Colorectal cancer pathophysiology: Difference between revisions
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__NOTOC__ | __NOTOC__ | ||
{{Colon cancer}} | {{Colon cancer}} | ||
{{CMG}} {{AE}} Saarah T. Alkhairy, M.D., Elliot B. Tapper, M.D. | |||
==Pathogenesis== | ==Pathogenesis== | ||
At a microbiological level, the development of the colorectal cancers (CRC) can be linked to defects within the [[cell cycle]]<ref name="pmid21190461">{{cite journal |author=Scully R |title=The spindle-assembly checkpoint, aneuploidy, and gastrointestinal cancer |journal=[[The New England Journal of Medicine]] |volume=363 |issue=27 |pages=2665–6 |year=2010 |month=December |pmid=21190461 |doi=10.1056/NEJMe1008017 |url=http://www.nejm.org/doi/abs/10.1056/NEJMe1008017?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed |accessdate=2011-12-12}}</ref>. Although its is poorly understood, the following five factors are recognized to be responsible for its neoplastic changes<ref name="Kim2014">{{cite journal|last1=Kim|first1=Eun Ran|title=Colorectal cancer in inflammatory bowel disease: The risk, pathogenesis, prevention and diagnosis|journal=World Journal of Gastroenterology|volume=20|issue=29|year=2014|pages=9872|issn=1007-9327|doi=10.3748/wjg.v20.i29.9872}}</ref>: | |||
*[[Genetic instability]] | |||
*Genetic instability | *[[Epigenetic alteration]] | ||
*Epigenetic alteration | *[[Chronic inflammation]] | ||
*Chronic inflammation | *[[Oxidative stress]] | ||
*Oxidative stress | *Intestinal [[microbiota]] | ||
*Intestinal microbiota | |||
===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 adenomatous polyposis ([[APC]]) function is common in sporadic CRC | ||
*A loss of P53 function is common in colitis-associated CRC | *A loss of 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) | :*[[Chromosomal instability]] (CIN) occurs when either whole chromosomes or parts of chromosomes are duplicated or deleted; it has a 85% frequency | ||
:*Microsatellite instability (MSI) | :*[[Microsatellite instability]] (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair; it a 15% frequency | ||
===Epigenetic alteration=== | ===Epigenetic alteration=== | ||
*Sporadic CRC can develop from dysplasia in 1 or 2 foci of the colon | *Sporadic CRC can develop from [[dysplasia]] in 1 or 2 foci of the colon | ||
*Colitis-associated CRC can develop from multifocal dysplasia | *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 | :*This indicates a field change effect where large areas of cells within the colon are affected by carcinogenic alterations | ||
===Chronic inflammation=== | ===Chronic inflammation=== | ||
*COX-2 is triggered by inflammatory stimuli such as IL-1, IFN-γ, and TNF-α | *[[COX-2]] is triggered by inflammatory stimuli such as [[IL-1]], [[IFN-γ, and [[TNF-α]] | ||
*COX-2 expression is elevated in nearly | *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 | ||
===Intestinal microbiota=== | ===Intestinal microbiota=== | ||
*The mechanism is still unclear | *The mechanism is still unclear | ||
< | ==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>: | |||
*Sporadic (75% of cases) - no apparent indications 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 MLH1 and MSH2 | |||
:*[[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 | |||
==Gross Pathology== | ==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]] | |||
[[Image:796px-Colon_cancer_2.jpg|200px|thumb|center|Appearance of the inside of the colon showing one invasive colorectal carcinoma (the crater-like, reddish, irregularly shaped tumor).]] | [[Image:796px-Colon_cancer_2.jpg|200px|thumb|center|Appearance of the inside of the colon showing one invasive colorectal carcinoma (the crater-like, reddish, irregularly shaped tumor).]] | ||
==Microscopic Pathology== | |||
Tumor cells form irregular tubular structures, harboring pleuristratification, multiple lumens, reduced stroma | *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 three degrees of differentiation: well, moderately, and 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.]] | ||
<br clear="left"/> | <br clear="left"/> | ||
===Video=== | ===Video=== | ||
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[[Category:Types of cancer]] | [[Category:Types of cancer]] | ||
[[Category:Conditions diagnosed by stool test]] | [[Category:Conditions diagnosed by stool test]] | ||
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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.
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 adenomatous polyposis (APC) function is common in sporadic CRC
- A loss of 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 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 indications 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 MLH1 and MSH2
- 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
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 three degrees of differentiation: well, moderately, and 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.