Chemoprevention of Cancer

 

Non-steroidal anti-inflammatory drugs (NSAIDs) are a structurally diverse family of compounds that are effective in the prevention of several types of human cancer including colorectal cancer (CRC).  Acetylsalicylic acid (ASA), commonly known as aspirin, is the archetype of the NSAID family.  A number of epidemiological studies have demonstrated an inverse relationship between ASA use and the incidence of CRC.  A recent clinical analysis reported that regular ASA use was associated with a lower risk of cancer-specific mortality in individuals already diagnosed with colorectal cancer.  Moreover, a variety of animal models have confirmed that administration of various NSAIDs results in fewer tumors.  While several explanations have been proffered over the years, a clear elucidation of the molecular mechanism(s) responsible for NSAIDs cancer chemoprevention efficacy has been elusive.

 

Clinical Analysis of Aspirin Chemoprevention in LS/HNPCC -Lynch syndrome or hereditary non-polyposis colorectal cancer (LS/HNPCC) is the most common hereditary cancer syndrome; accounting for 2-5% of CRC.  Greater than 90% of LS/HNPCC is caused by unambiguous mutations in the human mismatch repair (MMR) genes.  In addition, 15-40% of sporadic colorectal, endometrial, ovarian, and upper urinary tract tumors display instability of simple repeat sequences (microsatellite instability or MSI) that is diagnostic of MMR defects.  The Colorectal Adenoma-Carcinoma Prevention Program (CAPP) has examined the potential of ASA to reduce colorectal neoplasia in LS/HNPCC carriers in a randomized trial.  The end-point for these studies was the detection of LS/HNPCC cancers during yearly colonoscopy screens.  Remarkably, the benefits for LS/HNPCC patients only begins after 5 yrs of ASA exposure and results in at least a 2-fold decrease in the rate of tumor formation compared to the placebo-treated cohort.

 

These and other accumulating cellular, mouse and human studies strongly suggest that ASA as well as other NSAIDs significantly suppresses LS/HNPCC tumorigenesis (Fig. 1).  A substantial NSAID chemopreventive effect on a common genetic cause of cancer that is recapitulated from the mouse model to the human disease provides a unique tool capable of dissecting the molecular mechanism(s) responsible for NSAIDs cancer chemoprevention efficacy.

 


Figure 1.  NSAID Treatment Increases Survival of LS/HNPCC Mice.
 Msh2flox/floxVpC+/+ (LS/HNPCC) and VpC+/+ (wild type) were treated with eight NSAIDs at two doses.  Representative survival data is shown and separated into (A) No Effect (Sulindac Sulfone and NO-Sulindac Sulphone), (B) Modest Effect (20-50% increase in life span; Aspirin, Sulindac, NO-Sulindac), and (C) Naproxen (~100% increase in life span).  The survival of untreated Msh2flox/floxVpC+/+ animals is shown in red squares .  Aspirin treatment is shown with blackdots for comparison.  Treatment of selected wild type controls is shown with purple triangles.  Note: While Sulindac treatment increases lifespan similar to aspirin, it also induces tumors in the wild type controls (Panel B).
Chemo Fig 1

 

We use a mouse model of LS/HNPCC where exon 12 of Msh2 is flanked by LoxP recombination sites (Msh2flox/flox).Msh2 deletion is targeted to the intestinal epithelia by tissue-specific expression of Cre recombinase under the control of the villin promoter (VpC+/+), which results in absent Msh2 protein in affected tissues. Tumorigenesis is confined to the intestines and has all of the pathological hallmarks of HNPCC-like tumors including MSI.  When considering the utility of this mouse model it is important to note that while modern day LS/HNPCC largely occurs in the colon, it was originally described as a gastric cancer.  Moreover, like their human counterparts, the LS/HNPCC mice develop (and ultimately succumb to) 1-2 tumors that appear to progress rapidly.  This latter phenotype is one of the disadvantages of this LS/HNPCC mouse model since the effect of NSAIDs on tumor multiplicity is virtually impossible to determine.  However, because the tumor numbers are small even modest effects on tumor initiation and/or progression can have a demonstrated effect on the survival of these LS/HNPCC mice.

 

Questions:

 

1. Does NSAID chemoprevention target the kinetics of tumor initiation or tumor progression?

 

2. Does the pattern of NSAID administration affect survival?

 

3. What is the minimal dose of NSAID that will elicit a chemopreventive effect and does decreasing NSAID dose affect the kinetics of tumor initiation and/or tumor progression?  

 

4. What are the quantitative changes in tissue expression of the initial panel of NSAID chemoprevention pathway biomarkers?

 

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