Abstract 4993: The effect of mast cell inhibition on tumor response to 5-FU in ApcMin/+mice.

Tumors are complex organs consisting of a heterogeneous population of cancer cells that are infiltrated and interact with an equally heterogeneous collection of host-derived non-cancer cells. These non-neoplastic cells compose the tumor stroma or microenvironment, and have been shown to play a critical role in tumor initiation, progression, metastasis, and response to therapy. This has led to a paradigm shift in the development of anti-cancer therapies, wherein chemotherapies must not only target tumor cells but also non-tumor cells in the microenvironment that might contribute to tumor resistance during therapy or its recurrence post-therapy. Among these stromal cells, mast cells have shown to promote the development of adenomas during colon cancer progression. Mast cell precursors originate in the bone marrow, are distributed through the blood, and migrate into tissues where they undergo terminal differentiation and maturation. They are essential in allergic and inflammatory stimuli. When activated they can release an array of cytokines such as histamine, chymase, tryptase, TNF-α, IL-4, IL-5, IL-6, and IL-13 through their degranulation or by de novo synthesis. Mast cells have been shown to infiltrate the microenvironment of gastrointestinal polyps in mouse models of colorectal cancer (CRC) such as the ApcMin/+ mouse, where they are essential particularly in the initial stages of adenoma development. In response to treatment with 5-fluoruracil, an inhibitor of the enzyme thymidylate synthase that has been used in the treatment or CRC for many years, we found that mast cells are recruited into the tumors beds of adenomatous polyps in ApcMin/+ mouse. Due to this, we hypothesized that pharmacological inhibition of mast cells might play a synergistic role in chemotherapy using 5-FU. The objectives of this study are two-fold: 1) to determine if pharmacological inhibition of mast cells can interfere with tumor development, and 2) to determine if mast cell inhibition can enhance the antitumor effects of 5-FU or prolong tumor recurrence post therapy. We used the ApcMin/+ mouse as a model for intestinal tumorigenesis because the impact of therapeutic treatments can be conveniently assessed by determining tumor burden. Mice were subjected to a regimen of 5-FU or Cromolyn, a mast cell inhibitor, alone or in combination. Our findings suggest that inhibition of mast cells influences tumor development, but has little impact on tumor recurrence post therapy when administered on advanced adenomas. Further studies are aimed at investigating tumor response to mast cell inhibition at earlier stages of tumor development and identifying the cytokines and chemokines that play critical roles in their response to therapy. Citation Format: Nikeya Tisdale, Celestia Davis, Grishma Acharya, Maria Pena. The effect of mast cell inhibition on tumor response to 5-FU in ApcMin/+mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4993. doi:10.1158/1538-7445.AM2013-4993