Field cancerization or field effect (also termed field change, field change cancerization, field carcinogenesis, cancer field effect or premalignant field defect) is a biological process in which large areas of cells at a tissue surface or within an organ are affected by carcinogenic alterations. The process arises from exposure to an injurious environment, often over a lengthy period. [1]
The initial step in field cancerization is associated with various molecular lesions such as acquired genetic mutations and epigenetic changes, occurring over a widespread, multi-focal "field". [2] [3] [4] [5] [6] [7] [8] These initial molecular changes may subsequently progress to cytologically recognizable premalignant foci of dysplasia, and eventually to carcinoma in situ (CIS) or cancer. [1] [5] The image of a longitudinally opened colon resection on this page shows an area of a colon resection that likely has a field cancerization or field defect. It has one cancer and four premalignant polyps.
Field cancerization can occur in any tissue. [1] Prominent examples of field cancerization include premalignant field defects in head and neck cancer, [9] lung cancer, [2] [3] colorectal cancer, [10] Barrett's esophagus, [11] [12] [13] skin, [4] [6] [8] breast ducts [7] [14] and bladder. [1] [15] Field cancerization has implications for cancer surveillance and treatment. [3] [4] [8] [11] [14] [16] Despite adequate resection and being histologically normal, the remaining locoregional tissue has an increased risk for developing multiple independent cancers, either synchronously or metachronously. [1] [9] [17]
A common carcinogenic alteration, found in many cancers and in their adjacent field defects from which the cancers likely arose, is reduced expression of one or more DNA repair enzymes. Since reduced DNA repair expression is often present in a field cancerization or a field defect, it is likely to have been an early step in progression to the cancer.
| Cancer | Gene | Frequency in Cancer | Frequency in Field Defect | Ref. |
|---|---|---|---|---|
| Colorectal | MGMT | 46% | 34% | [18] |
| Colorectal | MGMT | 47% | 11% | [19] |
| Colorectal | MGMT | 70% | 60% | [20] |
| Colorectal | MSH2 | 13% | 5% | [19] |
| Colorectal | ERCC1 | 100% | 40% | [21] |
| Colorectal | PMS2 | 88% | 50% | [21] |
| Colorectal | XPF | 55% | 40% | [21] |
| Head and Neck | MGMT | 54% | 38% | [22] |
| Head and Neck | MLH1 | 33% | 25% | [23] |
| Head and Neck | MLH1 | 31% | 20% | [24] |
| Stomach | MGMT | 88% | 78% | [25] |
| Stomach | MLH1 | 73% | 20% | [26] |
| Esophagus | MLH1 | 77%-100% | 23%-79% | [27] |
Field defects associated with gastrointestinal tract cancers also commonly displayed reduced apoptosis competence, aberrant proliferation and genomic instability. [28] Field defects of the gastrointestinal tract that show those common faults occurred in the oropharynx, esophagus, stomach, bile duct, pancreas, small intestine and colon/rectum.
The field defect adjacent to a colon cancer consists of the inner surface of the colon (the epithelium) that has about 1 million crypts (indentations in the surface of the epithelium). [21] Each crypt has about 5,000 cells in the shape of a test-tube and all 5,000 cells of the crypt are generated from the few stem cells at the base of the crypt. The stem cells at the base of the crypt can undergo "crypt conversion" where a stem cell with a selective advantage takes over the stem cell niche, and all cells of that crypt display consistent expression (high or low) of a protein being evaluated.
The diagram shows results obtained by Facista et al. [21] A particular colon resection from a colon cancer patient was evaluated for expression of 3 different DNA repair enzymes: Ku86 (active in the non-homologous end joining pathway), ERCC1 (active in the nucleotide excision DNA repair pathway) and PMS2 (active in the mismatch DNA repair pathway). The percent of crypts in 6 tissue samples taken within the field defect were evaluated for frequency of high levels of expression of each of the repair proteins. Almost every crypt in all tissue samples from this patient showed high expression of KU86. However, the majority of crypts in all 6 tissue samples were reduced or absent in protein expression of ERCC1 and PMS2. The crypts with reduced or absent expression of ERCC1 or PMS2 usually occurred in large patches of adjacent crypts. Both ERCC1 and PMS2, in these tissue samples, were thought to be deficient due to epigenetic alterations.
Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal or ectodermal germ layer during embryogenesis.
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.
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.
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.
A precancerous condition is a condition, tumor or lesion involving abnormal cells which are associated with an increased risk of developing into cancer. Clinically, precancerous conditions encompass a variety of abnormal tissues with an increased risk of developing into cancer. Some of the most common precancerous conditions include certain colon polyps, which can progress into colon cancer, monoclonal gammopathy of undetermined significance, which can progress into multiple myeloma or myelodysplastic syndrome. and cervical dysplasia, which can progress into cervical cancer. Bronchial premalignant lesions can progress to squamous cell carcinoma of the lung.
Gastrointestinal cancer refers to malignant conditions of the gastrointestinal tract and accessory organs of digestion, including the esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus. The symptoms relate to the organ affected and can include obstruction, abnormal bleeding or other associated problems. The diagnosis often requires endoscopy, followed by biopsy of suspicious tissue. The treatment depends on the location of the tumor, as well as the type of cancer cell and whether it has invaded other tissues or spread elsewhere. These factors also determine the prognosis.
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.
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.
DNA mismatch repair protein Msh2 also known as MutS homolog 2 or MSH2 is a protein that in humans is encoded by the MSH2 gene, which is located on chromosome 2. MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair.
DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. The gene is commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.
High-mobility group AT-hook 2, also known as HMGA2, is a protein that, in humans, is encoded by the HMGA2 gene.
Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene.
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
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.
ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ERCC4 gene. Together with ERCC1, ERCC4 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
Mouse models of colorectal cancer and intestinal cancer are experimental systems in which mice are genetically manipulated, fed a modified diet, or challenged with chemicals to develop malignancies in the gastrointestinal tract. These models enable researchers to study the onset, progression of the disease, and understand in depth the molecular events that contribute to the development and spread of colorectal cancer. They also provide a valuable biological system, to simulate human physiological conditions, suitable for testing therapeutics.
Somatic evolution is the accumulation of mutations and epimutations in somatic cells during a lifetime, and the effects of those mutations and epimutations on the fitness of those cells. This evolutionary process has first been shown by the studies of Bert Vogelstein in colon cancer. Somatic evolution is important in the process of aging as well as the development of some diseases, including cancer.
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.
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.
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.
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