# Impact of prostanoid metabolism on colon tumor development

> **NIH NIH R03** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $82,000

## Abstract

Project Summary
 Activation of the COX-2/mPGES-1/PGE2 signaling axis is a hallmark of many cancers, including
colorectal (CRC), leading to the implementation of therapeutic strategies for targeting COX-2 activity. Despite
their demonstrated chemopreventive efficacy, long-term treatment with COX inhibitors poses significant health
risks as a result of the global suppression of physiological prostanoids. We have shown that targeting the
downstream terminal PGE2 synthase, mPGES-1 (Ptges), specifically reduces inducible PGE2 formation and
confers protection against colon carcinogenesis in several mouse colon cancer models. In our lipidomic
analysis to define the redistribution of the COX products, we found significant metabolic shunting towards
PGD2 and thromboxane B2 (TXB2) in the colon tumors of mPGES-1-deficient Apc-mutant mice. These
metabolites are primarily produced by mast cells, a cell type that has been frequently detected within the tumor
microenvironment. Prostanoids have been shown to directly influence the functional activity of mast cells, and
a large body of evidence suggests that mast cell-derived mediators including PGD2 contribute to cancer
pathogenesis. These observations serve as a basis for our hypothesis that mPGES-1 targeting causes
metabolite shifts in the mast cells, which alters tumor microenvironment towards less growth-promoting. We
propose experiments to develop a better understanding of functional roles of mast cells on colon tumor
development, and how genetic targeting of mPGES-1 will affect its actions. Aim 1 will extend our pilot lipidomic
analysis of colon tumors to confirm the extent of prostanoid shunting and also to identify metabolically distinct
prostanoid profiles that are associated with both size and macroscopic features of Apc-driven tumors formed in
the presence or absence of mPGES-1. Aim 2 will isolate tumor-associated mast cells from the colon of Apc
mice and examine the impact of mPGES-1 blockade on mast cell activation. We will measure the release and
production of mediators including histamine, proteases and a panel of prostanoids and cytokines, which
directly impact the tumor microenvironment. We will also explore how mast cell responds to PGE2, which is
often found in high concentrations within the tumor microenvironment. Aim 3 will generate tumor organoids
from Apc mice with or without mPGES-1, and test the direct effects of mast cell-derived mediators (Aim 2) on
cancer stem cell homeostasis. Results from these studies will shed light on the roles of mPGES-1 activity in
mast cells, and also provide a novel paradigm for the tumor protective mechanism by PGE2 inhibition.

## Key facts

- **NIH application ID:** 9844456
- **Project number:** 5R03CA235232-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Masako Nakanishi
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $82,000
- **Award type:** 5
- **Project period:** 2019-01-03 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844456

## Citation

> US National Institutes of Health, RePORTER application 9844456, Impact of prostanoid metabolism on colon tumor development (5R03CA235232-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9844456. Licensed CC0.

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