Colorectal cancer pathophysiology
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Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753; Elliot B. Tapper, M.D., Beth Israel Deaconess Medical Center Michael Maddaleni, B.S.;Associate Editor(s)-in-Chief: Shivali Marketkar, M.B.B.S. [2]
Pathogenesis
- At a microbiological level, the development of the colon cancers (as well as other cancers) can be linked to defects within the cell cycle[1]
- Although the pathogenesis of colorectal cancer (CRC) is poorly understood, the following five factors are 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) with a 85% frequency
- Microsatellite instability (MSI) with a 15% frequency
- It is associated with a promotor hypermethylation of the mismatch repair gene hMLH1
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 induces inflammation
- COX-2 expression is elevated in nearly 50% of adenomas and 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
-
Description
Adapted from CDC
Gross Pathology
Adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the colorectal mucosa. It invades the wall, infiltrating the muscularis mucosae, the submucosa and thence the muscularis propria. Cancers on the right side (ascending colon and cecum) tend to be exophytic, that is, the tumour grows outwards from one location in the bowel wall. This very rarely causes obstruction of feces, and presents with symptoms such as anemia. Left-sided tumours tend to be circumferential, and can obstruct the bowel much like a napkin ring.
Microscopic Pathology
Tumor cells form irregular tubular structures, harboring pleuristratification, multiple lumens, reduced stroma ("back to back" aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus/colloid (optically "empty" spaces) - mucinous (colloid) adenocarcinoma, poorly differentiated. 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 three degrees of differentiation: well, moderately, and poorly differentiated. [3]
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Genetics
As of 1993, there was a discovery made in the mechanism of the development of colon cancers. It was found that HNPCC is caused by germline mutations of mismatch repair genes[1]. A germline mutation is defined as a gene change in a body's reproductive cell that becomes incorporated into the DNA of every cell in the body of the offspring. Colorectal cancer is a disease originating from the epithelial cells lining the gastrointestinal tract. Hereditary or somatic mutations in specific DNA sequences, among which are included DNA replication or DNA repair genes[4], and also the APC, K-Ras, NOD2 and p53 genes, lead to unrestricted cell division. The exact reason why (and whether) a diet high in fiber might prevent colorectal cancer remains uncertain. Chronic inflammation, as in inflammatory bowel disease, may predispose patients to malignancy. Another mechanism involves the WNT gene family. There are a total of 19 genes in the WNT gene family and they are responsible for providing the instructions to make proteins that are responsible for chemical signaling. Research has shown that up-regulation of WNT signaling will cause crypt cells in the intestine to proliferate for longer than normal before they differentiate and migrate[5]. Prolonged proliferation eventually causes polyps to form, which in turn creates a predisposition to colon cancer.
Video
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References
- ↑ 1.0 1.1 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.
- ↑ Pathology atlas (in Romanian)
- ↑ Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993). "Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis". Nature. 363 (6429): 558–61. PMID 8505985.
- ↑ Dolmans GH, Werker PM, Hennies HC, Furniss D, Festen EA, Franke L, Becker K, van der Vlies P, Wolffenbuttel BH, Tinschert S, Toliat MR, Nothnagel M, Franke A, Klopp N, Wichmann HE, Nürnberg P, Giele H, Ophoff RA, Wijmenga C (2011). "Wnt signaling and Dupuytren's disease". The New England Journal of Medicine. 365 (4): 307–17. doi:10.1056/NEJMoa1101029. PMID 21732829. Retrieved 2011-12-12. Unknown parameter
|month=ignored (help)