Abstract LB-504: Mast cell cytokines stimulate cancer-associated fibroblasts proliferation and promote pancreatic cancer progression

Abstract

Abstract Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a uniformly lethal disease and is notoriously resistant to most therapies. In patients, cancer cells exist in a complex microenvironment containing cancer-associated fibroblasts (pancreatic stellate cells, PSCs) and immune cells. These components provide a fibrotic niche that is an impediment to successful therapy. In our preliminary studies, we found that mast cells infiltrated at the tumor margin. This high infiltration of human mast cells into the tumor microenvironment was associated with poor survival. Mast cells were found to be essential to PDAC tumorigenesis in a mast cell-deficient Kitw-sh/w-sh mouse model compared to control mice. In addition, when we treated tumor-bearing mice with cromolyn, a mast cell stabilizer, tumor growth was depressed. How mast cells regulate the tumor microenvironment and contribute to PDAC tumorigenesis are unknown. We hypothesized that mast cell cytokines mediate cancer-associated fibroblasts proliferation that promotes PDAC progression. Methods: We measured mast cell infiltration in 16 normal human pancreas (NP), 26 pancreatic intraepithelial lesions (PanINs), and 25 PDAC patients’ tissue samples. In an in vitro co-culture system, we measured the crosstalk of human mast cells, PDAC cells, and PSCs. The effect of mast cell cytokine release on PDAC and PSC proliferation and migration was measured using conditioned medium. To determine the role of IL-1β, IL-13, and tryptase on PDAC and PSC proliferations, neutralizing antibodies were used. To determine whether inhibiting mast cell degranulation and cytokine production has a therapeutic effect in vivo, we treated tumor-bearing mice with masitinib, which is a tyrosine kinase inhibitor targeting c-KIT. Tumor sizes were measured by bioluminescence imaging. Results: Mast cell infiltration was associated with human malignancy progression (NP → PanIN, P > 0.05; PanIN → PDAC, P < 0.001), which was consistent with tryptase expression pattern in a spontaneous PDAC mouse model. In vitro, tumor cells promoted mast cell migration (P < 0.05). PDAC cells and PSCs stimulated mast cell activation, as measured by degranulation and tryptase release (P < 0.05). Conversely, mast cell-derived IL-13 stimulated PDAC proliferation (P < 0.001). Strikingly, IL-1β, tryptase, or IL-13 from mast cells promoted PSC proliferation. In vivo, PDAC growth was significantly reduced by masitinib (P < 0.01 vs saline control) in tumor-bearing mice. Conclusions: Mast cells promote PDAC progression. Tumor cells promote mast cell activation and migration to the tumor site. Once there, mast cell cytokines activate proliferation of both tumor cells and fibroblasts, potentially contributing to the fibrotic microenvironment found in PDAC. Therefore, therapy targeting mast cells cytokines, IL-1β, tryptase, or IL-13, may overcome stromal formation and improve PDAC therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-504. doi:1538-7445.AM2012-LB-504