Colorectal cancer pathophysiology

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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 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

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]:

  • The APC gene
  • It produces the APC protein, which prevents the accumulation of β-cateninprotein (responsible for stem cell renewal)
    • If there is a mutation of the APC protein, β-cateninprotein accumulates and causes inappropriately high levels of stem cell renewal
  • The TP53 gene
  • It produces the p53 protein, which monitors cell division and promotes apoptosis if there are cell defects
  • If there is a mutation, there is no control over cell division or apoptosis
  • TGF-β and DCC (Deleted in Colorectal Cancer)
  • Both of these proteins are responsible for apoptosis, but are deactivated in CRC
  • Oncogenes
  • These genes stimulate the cell to divide
  • If there is a mutation of an oncogene, there may be an over-activation of cell proliferation
  • Examples are K-RAS and RAF

Colitis-associated colorectal cancers

The picture below depicts the molecular pathogenesis of colitis-assocated 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

  • 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 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[5][6]
  • Colitis-associated CRC can develop from multifocal dysplasia[5][6]
  • This indicates a field change effect where large areas of cells within the colon are affected by carcinogenic alterations

Chronic inflammation

Oxidative stress

Intestinal microbiota

  • The Modification of enteric flora by probiotic lactobacilli is a proposed mechanism 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
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, 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[11]
Histopathologic image of colonic carcinoid stained by hematoxylin and eosin.


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

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References

  1. 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.
  2. 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.
  3. 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)
  4. 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.
  5. 5.0 5.1 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.
  6. 6.0 6.1 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. 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. 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.
  9. 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.
  10. 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.
  11. Pathology atlas (in Romanian)


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