Cancer 4th post

Pathophysiology

Main article: Carcinogenesis

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

Genetics

Cancer is fundamentally a disease of tissue growth regulation failure. In order for a normal cell to transform into a cancer cell, the genes that regulate cell growth and differentiation must be altered.^[61]

The affected genes are divided into two broad categories. Oncogenes are genes that promote cell growth and reproduction. Tumor suppressor genes are genes that 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 in many genes are required to transform a normal cell into a cancer cell.^[62]

Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs 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.Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenictyrosine kinase.

Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, leading to the expression of viraloncogenes in the affected cell and its descendants.

Replication of the enormous amount of data contained within the DNA of living cells will probabilistically result 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, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells.

Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances called carcinogens, repeated physical injury, heat, ionising radiation, or hypoxia.^[63]

The errors that cause cancer are self-amplifying and compounding, 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 tumor 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 a chain reaction caused 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 undesirable survival of the fittest, where the driving forces of evolution work against the body's design and enforcement of order. Once cancer has begun to develop, this ongoing process, termed clonal evolution, drives progression towards more invasive stages.^[64] Clonal evolution leads to intra-tumour heterogeneity that complicates designing effective treatment strategies.

Characteristic abilities developed by cancers are divided into a number of categories. Six categories were originally proposed, in a 2000 article called "The Hallmarks of Cancer" by Douglas Hanahan and Robert Weinberg: evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, and metastasis. Based on further work, the same authors added two more categories in 2011: reprogramming of energy metabolism and evasion of immune destruction.^[24][25]

Epigenetics

The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis

Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumor-suppressor genes and oncogenes, and chromosomal abnormalities. However, it has become apparent that cancer is also driven by epigenetic alterations.^[65]

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 in DNA methylation (hypermethylation and hypomethylation) andhistone modification^[66] and changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1).^[67] Each of these epigenetic alterations serves to regulate gene expression without altering the underlying DNA sequence. These changes may remain through cell 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^[68] 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 the genetic instability characteristic of cancers.^{[69][70][71][72]}

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 in DNA mismatch repair^[73][74] or in homologous recombinational repair (HRR).^[75] Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.^[76]

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.^[77][78]

Deficient expression of DNA repair proteins due to an inherited mutation can cause an increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA 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).^[79] 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.^[80]

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. 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. In addition, there are frequent epigenetic alterations of the DNA sequences coding for small RNAs called microRNAs (or miRNAs). MiRNAs do not code for proteins, but can "target" protein-coding genes and reduce their expression.

Cancers usually arise from an assemblage of mutations and epimutations that confer a selective advantage leading to clonal expansion (see Field 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 three or four may be "driver" mutations, and the remaining ones may be "passenger" mutations.^[81]

As pointed out above under genetic alterations, cancer is caused by failure to regulate tissue growth, when the genes that regulate cell growth and differentiation are altered. It has become clear that these alterations are caused by both DNA sequence mutation in oncogenes and tumor suppressor genes as 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.

Metastasis

Main article: Metastasis

Metastasis is the spread of cancer to other locations in the body. The new tumors are called metastatic tumors, while the original is called the primary tumor. Almost all cancers can metastasize.^[82] Most cancer deaths are due to cancer that has spread from its primary site to other organs (metastasized).^[83]

Metastasis is very common in the late stages of cancer, and it can occur via the blood or the lymphatic system or both. The typical steps in metastasis are local invasion, intravasation into the blood or lymph, circulation through the body,extravasation into the new tissue, proliferation, and angiogenesis. Different types of cancers tend to metastasize to particular organs, but overall the most common places for metastases to occur are the lungs, liver, brain, and the bones.^[82]