J Cancer Prev 2021; 26(4): 304-308
Published online December 30, 2021
© Korean Society of Cancer Prevention
Center for Molecular Oncology, University of Connecticut Health Center, Farmington, CT, USA
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Activation of the COX-2/microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) signaling axis is a hallmark of many cancers, including colorectal cancer, prompting the implementation of prevention strategies targeting COX-2 activity. We have previously shown that targeting the downstream terminal PGE2 synthase, mPGES-1 (Ptges), specifically reduces inducible PGE2 formation without disrupting synthesis of other essential prostanoids, thereby conferring dramatic cancer protection against colon carcinogenesis in multiple mouse models. In order to accelerate its development as a viable drug target, and to better understand the mechanisms by which PGE2 influences colon carcinogenesis, we recently developed a conditional Ptges knockout mouse model (cKO). To evaluate the functional role of Ptges directly within the colonic epithelia, cKO mice were crossed with carbonic anhydrase 1 (Car1)-Cre mice (cKO.Car1), and colon tumors were induced using the azoxymethane/dextran sodium sulfate protocol. Unexpectedly, epithelial-specific blockade of Ptges failed to protect mice against colon tumor development. Further studies using the cKO mouse model will be necessary to pinpoint the cell type-specific location of mPGES-1 and its control of inducible PGE2 formation that drives tumor formation in the colon.
Keywords: PGE2, mPGES-1, Colonic neoplasms, Azoxymethane, Dextran sulfate sodium
Increased production of prostaglandin E2 (PGE2) is often associated with the pathogenesis of inflammation and cancer . PGE2 is generated from the arachidonic acid-COX pathway, and non-steroidal anti-inflammatory drugs have been widely used to suppress PGE2 by inhibiting the functional activity of the COX enzymes . Unfortunately, long-term treatment of patients with NSAIDs, and particularly the COX-2 specific inhibitors (Coxibs), are associated with toxicity, including stomach ulcerations, cardiovascular events and kidney damage . Interest in this pathway, however, has been renewed by recent findings that inhibition of the terminal prostaglandin synthase, microsomal prostaglandin E synthase-1 (mPGES-1), is sufficient to achieve the same degree of cancer protection as direct COX-2 inhibition [4-6]. However, during the course of our preclinical studies in several mouse cancer models, we observed a range of mucosal alterations that may complicate mPGES-1 as an effective cancer chemoprevention target .
In order to accelerate its development as a viable drug target, and to better understand the underlying mechanisms that contribute to cancer prevention, we recently developed a conditional
Fixed whole-mount colons were stained with 0.2% methylene blue and the number and size of tumors were scored under a dissecting microscope. Colon tumor load per mouse was determined using tumor diameter to calculate the spherical tumor volume (mm3), V = (4/3) *
Fixed tissues were embedded in paraffin and sectioned at 5 µm thickness. Tissue sections were deparaffinized and stained with H&E, or incubated overnight with primary antibody for mPGES-1 (1:4,000, Abnova, Taipei City, Taiwan). Sections were incubated with HRP-conjugated anti-rabbit secondary antibody (Cell Signaling Technology, Beverly, MA, USA), then counter stained with hematoxylin. Images were captured using conventional microscope or confocal microscope using Q-capture Pro 7 (Tucson, AZ, USA).
Statistical analyses were performed using GraphPad Prism 9 software (GraphPad Software, Inc., San Diego, CA, USA). Data are presented as the means ± SEM.
To further validate the functional role of mPGES-1 in colon tumor development, we generated a conditional knockout mouse model (
After development and characterization of the
Elevated expression of COX-2 and the concomitant increase in PGE2 formation occur in up to 85% of human colorectal cancers . Despite growing evidence for a plethora of unwanted side-effects associated with long-term NSAID use in patient populations, COX inhibition still remains one of the most effective strategies for colon cancer prevention . To minimize the gastrointestinal and cardiovascular toxicities that have been associated with long-term treatment with these drugs, alternative approaches that target the COX-2/PGE2 signaling pathway have been considered. Our data and others (reviewed in ) have suggested that the inducible terminal synthase, mPGES-1, may provide a reasonable candidate for chemoprevention. In order to accelerate its development as a viable drug target, and to better understand the mechanisms by which mPGES-1 and its metabolic product, inducible PGE2, contribute to colon tumor promotion, we have generated a conditional mouse model in which mPGES-1 activity can be abrogated directly within distinct cellular compartments of the colonic mucosa.
The present study is the first of its kind to evaluate the influence of cell type-specific inactivation of mPGES-1 on colon carcinogenesis. Using our newly created conditional mouse model, we have selectively inactivated mPGES-1 directly within the colonic epithelial lineage via genetic inactivation. Our rationale for targeting the epithelial compartment is based primarily on the overwhelming abundance of literature ascribing its functional activity to the epithelia [11-13]. These conclusions are based, in part, on evidence acquired in cancer cell lines that are typically derived from cells of epithelial origin [11-13] as well as the results obtained from several immunohistochemical studies [11,14,15]. However, our findings clearly demonstrate that colonocytes harvested from
Several studies indicate that mPGES-1 expression is largely confined to macrophages and dendritic cells [16,17]. In fact, Chen et al. [18-20] generated a
This study was funded by NIH/NCI R03CA235225.
On behalf of all authors, the corresponding author states that there is no conflict of interest.
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