Colorectal cancer pathophysiology: Difference between revisions
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===Genetic instability=== | ===Genetic instability=== | ||
*[[Aneuploidy]] is demonstrated in about 50%-90% of cancers | *[[Aneuploidy]] is demonstrated in about 50%-90% of cancers | ||
*A loss of adenomatous polyposis ([[APC]]) function is common in sporadic CRC | *A loss of the adenomatous polyposis ([[APC]]) function is common in sporadic CRC | ||
*A loss of P53 function is common in colitis-associated CRC | *A loss of the P53 function is common in colitis-associated CRC | ||
*The following are two types of genomic instability | *The following are two types of genomic instability | ||
:*Chromosomal instability (CIN) occurs when either whole chromosomes or parts of chromosomes are duplicated or deleted; it has a 85% frequency | :*Chromosomal instability (CIN) occurs when either whole chromosomes or parts of chromosomes are duplicated or deleted; it has a 85% frequency | ||
:*[[Microsatellite instability]] (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair; it a 15% frequency | :*[[Microsatellite instability]] (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair; it has a 15% frequency | ||
===Epigenetic alteration=== | ===Epigenetic alteration=== | ||
| Line 30: | Line 30: | ||
===Chronic inflammation=== | ===Chronic inflammation=== | ||
*[[COX-2]] is triggered by inflammatory stimuli such as [[IL-1]], | *[[COX-2]] is triggered by inflammatory stimuli such as [[IL-1]], IFN-γ, and [[TNF-α]] | ||
*COX-2 expression is elevated in nearly 85% of [[adenocarcinomas]] | *COX-2 expression is elevated in nearly 85% of [[adenocarcinomas]] | ||
===Oxidative stress=== | ===Oxidative stress=== | ||
*[[Oxidative stress]] results from inflammatory reactions which include inflammatory cells, activated neutrophils, and [[macrophages]] | *[[Oxidative stress]] results from inflammatory reactions which include inflammatory cells, activated [[neutrophils]], and [[macrophages]] | ||
*[[Macrophages]] produce large amounts of reactive oxygen and nitrogen species (RONS) | *[[Macrophages]] produce large amounts of reactive oxygen and nitrogen species (RONS) | ||
*RONs can interact with key genes involved in carcinogenic pathways such as [[P53]] and [[DNA mismatch repair]] genes | *RONs can interact with key genes involved in carcinogenic pathways such as [[P53]] and [[DNA mismatch repair]] genes | ||
| Line 43: | Line 43: | ||
==Genetics== | ==Genetics== | ||
CRC can be grouped into three categories from a genetic perspective<ref name="pmid25276405">{{cite journal| author=Schlussel AT, Gagliano RA, Seto-Donlon S, Eggerding F, Donlon T, Berenberg J et al.| title=The evolution of colorectal cancer genetics-Part 1: from discovery to practice. | journal=J Gastrointest Oncol | year= 2014 | volume= 5 | issue= 5 | pages= 326-35 | pmid=25276405 | doi=10.3978/j.issn.2078-6891.2014.069 | pmc=PMC4173047 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25276405 }} </ref>: | CRC can be grouped into three categories from a genetic perspective<ref name="pmid25276405">{{cite journal| author=Schlussel AT, Gagliano RA, Seto-Donlon S, Eggerding F, Donlon T, Berenberg J et al.| title=The evolution of colorectal cancer genetics-Part 1: from discovery to practice. | journal=J Gastrointest Oncol | year= 2014 | volume= 5 | issue= 5 | pages= 326-35 | pmid=25276405 | doi=10.3978/j.issn.2078-6891.2014.069 | pmc=PMC4173047 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25276405 }} </ref>: | ||
*Sporadic (75% of cases) - no apparent | *Sporadic (75% of cases) - no apparent indication of a hereditary component | ||
*[[Familial]] (20% of cases) - multifactorial hereditary factors or common exposures to non-genetic risk factors or both | *[[Familial]] (20% of cases) - multifactorial hereditary factors or common exposures to non-genetic risk factors or both | ||
*[[Hereditary]] (10% of cases) | *[[Hereditary]] (10% of cases) | ||
| Line 67: | Line 67: | ||
*Sometimes, tumor cells are discohesive and secrete [[mucus]], which invades the [[interstitium]] producing large pools of mucus/colloid (optically "empty" spaces) | *Sometimes, tumor cells are discohesive and secrete [[mucus]], which invades the [[interstitium]] producing large pools of mucus/colloid (optically "empty" spaces) | ||
*If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery (signet-ring cell) | *If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery (signet-ring cell) | ||
*Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present in three degrees of differentiation: well, moderately, | *Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present in one of three degrees of differentiation: well, moderately, or poorly differentiated<ref[http://www.pathologyatlas.ro/Colon%20Cancer.html Pathology atlas (in Romanian)]</ref> | ||
[[Image:Colonic carcinoid (1) Endoscopic resection.jpg|thumb|center|Histopathologic image of colonic carcinoid stained by hematoxylin and eosin.]] | [[Image:Colonic carcinoid (1) Endoscopic resection.jpg|thumb|center|Histopathologic image of colonic carcinoid stained by hematoxylin and eosin.]] | ||
Revision as of 17:33, 15 July 2015
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Colorectal cancer Microchapters |
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Colorectal cancer pathophysiology On the Web |
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Risk calculators and risk factors for Colorectal cancer pathophysiology |
To view the pathophysiology of familial adenomatous polyposis (FAP), click here
To view the pathophysiology of hereditary nonpolyposis colorectal cancer (HNPCC), click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saarah T. Alkhairy, M.D., Elliot B. Tapper, M.D.
Overview
The pathogenesis of colorectal carcinoma (CRC) involves genetic instability, epigenetic alteration, chronic inflammation, oxidative stress, and intestinal microbiota. Some examples of the types of colorectal carcinoma that can be linked to genetics are hereditary nonpolyposis colon cancer (HNPCC), familial adenomatous polyposis (FAP), and MUTYH-associated polyposis (MAP). Right-sided and left-sided tumors differ in their gross pathology. Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present in three degrees of differentiation: well, moderately, and poorly differentiated.
Pathogenesis
At a microbiological level, the development of the colorectal cancers (CRC) can be linked to defects within the cell cycle[1]. Although its is poorly understood, the following five factors are recognized to be responsible for its neoplastic changes[2]:
- Genetic instability
- Epigenetic alteration
- Chronic inflammation
- Oxidative stress
- Intestinal microbiota
Genetic instability
- Aneuploidy is demonstrated in about 50%-90% of cancers
- A loss of the adenomatous polyposis (APC) function is common in sporadic CRC
- A loss of the P53 function is common in colitis-associated CRC
- The following are two types of genomic instability
- Chromosomal instability (CIN) occurs when either whole chromosomes or parts of chromosomes are duplicated or deleted; it has a 85% frequency
- Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair; it has a 15% frequency
Epigenetic alteration
- Sporadic CRC can develop from dysplasia in 1 or 2 foci of the colon
- Colitis-associated CRC can develop from multifocal dysplasia
- This indicates a field change effect where large areas of cells within the colon are affected by carcinogenic alterations
Chronic inflammation
- COX-2 is triggered by inflammatory stimuli such as IL-1, IFN-γ, and TNF-α
- COX-2 expression is elevated in nearly 85% of adenocarcinomas
Oxidative stress
- Oxidative stress results from inflammatory reactions which include inflammatory cells, activated neutrophils, and macrophages
- Macrophages produce large amounts of reactive oxygen and nitrogen species (RONS)
- RONs can interact with key genes involved in carcinogenic pathways such as P53 and DNA mismatch repair genes
Intestinal microbiota
- The mechanism is still unclear
Genetics
CRC can be grouped into three categories from a genetic perspective[3]:
- Sporadic (75% of cases) - no apparent indication of a hereditary component
- Familial (20% of cases) - multifactorial hereditary factors or common exposures to non-genetic risk factors or both
- Hereditary (10% of cases)
- Hereditary nonpolyposis colon cancer (HNPCC) also known as Lynch Syndrome results from mutations in hMLH1, hMSH2, hMSH6, and PMS2
- Familial adenomatous polyposis (FAP) results from mutations in the APC gene located on chromosome 5p22.2
- MUTYH-associated polyposis (MAP) results from biallelic mutation of the MutY, E. Coli, Homolog gene which functions to remove adenine residues mispaired with 8-hydroxyguanine in DNA
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Molecular pathogenesis of sporadic colon cancer and colitis-associated colon cancer
Adapted from APS Journals
Gross Pathology
- Right-sided tumors (ascending colon and cecum) tends to grow outwards from one location in the bowel wall (exophytic)
- Left-sided tumours tend to be circumferential
Microscopic Pathology
- Tumor cells form irregular tubular structures, harboring pleuristratification, multiple lumens, and reduced stroma
- Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus/colloid (optically "empty" spaces)
- If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery (signet-ring cell)
- Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present in one of three degrees of differentiation: well, moderately, or poorly differentiated<refPathology atlas (in Romanian)</ref>
_Endoscopic_resection.jpg)
Video
{{#ev:youtube|Sh65aXndqXk}}
References
- ↑ Scully R (2010). "The spindle-assembly checkpoint, aneuploidy, and gastrointestinal cancer". The New England Journal of Medicine. 363 (27): 2665–6. doi:10.1056/NEJMe1008017. PMID 21190461. Retrieved 2011-12-12. Unknown parameter
|month=ignored (help) - ↑ Kim, Eun Ran (2014). "Colorectal cancer in inflammatory bowel disease: The risk, pathogenesis, prevention and diagnosis". World Journal of Gastroenterology. 20 (29): 9872. doi:10.3748/wjg.v20.i29.9872. ISSN 1007-9327.
- ↑ Schlussel AT, Gagliano RA, Seto-Donlon S, Eggerding F, Donlon T, Berenberg J; et al. (2014). "The evolution of colorectal cancer genetics-Part 1: from discovery to practice". J Gastrointest Oncol. 5 (5): 326–35. doi:10.3978/j.issn.2078-6891.2014.069. PMC 4173047. PMID 25276405.