Malignant transformation

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Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor.

Contents

Causes

There are many causes of primary malignant transformation, or tumorigenesis. Most human cancers in the United States are caused by external factors, and these factors are largely avoidable. [1] [2] [3] These factors were summarized by Doll and Peto in 1981, [1] and were still considered to be valid in 2015. [2] These factors are listed in the table.

External factors in cancer
FactorEstimated percent of cancer deaths
Diet35
Tobacco30
Infection10
Reproductive and sexual behaviora7
Occupation4
Alcohol3
Sunlight (UV)3
Pollution2
Medicines and medical procedures1
Food additives<1
Industrial products<1

a Reproductive and sexual behaviors include: number of partners; age at first menstruation; zero versus one or more live births

Diet and colon cancer

Colon cancer provides one example of the mechanisms by which diet, the top factor listed in the table, is an external factor in cancer. The Western diet of African Americans in the United States is associated with a yearly colon cancer rate of 65 per 100,000 individuals, while the high fiber/low fat diet of rural Native Africans in South Africa is associated with a yearly colon cancer rate of <5 per 100,000. [4] Feeding the Western diet for two weeks to Native Africans increased their secondary bile acids, including carcinogenic deoxycholic acid, [5] by 400%, and also changed the colonic microbiota. [4] Evidence reviewed by Sun and Kato [6] indicates that differences in human colonic microbiota play an important role in the progression of colon cancer.

Diet and lung cancer

A second example, relating a dietary component to a cancer, is illustrated by lung cancer. Two large population-based studies were performed, one in Italy and one in the United States. [7] In Italy, the study population consisted of two cohorts: the first, 1721 individuals diagnosed with lung cancer and no severe disease, and the second, 1918 control individuals with absence of lung cancer history or any advanced diseases. All individuals filled out a food frequency questionnaire including consumption of walnuts, hazelnuts, almonds, and peanuts, and indicating smoking status. In the United States, 495,785 members of AARP were questioned on consumption of peanuts, walnuts, seeds, or other nuts in addition to other foods and smoking status. In this U.S. study 18,533 incident lung cancer cases were identified during up to 16 years of follow-up. Overall, individuals in the highest quintile of frequency of nut consumption had a 26% lower risk of lung cancer in the Italian study and a 14% lower risk of lung cancer in the U.S. study. Similar results were obtained among individuals who were smokers.

Due to tobacco

The most important chemical compounds in smoked tobacco that are carcinogenic are those that produce DNA damage since such damage appears to be the primary underlying cause of cancer. [8] Cunningham et al. [9] combined the microgram weight of the compound in the smoke of one cigarette with the known genotoxic effect per microgram to identify the most carcinogenic compounds in cigarette smoke. These compounds and their genotoxic effects are listed in the article Cigarette. The top three compounds are acrolein, formaldehyde and acrylonitrile, all known carcinogens.

Due to infection

Viruses

In 2002 the World Health Organizations International Agency for Research on Cancer [10] estimated that 11.9% of human cancers are caused by one of seven viruses (see Oncovirus overview table). These are Epstein-Barr virus (EBV or HHV4); Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8); Hepatitis B and Hepatitis C viruses (HBV and HCV); Human T-lymphotrophic virus 1 (HTLV-1); Merkel cell polyomavirus (MCPyV); and a group of alpha Human papillomaviruses (HPVs). [11]

Bacteria

Helicobacter pylori and gastric cancer

In 1995 epidemiologic evidence indicated that Helicobacter pylori infection increases the risk for gastric carcinoma. [12] More recently, experimental evidence showed that infection with Helicobacter pylori cagA-positive bacterial strains results in severe degrees of inflammation and oxidative DNA damage, leading to progression to gastric cancer. [13]

Other bacterial roles in carcinogenesis

Perera et al. [14] referred to a number of articles pointing to roles of bacteria in other cancers. They pointed to single studies on the role of Chlamydia trachomatis in cervical cancer, Salmonella typhi in gallbladder cancer, and both Bacteroides fragilis and Fusobacterium nucleatum in colon cancer. Meurman has recently summarized evidence connecting oral microbiota with carcinogenesis. [15] Although suggestive, these studies need further confirmation.

Common underlying factors in cancer

Mutations

One underlying commonality in cancers is genetic mutation, acquired either by inheritance, or, more commonly, by mutations in one's somatic DNA over time. The mutations considered important in cancers are those that alter protein coding genes (the exome). As Vogelstein et al. point out, a typical tumor contains two to eight exome "driver gene" mutations, and a larger number of exome mutations that are "passengers" that confer no selective growth advantage. [16]

Cancers also generally have genome instability, that includes a high frequency of mutations in the noncoding DNA that makes up about 98% of the human genome. The average number of DNA sequence mutations in the entire genome of breast cancer tissue is about 20,000. [17] In an average melanoma (where melanomas have a higher exome mutation frequency [16] ) the total number of DNA sequence mutations is about 80,000. [18]

Epigenetic alterations

Transcription silencing

A second underlying commonality in cancers is altered epigenetic regulation of transcription. In cancers, loss of gene expression occurs about 10 times more frequently by epigenetic transcription silencing (caused, for example, by promoter hypermethylation of CpG islands) than by mutations. As Vogelstein et al. [16] point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker, or passenger, mutations. [16] In contrast, the frequency of epigenetic alterations is much higher. In colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in promoters of genes in the tumors while the corresponding CpG islands are not methylated in the adjacent mucosa. [19] [20] [21] Such methylation turns off expression of a gene as completely as a mutation would. Around 60–70% of human genes have a CpG island in their promoter region. [22] [23] In colon cancers, in addition to hypermethylated genes, several hundred other genes have hypomethylated (under-methylated) promoters, thereby causing these genes to be turned on when they ordinarily would be turned off. [21]

Post-transcriptional silencing

Epigenetic alterations are also carried out by another major regulatory element, that of microRNAs (miRNAs). In mammals, these small non-coding RNA molecules regulate about 60% of the transcriptional activity of protein-encoding genes. [24] Epigenetic silencing or epigenetic over-expression of miRNA genes, caused by aberrant DNA methylation of the promoter regions controlling their expression, is a frequent event in cancer cells. Almost one third of miRNA promoters active in normal mammary cells were found to be hypermethylated in breast cancer cells, and that is a several fold greater proportion of promoters with altered methylation than is usually observed for protein coding genes. [25] Other microRNA promoters are hypomethylated in breast cancers, and, as a result, these microRNAs are over-expressed. Several of these over-expressed microRNAs have a major influence in progression to breast cancer. BRCA1 is normally expressed in the cells of breast and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired. [26] BRCA1 is involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double-strand breaks. [27] BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers. [28] Only about 3–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2. [29] BRCA1 promoter hypermethylation was present in only 13% of unselected primary breast carcinomas. [30] However, breast cancers were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue. [31] In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression. [32] Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182. In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression. These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation. [33] Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.

Post-transcriptional regulation by microRNA occurs either through translational silencing of the target mRNA or through degradation of the target mRNA, via complementary binding, mostly to specific sequences in the three prime untranslated region of the target gene's mRNA. [34] The mechanism of translational silencing or degradation of target mRNA is implemented through the RNA-induced silencing complex (RISC).

DNA repair gene silencing

Silencing of a DNA repair gene by hypermethylation or other epigenetic alteration appears to be a frequent step in progression to cancer. As summarized in a review,[ citation needed ] promoter hypermethylation of DNA repair gene MGMT occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers. In addition, promoter hypermethylation of DNA repair genes LIG4 , NEIL1 , ATM , MLH1 or FANCB occurs at frequencies of between 33% and 82% in one or more of head and neck cancers, non-small-cell lung cancers or non-small-cell lung cancer squamous cell carcinomas. Further, the article Werner syndrome ATP-dependent helicase indicates the DNA repair gene WRN has a promoter that is often hypermethylated in a variety of cancers, with WRN hypermethylation occurring in 11% to 38% of colorectal, head and neck, stomach, prostate, breast, thyroid, non-Hodgkin lymphoma, chondrosarcoma and osteosarcoma cancers.

Such silencing likely acts similarly to a germ-line mutation in a DNA repair gene, and predisposes the cell and its descendants to progression to cancer. [35] Another review [36] points out that when a gene necessary for DNA repair is epigenetically silenced, DNA repair would tend to be deficient and DNA damages can accumulate. Increased DNA damage can cause increased errors during DNA synthesis, leading to mutations that give rise to cancer.

Induced by heavy metals

The heavy metals cadmium, arsenic and nickel are all carcinogenic when present above certain levels. [37] [38] [39] [40]

Cadmium is known to be carcinogenic, possibly due to reduction of DNA repair. Lei et al. [41] evaluated five DNA repair genes in rats after exposure of the rats to low levels of cadmium. They found that cadmium caused repression of three of the DNA repair genes: XRCC1 needed for base excision repair, OGG1 needed for base excision repair, and ERCC1 needed for nucleotide excision repair. Repression of these genes was not due to methylation of their promoters.

Arsenic carcinogenicity was reviewed by Bhattacharjee et al. [39] They summarized the role of arsenic and its metabolites in generating oxidative stress, resulting in DNA damage. In addition to causing DNA damage, arsenic also causes repression of several DNA repair enzymes in both the base excision repair pathway and the nucleotide excision repair pathway. Bhattacharjee et al. further reviewed the role of arsenic in causing telomere dysfunction, mitotic arrest, defective apoptosis, as well as altered promoter methylation and miRNA expression. Each of these alterations could contribute to arsenic-induced carcinogenesis.

Nickel compounds are carcinogenic and occupational exposure to nickel is associated with an increased risk of lung and nasal cancers. [42] Nickel compounds exhibit weak mutagenic activity, but they considerably alter the transcriptional landscape of the DNA of exposed individuals. [42] Arita et al. [42] examined the peripheral blood mononuclear cells of eight nickel-refinery workers and ten non-exposed workers. They found 2756 differentially expressed genes with 770 up-regulated genes and 1986 down-regulated genes. DNA repair genes were significantly over-represented among the differentially expressed genes, with 29 DNA repair genes repressed in the nickel-refinery workers and two over-expressed. The alterations in gene expression appear to be due to epigenetic alterations of histones, methylations of gene promoters, and hypermethylation of at least microRNA miR-152. [40] [43]

Clinical signs

Malignant transformation of cells in a benign tumor may be detected by pathologic examination of tissues. Often the clinical signs and symptoms are suggestive of a malignant tumor. The physician, during the medical history examination, can find that there have been changes in size or patient sensation and, upon direct examination, that there has been a change in the lesion itself.

Risk assessments can be done and are known for certain types of benign tumor which are known to undergo malignant transformation. One of the better-known examples of this phenomenon is the progression of a nevus to melanoma.

See also

Related Research Articles

<span class="mw-page-title-main">CpG site</span> Region of often-methylated DNA with a cytosine followed by a guanine

The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.

<span class="mw-page-title-main">BRCA1</span> Gene known for its role in breast cancer

Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the BRCA1 gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. BRCA1 is a human tumor suppressor gene and is responsible for repairing DNA.

<span class="mw-page-title-main">Regulation of gene expression</span> Modifying mechanisms used by cells to increase or decrease the production of specific gene products

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products. Sophisticated programs of gene expression are widely observed in biology, for example to trigger developmental pathways, respond to environmental stimuli, or adapt to new food sources. Virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing, and to the post-translational modification of a protein. Often, one gene regulator controls another, and so on, in a gene regulatory network.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">Neoplasm</span> Tumor or other abnormal growth of tissue

A neoplasm is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists in growing abnormally, even if the original trigger is removed. This abnormal growth usually forms a mass, which may be called a tumour or tumor.

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.

<span class="mw-page-title-main">Oncogenomics</span> Sub-field of genomics

Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer.

<span class="mw-page-title-main">MSH6</span> Protein-coding gene in the species Homo sapiens

MSH6 or mutS homolog 6 is a gene that codes for DNA mismatch repair protein Msh6 in the budding yeast Saccharomyces cerevisiae. It is the homologue of the human "G/T binding protein," (GTBP) also called p160 or hMSH6. The MSH6 protein is a member of the Mutator S (MutS) family of proteins that are involved in DNA damage repair.

<span class="mw-page-title-main">Methylated-DNA-protein-cysteine methyltransferase</span> Mammalian protein found in Homo sapiens

Methylated-DNA--protein-cysteine methyltransferase(MGMT), also known as O6-alkylguanine DNA alkyltransferaseAGT, is a protein that in humans is encoded by the MGMT gene. MGMT is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Accordingly, loss of MGMT increases the carcinogenic risk in mice after exposure to alkylating agents. The two bacterial isozymes are Ada and Ogt.

<span class="mw-page-title-main">XPC (gene)</span> Protein-coding gene in the species Homo sapiens

Xeroderma pigmentosum, complementation group C, also known as XPC, is a protein which in humans is encoded by the XPC gene. XPC is involved in the recognition of bulky DNA adducts in nucleotide excision repair. It is located on chromosome 3.

Post-transcriptional regulation is the control of gene expression at the RNA level. It occurs once the RNA polymerase has been attached to the gene's promoter and is synthesizing the nucleotide sequence. Therefore, as the name indicates, it occurs between the transcription phase and the translation phase of gene expression. These controls are critical for the regulation of many genes across human tissues. It also plays a big role in cell physiology, being implicated in pathologies such as cancer and neurodegenerative diseases.

Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death or death of an organism. Although the foregoing explanation is wider than this, it is common when referring to synthetic lethality to mean the situation arising by virtue of a combination of deficiencies of two or more genes leading to cell death, whereas a deficiency of only one of these genes does not. In a synthetic lethal genetic screen, it is necessary to begin with a mutation that does not result in cell death, although the effect of that mutation could result in a differing phenotype, and then systematically test other mutations at additional loci to determine which, in combination with the first mutation, causes cell death arising by way of deficiency or abolition of expression.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

Epigenetics of physical exercise is the study of epigenetic modifications to the cell genome resulting from physical exercise. Environmental factors, including physical exercise, have been shown to have a beneficial influence on epigenetic modifications. Generally, it has been shown that acute and long-term exercise has a significant effect on DNA methylation, an important aspect of epigenetic modifications.

Melanoma is a rare but aggressive malignant cancer that originates from melanocytes. These melanocytes are cells found in the basal layer of the epidermis that produce melanin under the control of melanocyte-stimulating hormone. Despite the fact that melanoma represents only a small number of all skin cancers, it is the cause of more than 50% of cancer-related deaths. The high metastatic qualities and death rate, and also its prevalence among people of younger ages have caused melanoma to become a highly researched malignant cancer. Epigenetic modifications are suspected to influence the emergence of many types of cancer-related diseases, and are also suspected to have a role in the development of melanoma.

Generally, in progression to cancer, hundreds of genes are silenced or activated. Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation. DNA methylation causing silencing in cancer typically occurs at multiple CpG sites in the CpG islands that are present in the promoters of protein coding genes.

DNA methylation in cancer plays a variety of roles, helping to change the healthy cells by regulation of gene expression to a cancer cells or a diseased cells disease pattern. One of the most widely studied DNA methylation dysregulation is the promoter hypermethylation where the CPGs islands in the promoter regions are methylated contributing or causing genes to be silenced.

CpG island hypermethylation is a phenomenon that is important for the regulation of gene expression in cancer cells, as an epigenetic control aberration responsible for gene inactivation. Hypermethylation of CpG islands has been described in almost every type of tumor.

Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.

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