ONCOLOGY REPORTS 26: 1127-1132, 2011
Abstract. This study was undertaken to examine the gender-
sensitivity and chemopreventive responsiveness of celecoxib
on intestinal stem-like cells as a biomarker of colon carcino-
genesis, using the MIN mouse model. Male and female MIN
mice (6-7-weeks old) were randomized to either control diet
or to a diet supplemented with celecoxib (1,500 ppm). The
animals were euthanized ten weeks later and the intestines
were flushed and opened longitudinally to assess tumor count.
Small intestinal segments were formalin-fixed and tissue
sections were subjected to immunohistochemical evaluation
of DCAMKL1, a known marker of stem-like cells. We found
that in animals receiving control (AIN 76A diet) alone, female
MIN mice had a higher polyp count than males (52.32±13.89
vs. 35.43±16.05; p<0.0005). However, compared to control diet
groups, celecoxib supplementation caused a larger reduction
in the number of polyps in females than their male cohorts
(6.38±1.43 vs. 12.83±6.74; a reduction of 88% in females to
64% in males). Significant differences (p=0.013) were observed
in the number of DCAMKL1-stained cells in the crypts of the
wild-type (WT) (10.01±1.07 stem cells per high powered field;
HPF) compared to the MIN mice (24.15±8.08 stem cells per
HPF), illustrating increased stem-like cells in animals that are
more prone to neoplasia. DCAMKL1 labeled stem-like cells
were equal in number in the male and female groups receiving
the control AIN 76A diet alone (females, 25.73 stem-like cells/
HPF); males, 24.15 stem-like cells/HPF). However, females
showed a greater reduction in the number of DCAMKL1-
labeled stem-like cells with celecoxib supplementation than
the respective males (16.63±4.23 vs. 21.56±9.06; a reduction
of 35.4% in females to 10.7% in males). We conclude that a
higher number of stem-like cells in the uninvolved mucosa
paralleled tumorigenesis and mirrored greater chemopreventive
responsiveness of female MIN mice compared to males.
Colorectal malignancies remain the third leading cause of
cancer-related deaths in both men and women, underscoring
the need for more effective cancer prevention efforts (1). The
cornerstone of these endeavors has been precise population
screening with an emerging component of risk factor modi-
fication/chemoprevention. Colonoscopy has been particularly
promising given that it not only can diagnose early stage
colorectal cancers (CRCs), but also helps prevent it through
precise selection and extraction of the precursor lesions, the
adenomatous polyps. However, from a screening perspective,
colonoscopy is usually inadequate for CRC prevention in
women, potentially due to the higher distribution of proximal
lesions that are not as easily revealed by colonoscopy (2).
Emerging evidence has revealed a significant disparity in the
biology and epidemiology of CRC between men and women.
However, despite these significant differences the clinical
recommendations have, by and large, remained gender-neutral.
Furthermore, the issue of gender and chemoprevention has
largely been unexplored except for the documented role of
estrogens in CRC prevention, although with numerous untoward
effects that make it untenable for clinical implementation.
There have been a myriad of agents purported to have
chemopreventive benefits against colorectal cancer. Of these,
non-steroidal anti-inflammatory drugs (NSAIDs) have been
utilized in the majority of studies. For instance, several recent
large scale multi-center trials have shown a profound reduction
(50-60%) in advanced adenomas (3). Although cardiac toxicity
would prevent widespread adoption, this provides a significant
proof of concept that chemoprevention may herald a new
generation of safer and effective pharmaceutical or neutra-
ceutical chemopreventive agents. This could precisely be
achieved by targeting the population with novel agents to
maximize their chemopreventive sensitivity while minimizing
the toxicity (by not treating patients who are unlikely to achieve
an anti-neoplastic benefit).
Association of stem-like cells in gender-specific
chemoprevention against intestinal neoplasia in MIN mouse
SEEMA R. GANDHI1, ASHISH K. TIWARI1, DHANANJAY P. KUNTE1, MART ANGELO DE LA CRUZ1,
YOLANDA STYPULA2, TINA GIBSON1, JEFFREY BRASKY1, VADIM BACKMAN2,
RAMESH K. WALI1 and HEMANT K. ROY1
1Department of Internal Medicine, NorthShore University HealthSystem, Evanston;
2Department of Biomedical Engineering, Northwestern University, Evanston, IL 60201, USA
Received April 4, 2011; Accepted May 6, 2011
Correspondence to: Dr Ramesh K. Wali, Department of Internal
Medicine, NorthShore University HealthSystem, 1001 University
Place, Suite 314, Evanston, IL60201, USA
Key words: gender, chemoprevention, celecoxib, doublecortin and
calcium/calmodulin-dependent protein kinase-like-1, intestine,
GANDHI et al: ROLE OF GENDER-SPECIFIC CHEMOPREVENTION AGAINST NEOPLASIA
we need to consider whether stem-like cells are a target of
NSAIDs or simply represent a biomarker. The notion of stem
cells as targets of NSAIDs was strengthened by a recent report
showing that stem cell elimination may be an effective
chemoprevention of colon cancer by NSAIDs (34). Either way,
the novel finding that these stem-like cells are modulated by
chemopreventive agents is of great significance.
In conclusion, we demonstrate for the first time that female
MIN mice appeared to have a more robust chemopreventive
response than males. This was paralleled by the reduction in
stem-like cells as assessed by DCAMKL1 immunostaining.
This preliminary report provides the first compelling evidence
to suggest that there is a gender-related difference that needs
to be accounted for with chemoprevention and this may,
potentially, be related to alteration in stem-like cell number.
Future studies will address the translatability of these issues
to human CRC prevention.
The study was supported by grants from the National
Institutes of Health (NIH), Bethesda, MD, USA (21-CA141112,
UO1CA111257, RO1CA156186 and R21-CA140936). This study
was partially presented in an abstract form at the 111th Digestive
Disease Week, May 2010, in New Orleans, LA, USA.
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