How aspirin might prevent colorectal cancer?

Posted: Sunday, January 2, 2011 | Posted by Debajyoti Datta | Labels: ,

I must confess that I am fascinated by the potential of aspirin in colorectal carcinoma prevention. It is worthwhile to look into this in some detail. Before we delve into the mechanism of colorectal carcinoma prevention by aspirin we must examine how colorectal carcinoma develops.


Colorectal carcinogenesis is characterized by a set of genetic alterations. The Fearon and Vogelstein model is a well accepted model explaining the sequence of colorectal cancer development. Their model is based on adenoma-carcinoma sequence. This suggests that colorectal carcinoma is preceded by adenomatous changes. Where adenomatous changes can not be identified, it is considered that the carcinoma directly arose from a dysplastic lesion. The development of colorectal carcinogenesis is taken to occur through through two distinct pathways –
  • APC/β-catenin pathway.
  • Microsatellite instability pathway.
In both the pathways there is step-wise accumulation of mutations but the genes involved and mutations occurring are different.

The APC/ β-catenin pathway is characterized by the loss of Adenomatous polyposis coli (APC) gene. The APC gene is located in the long arm of the 5th chromosome (5q21). APC is a dual-function tumor suppressor gene coding for a protein that binds to bundles of microtubules and promotes cell adhesion and migration. The level of β-catenin is also regulated by APC. β-catenin is a mediator in the Wnt/ β-catenin signaling pathway which plays a significant role in normal development of the intestinal epithelium. It is also involved in colorectal carcinoma development. Inactivated APC can be found in more than 80% cases of colorectal cases and 50% of the cases that don’t have APC mutation have β-catenin mutation.

β-catenin, a member of the cadherin based cell adhesive complex, acts as a transcription factor when translocated to the nucleus. In case of APC gene mutation, β-catenin accumulates in the cytoplasm and is subsequently translocated to the nucleus. When inside the nucleus it binds with a family of transcription factors called T-cell factor or lymphoid enhancer factor (TCF or LEF). β-catenin –TCF complex is considered to activate genes associated with regulation of cellular proliferation and apoptosis like c-MYC and CYCLIN D1. Thus mutation in APC gene leads to increased cellular proliferation and decreased cell adhesion.

Mutation of the oncogene K-RAS is thought to occur next. This is the most commonly activated oncogene seen in adenomas and colorectal carcinomas. Allelic loss at chromosome 18q21 occurs and it is suggested to be SMAD2 and SMAD4 which are involved in TGF β signaling. p53 gene mutations occur late in colorectal carcinogenesis and are seen in 70 to 80% cases of colon cancer. Increased telomerase activity has also been found in colorectal cancers.

The microsatellite instability pathway is characterized by genetic lesions in the DNA mismatch repair genes. These lesions are found in the HNPCC (Hereditary Nonpolyposis Colorectal cancer) syndrome and in 10 to 15% of sporadic cases. Inactivation of the DNA mismatch repair genes results in defective DNA repair. Any of the human mismatch repair genes hMSH2, hMLH1, MSH6, hPMS1, hPMS2 may be involved in HNPCC syndrome.

Mutations in mismatch repair genes cause alterations in microsatellites (fragments of repeat sequences in human genome that are prone to misalignment during DNA replication). This leads to microsatellite instability. Some microsatellites are located in the coding or promoter regions of genes like type II TGF – β receptor and BAX. TGF – β signaling is involved in inhibiting the growth of colonic epithelial cells and BAX genes cause apoptosis. Microsatellite instability thus leads to their nonfunctioning and colorectal carcinogenesis.

Now where does aspirin come in all these? Aspirin belongs to a group of drugs called NSAIDs (Non Steroidal Anti Inflammatory Drugs) that inhibit cyclooxygenase (COX) enzymes resulting in decreased prostaglandin synthesis. There are two isoforms of COX, COX-1 which is constitutively expressed and COX-2 which is inducible.

In colorectal carcinogenesis there is overexpression of COX-2 enzyme, there by giving aspirin the chance to bite. However the exact step where aspirin might act is unclear.

development pathway of colorectal cancer
Multistep progression of colon cancer and sites of NSAID action. From Postgrad Med J 2005;81:223-227 doi:10.1136/pgmj.2003.008227

Aspirin and other NSAIDs might also act through COX independent pathways to prevent colon cancer. High doses of aspirin have been shown to oppose the survival signaling pathway mediated by the transcription factor NF-kB. This is considered to occur through the inactivation of IkB kinase β. IkB kinase β is responsible for the activation of NF-kB cycle by phosphorylation of the inhibitory subunit of NF-kB. Hence aspirin inhibits the NF-kB pathway and interferes with cell survival.

pathway of action of aspirin in colorectal cancer prevention

Molecular mechanisms that mediate the effects of NSAIDs and anticancer drugs on survival and apoptosis in colon cancer cells. Schematic representation of cytokine, EGF-related growth factors and TRAIL ligand-dependent signal transduction pathways for survival and apoptosis. Stimulatory and inhibitory effects are indicated by arrows and bars, respectively. Abbreviations: MAPK=mitogen-activated protein kinase, MAPKK=mitogen-activated protein kinase kinase, JNK=jun kinase, IkB=inhibitor kinase B, NF-kB=nuclear factor kappa B, COX=cyclooxygenase, PI3K=phosphatidylinositol 3 kinase. From:Br J Cancer. 2003 March 24; 88(6): 803–807.
Synergistic effect of NSAIDs with conventional chemotherapeutic drugs has also been observed. The effect of NSAIDs in preventing neoangiogenesis is also important. Neoangiogenesis is a vital event in tumor growth and metastasis and tumor cells need adequate blood supply to derive nutrients. Prostaglandins are thought to be involved in angiogenesis by regulating proangiogenic factor synthesis like vascular endothelial growth factor (VEGF). Both COX-1 and COX-2 are considered to be involved in this.

Relative levels of Bcl-2 proteins regulate eukaryotic cell survival and apoptosis. SC-58125 and NS-398, COX-2 selective inhibitors, downregulates anti-apoptotic protein bcl-1 and sensitizes colorectal and proastate cancer cels to apoptosis. Aspirin upregulates bax and bak (proapoptotic proteins) and activates caspase 3 resulting in apoptosis. AKT, an anti-apoptotic protein kinase and the Fas-associated death domain has also been implicated in NSIAD induced apoptosis.

What remains to be seen is whether the advantages of aspirin will be sufficient considering the risk of GI adverse effects and how much benefit aspirin or any other NSAID provides. I want to remain hopeful.

Reference:
ResearchBlogging.org
Sangha, S. (2005). Non-steroidal anti-inflammatory drugs and colorectal cancer prevention Postgraduate Medical Journal, 81 (954), 223-227 DOI: 10.1136/pgmj.2003.008227
ResearchBlogging.org
Ricchi, P., Zarrilli, R., di Palma, A., & Acquaviva, A. (2003). Minireview: Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy British Journal of Cancer, 88 (6), 803-807 DOI: 10.1038/sj.bjc.6600829
ResearchBlogging.org
KINZLER, K. (1996). Lessons from Hereditary Colorectal Cancer Cell, 87 (2), 159-170 DOI: 10.1016/S0092-8674(00)81333-1

5 comments:

  1. Phenocane said...
  2. Hello, Many many thanks to Debajyoti Datta for the valuable information regarding How aspirin might prevent colorectal cancer? Thanks a lot.

  3. Debajyoti Datta said...
  4. You are welcome Phenocane

  5. Dr. Skeptic said...
  6. The BMJ ran an interesting feature and editorial based on this finding a few days ago. I strongly recommend you check it out if you already haven't. As always, great writing! :-)

  7. Debajyoti Datta said...
  8. Thanks for the heads up Dr. Skeptic!

  9. Ketsumeisei said...
  10. Nice post: I read your post and knew very well about colorectal canter. Thanks for great resource. Keep in touch.

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