Colorectal cancer pathophysiology: Difference between revisions
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==Pathogenesis== | ==Pathogenesis== | ||
The pathogenesis of colorectal carcinoma (CRC) involves the molecular pathways for both sporadic and colitis-associated CRC. | |||
===Sporadic colorectal cancers=== | ===Sporadic colorectal cancers=== | ||
The picture below depicts the molecular pathogenesis of sporadic colon cancer | The picture below depicts the molecular pathogenesis of sporadic colon cancer:<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> | ||
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Sporadic colorectal cancer originates from the [[epithelial cells]] that line the [[colon]] or [[rectum]] | Sporadic colorectal cancer originates from the [[epithelial cells]] that line the [[colon]] or [[rectum]]; it may involve the following:<ref name="pmid20018966">{{cite journal| author=Markowitz SD, Bertagnolli MM| title=Molecular origins of cancer: Molecular basis of colorectal cancer. | journal=N Engl J Med | year= 2009 | volume= 361 | issue= 25 | pages= 2449-60 | pmid=20018966 | doi=10.1056/NEJMra0804588 | pmc=PMC2843693 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20018966 }} </ref> | ||
*'''[[APC gene]]''' | *'''[[APC gene]]''' | ||
:* | :*Produces the APC protein, which prevents the accumulation of [[β-catenin]] protein (responsible for stem cell renewal) | ||
:** | :**Mutation of the APC protein leads to the accumulation of [[β-catenin]] protein and causes inappropriately high levels of stem cell renewal. | ||
*'''[[TP53|TP53 gene]]''' | *'''[[TP53|TP53 gene]]''' | ||
:* | :*Produces the [[P53 (protein)|p53 protein]], which monitors cell division and promotes [[apoptosis]] if there are cell defects | ||
:* | :*M[[mutation|utation]]<nowiki/>s result in loss of control over cell division or apoptosis | ||
*'''[[TGF beta|TGF-β]] and [[DCC]] (Deleted in Colorectal Cancer)''' | *'''[[TGF beta|TGF-β]] and [[DCC]] (Deleted in Colorectal Cancer)''' | ||
:*Both of these proteins are responsible for [[apoptosis]], but are deactivated in CRC | :*Both of these proteins are responsible for [[apoptosis]], but are deactivated in CRC | ||
Revision as of 18:04, 21 January 2019
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Colorectal cancer Microchapters |
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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 the molecular pathways for both sporadic and colitis-associated CRC. Sporadic instability originates from the epithelial cells that line the colon or rectum. Colitis-associated CRC includes genetic instability, epigenetic alteration, chronic inflammation, oxidative stress, and intestinal microbiota. 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
The pathogenesis of colorectal carcinoma (CRC) involves the molecular pathways for both sporadic and colitis-associated CRC.
Sporadic colorectal cancers
The picture below depicts the molecular pathogenesis of sporadic colon cancer:[1]
Sporadic colorectal cancer originates from the epithelial cells that line the colon or rectum; it may involve the following:[2]
- Produces the p53 protein, which monitors cell division and promotes apoptosis if there are cell defects
- Mutations result in loss of control over cell division or apoptosis
- Both of these proteins are responsible for apoptosis, but are deactivated in CRC
- These genes stimulate the cell to divide
- If there is a mutation of an oncogene, there may be an over-activation of cell proliferation
Colitis-associated colorectal cancers
The picture below depicts the molecular pathogenesis of colitis-associated colon cancer[1]
At a microbiological level, the development of colitis-associated colorectal cancers (CRC) can be linked to defects within the cell cycle.[3] Although it is poorly understood, the following five factors may be responsible for its neoplastic changes:[1]
- Genetic instability
- Epigenetic alteration
- Chronic inflammation
- Oxidative stress
- Intestinal microbiota
Genetic instability
- Aneuploidy is present in approximately 50%-90% of cancers[1]
- A loss of the P53 function is common in colitis-associated CRC, although it can be found in sporadic colon cancer[1]
- A loss of the adenomatous polyposis (APC) function is common in sporadic CRC, although it can be found in colitis-associated colon cancer[1]
- The following are two types of genomic instability[4]
- Chromosomal instability (CIN) occurs when either whole chromosomes or parts of chromosomes are duplicated or deleted; it occurs with 85% frequency
- Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair; it occurs with 15% frequency
Epigenetic alteration
- Sporadic CRC can develop from dysplasia in 1 or 2 foci of the colon[5]
- Colitis-associated CRC can develop from multifocal dysplasia[6]
- 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[7]
- COX-2 expression is elevated in approximately 85% of adenocarcinomas[7]
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)[8]
- RONs can interact with key genes involved in carcinogenic pathways such as P53 and DNA mismatch repair genes[8]
Intestinal microbiota
- The Modification of enteric flora by probiotic lactobacilli is a proposed mechanism that may contribute to the development of colitis-associated cancer[9]
Genetics
CRC can be grouped into three categories from a genetic perspective:[10]
- 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
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
_Endoscopic_resection.jpg)
Histology
- Most tumors affecting the colon are carcinomas, and of these carcinomas almost 90% are adenocarcinomas.
- Rarely, tumors of the colon are of other histologic types including hamartomas, neuroendocrine neoplasms, mesenchymal, or lymphomas.
- The College of American Pathologists (CAP) and the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) have both recommended the adoption of a two-tiered grading system for CRC and the use of gland formation as the only feature by which grade is assessed.[11]
- 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)
Grades of Colorectal Cancer
The grade describes how closely the cancer looks like normal tissue when seen under a microscope. This is sometimes used to distinguish whether a patient should get adjuvant treatment with chemotherapy after surgery.
- Grade 1 - Well differentiated
- Grade 2 - Moderately differentiated
- Grade 3 - Poorly differentiated
- Grade 4 - Undifferentiated
Video
{{#ev:youtube|Sh65aXndqXk}}
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 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.
- ↑ Markowitz SD, Bertagnolli MM (2009). "Molecular origins of cancer: Molecular basis of colorectal cancer". N Engl J Med. 361 (25): 2449–60. doi:10.1056/NEJMra0804588. PMC 2843693. PMID 20018966.
- ↑ 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.
- ↑ Zivić R, Bjelaković G, Koraćević D (1975). "[Amino acid constitution of the urine in children with rheumatic fever]". Reumatizam. 22 (1): 21–5. PMID 1118685.
- ↑ Kraus S, Arber N (2009). "Inflammation and colorectal cancer". Curr Opin Pharmacol. 9 (4): 405–10. doi:10.1016/j.coph.2009.06.006. PMID 19589728.
- ↑ Itzkowitz S (2003). "Colon carcinogenesis in inflammatory bowel disease: applying molecular genetics to clinical practice". J Clin Gastroenterol. 36 (5 Suppl): S70–4, discussion S94-6. PMID 12702969.
- ↑ 7.0 7.1 Elzagheid A, Emaetig F, Alkikhia L, Buhmeida A, Syrjänen K, El-Faitori O; et al. (2013). "High cyclooxygenase-2 expression is associated with advanced stages in colorectal cancer". Anticancer Res. 33 (8): 3137–43. PMID 23898071.
- ↑ 8.0 8.1 Ullman TA, Itzkowitz SH (2011). "Intestinal inflammation and cancer". Gastroenterology. 140 (6): 1807–16. doi:10.1053/j.gastro.2011.01.057. PMID 21530747.
- ↑ O'Mahony L, Feeney M, O'Halloran S, Murphy L, Kiely B, Fitzgibbon J; et al. (2001). "Probiotic impact on microbial flora, inflammation and tumour development in IL-10 knockout mice". Aliment Pharmacol Ther. 15 (8): 1219–25. PMID 11472326.
- ↑ 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.
- ↑ Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR; et al. (2000). "Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999". Arch Pathol Lab Med. 124 (7): 979–94. doi:10.1043/0003-9985(2000)124<0979:PFICC>2.0.CO;2. PMID 10888773.