-stage processes to occur with aging (McCance & Roberts, 1998; Fraumeni, 1982).Genetic or inherited cancers and familial susceptibility contribute to only a small percentage of cancers (McCance & Roberts, 1998; Fraumeni, 1998). A primary cause of cancer is damage to a specific gene. If the damaged gene is part of the genetic line, then the cancer can be inherited by succeeding generations. However, if the damaged gene is a somatic or general body cell, as most cancers appear to be, then the cancer will not be passed to future generations. The genetic or inherited cancers can be passed along through autosomal dominant, autosomal recessive, and X-linked transmission. Examples of inherited cancers include familial breast cancer, familial polyposis of the colon, adenomas of the colon, retinoblastomas (a childhood cancer of the eye), Wilms tumor (a childhood cancer of the kidney), and neurofibromatosis (McCance & Roberts, 1998).The mechanisms involved in familial susceptibility for cancer are less well understood than those for inherited or genetic cancers. Cancers that tend to run in families include breast, colorectal, and prostate cancers. The impact of the environment in determining whether an individual with a familial susceptibility for cancer will actually develop cancer is not fully understood at this time. Most researchers believe that lifestyle and environmental factors markedly influence whether a person with a familial susceptibility for cancer will develop cancer (Lichtenstein, et al., 2000; McCance & Roberts, 1998; Fraumeni, 1982). Therefore, even when there is increased familial susceptibility for certain cancers, a person can modify his or her risk for developing cancer by changing environment or lifestyle practices.Cancer also can be caused by a virus. Oncogenic viruses infect normal cells and cause alterations in the cell's genetic material. These genetic alterations can cause specific types of malignant and benign cancers in susceptible individuals by allowing uncontrolled growth in cells. Oncogenic viruses can affect DNA or RNA. Oncogenic viruses that affect DNA can cause cancers in the cervix, liver, anogenital area, mouth, larynx, nasal and paranasal tissues, and conjunctival tissues (McCance & Roberts, 1998). Oncogenic viruses that affect the RNA can cause Human T-cell leukemia. Interestingly, infection by an oncogenetic virus does not necessarily lead to the development of cancer. In some industrial regions, the Epstein-Barr virus, which causes Burkitt lymphoma, nasopharyngeal cancer, and B-cell lymphoma, has an infection rate of up to 90% of the young adult population; however, low numbers of infected individuals in these areas develop cancer (McCance & Roberts, 1998).- See more at: http://www.ncpad.org/163/1258/Cancer~and~Exercise#sthash.Bm16JORo.dpufhttp://www.ncpad.org/163/1257/Cancer~and~Exercise PathophysiologyMain article:Carcinogenesis

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.Genetic alterationsCancer is fundamentally a disease of tissue growth regulation failure. In order for a normal cell totransforminto a cancer cell, thegeneswhich regulate cell growth and differentiation must be altered.[48]The affected genes are divided into two broad categories.Oncogenesare genes which promote cell growth and reproduction.Tumor suppressor genesare genes which inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes inmanygenes are required to transform a normal cell into a cancer cell.[49]Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entirechromosomecan occur through errors inmitosis. More common aremutations, which are changes in thenucleotidesequence of genomic DNA.Large-scale mutations involve the deletion or gain of a portion of a chromosome.Genomic amplificationoccurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material.Translocationoccurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is thePhiladelphia chromosome, or translocation of chromosomes 9 and 22, which occurs inchronic myelogenous leukemia, and results in production of theBCR-ablfusion protein, an oncogenictyrosine kinase.Small-scale mutations include point mutations, deletions, and insertions, which may occur in thepromoterregion of a gene and affect itsexpression, or may occur in the gene'scoding sequenceand alter the function or stability of itsproteinproduct. Disruption of a single gene may also result fromintegration of genomic materialfrom aDNA virusorretrovirus, and resulting in the expression ofviraloncogenes in the affected cell and its descendants.Replication of the enormous amount of data contained within the DNA of living cells willprobabilisticallyresult in some errors (mutations). Complex error correction and prevention is built into the process, and safeguards the cell against cancer. If significant error occurs, the damaged cell can "self-destruct" through programmed cell death, termedapoptosis. If the error control processes fail, then the mutations will survive and be passed along todaughter cells.Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances calledcarcinogens, repeated physical injury, heat, ionising radiation, orhypoxia.[50]The errors which cause cancer areself-amplifyingandcompounding, for example: A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly. A further mutation in an oncogene might cause the cell to reproduce more rapidly and more frequently than its normal counterparts. A further mutation may cause loss of a tumour suppressor gene, disrupting the apoptosis signalling pathway and resulting in the cell becoming immortal. A further mutation in signaling machinery of the cell might send error-causing signals to nearby cells.The transformation of normal cell into cancer is akin to achain reactioncaused by initial errors, which compound into more severe errors, each progressively allowing the cell to escape the controls that limit normal tissue growth. This rebellion-like scenario becomes an undesirablesurvival of the fittest, where the driving forces ofevolutionwork against the body's design and enforcement of order. Once cancer has begun to develop, this ongoing process, termedclonal evolutiondrives progression towards more invasivestages.[51]Epigenetic alterations

The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesisClassically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumour-suppressor genes and oncogenes, and chromosomal abnormalities. However, it has become apparent that cancer is also driven byepigenetic alterations.[52]Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes inDNA methylation(hypermethylation and hypomethylation) andhistone modification[53]and changes in chromosomal architecture (caused by inappropriate expression of proteins such asHMGA2orHMGA1).[54]Each of these epigenetic alterations serves to regulate gene expression without altering the underlyingDNA sequence. These changes may remain throughcell divisions, last for multiple generations, and can be considered to be epimutations (equivalent to mutations).Epigenetic alterations occur frequently in cancers. As an example, Schnekenburger and Diederich[55]listed protein coding genes that were frequently altered in their methylation in association with colon cancer. These included 147 hypermethylated and 27 hypomethylated genes. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers.While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, may be of particular importance. Such alterations are thought to occur early in progression to cancer and to be a likely cause of thegeneticinstability characteristic of cancers.[56][57][58][59]Reduced expression of DNA repair genes causes deficient DNA repair. This is shown in the figure at the 4th level from the top. (In the figure, red wording indicates the central role of DNA damage and defects in DNA repair in progression to cancer.) When DNA repair is deficient DNA damages remain in cells at a higher than usual level (5th level from the top in figure), and these excess damages cause increased frequencies of mutation and/or epimutation (6th level from top of figure). Mutation rates increase substantially in cells defective inDNA mismatch repair[60][61]or inhomologous recombinationalrepair (HRR).[62]Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.[63]Higher levels of DNA damage not only cause increased mutation (right side of figure), but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.[64][65]Deficient expression of DNA repair proteins due to an inherited mutation can cause increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see articleDNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations).[66]Germ line DNA repair mutations are noted in a box on the left side of the figure, with an arrow indicating their contribution to DNA repair deficiency. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.[67]In sporadic cancers, deficiencies in DNA repair are occasionally caused by a mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. This is indicated in the figure at the 3rd level from the top. For example, when 113 colorectal cancers were examined in sequence, only four had amissense mutationin the DNA repair geneMGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).[68]Five different studies found that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.[69][70][71][72][73]Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair genePMS2expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partnerMLH1was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).[74]In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of themicroRNA,miR-155, which down-regulates MLH1.[75]In further examples, tabulated in the articleEpigenetics, epigenetic defects were found at frequencies of between 13%-100% for the DNA repair genesBRCA1,WRN,FANCB,FANCF, MGMT,MLH1,MSH2,MSH4,ERCC1, XPF,NEIL1andATMin cancers including those in breast, ovarian, colorectal, and head and neck. In particular, two or more epigenetic deficiencies in expression of ERCC1, XPF and/or PMS2 occurred simultaneously in the majority of the 49 colon cancers evaluated by Facista et al.[76]Many studies of heavy metal-induced carcinogenesis show that such heavy metals cause reduction in expression of DNA repair enzymes, some through epigenetic mechanisms. In some cases, DNA repair inhibition is proposed to be a predominant mechanism in heavy metal-induced carcinogenicity. For example, one group of studies shows that arsenic inhibits the DNA repair genesPARP,XRCC1,Ligase III,Ligase IV,DNA POLB,XRCC4,DNA PKCS,TOPO2B,OGG1,ERCC1,XPF,XPB,XPC,XPEandP53.[77][78][79][80][81][82]Another group of studies shows that cadmium inhibits the DNA repair genesMSH2,ERCC1,XRCC1,OGG1,MSH6,DNA-PK,XPDandXPC.[83][84][85][86][87]Cancers usually arise from an assemblage of mutations and epimutations that confer a selective advantage leading to clonal expansion (seeField defects in progression to cancer). Mutations, however, may not be as frequent in cancers as epigenetic alterations. An average cancer of the breast or colon can have about 60 to 70 protein-altering mutations, of which about 3 or 4 may be driver mutations, and the remaining ones may be passenger mutations.[88]Colon cancers were also found to have an average of 17 duplicated segments of chromosomes, 28 deleted segments of chromosomes and up to 10 translocations.[89]However, by comparison, epigenetic alterations appear to be more frequent in colon cancers. There are large numbers of hypermethylated genes in colon cancer, as discussed above.[55]In addition, there are frequent epigenetic alterations of the DNA sequences coding for small RNAs calledmicroRNAs(or miRNAs). MiRNAs do not code for proteins, but can target protein-coding genes and reduce their expression. For instance, epigenetic increase inCpG islandmethylation of the DNA sequence encoding miR-137 reduces its expression and is a frequent early epigenetic event in colorectal carcinogenesis, occurring in 81% of colon cancers and in 14% of the normal appearing colonic mucosa adjacent to the cancers. Silencing of miR-137 can affect expression of over 400 genes, the targets of this miRNA.[90]Changes in the level of miR-137 expression cause altered mRNA expression of the target genes by 2 to 20-fold and corresponding, though often smaller, changes in expression of the protein products of the genes. Other microRNAs, with likely comparable numbers of target genes, are even more frequently epigenetically altered in colonicfield defectsand in the colon cancers that arise from them. These include miR-124a, miR-34b/c and miR-342 which are silenced by CpG island methylation of their encoding DNA sequences in primary tumors at rates of 99%, 93% and 86%, respectively, and in the adjacent normal appearing mucosa at rates of 59%, 26% and 56%, respectively.[91][92]Thus, epigenetic alterations are a major source of changes in gene expression, important in cancer.As pointed out above under genetic alterations, cancer is caused by failure to regulate tissue growth, when the genes which regulate cell growth and differentiation are altered. It has become clear that these alterations are caused by both DNA sequence mutation inoncogenesandtumor suppressor genesas well as by epigenetic alterations. The epigenetic deficiencies in expression of DNA repair genes, in particular, likely cause an increased frequency of mutations, some of which then occur in oncogenes and tumor suppressor genes.