Dynamic Mast Cell–Stromal Cell Interactions Promote Growth of Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) exists in a complex desmoplastic microenvironment, which includes cancer-associated fibroblasts (also known as pancreatic stellate cells, PSCs) and immune cells that provide a fibrotic niche that impedes successful cancer therapy. We have found that mast cells are essential for PDAC tumorigenesis. Whether mast cells contribute to the growth of PDAC and/or PSCs is unknown. Here we tested the hypothesis that mast cells contribute to the growth of PSCs and tumor cells, thus contributing to PDAC development. Tumor cells promoted mast cell migration. Both tumor cells and PSCs stimulated mast cell activation. Conversely, mast cell-derived IL-13 and tryptase stimulated PSC proliferation. Treating tumor-bearing mice with agents that block mast cell migration and function depressed PDAC growth. Our findings suggest that mast cells exacerbate the cellular and extracellular dynamics of the tumor microenvironment found in PDAC. Therefore, targeting mast cells may inhibit stromal formation and improve therapy.

Microvascular density and endothelial area correlate with Ki-67 proliferative index in surgically-treated pancreatic ductal adenocarcinoma patients

“…Previous studies have demonstrated that angiogenesis and Ki-67-positive fraction are essential for the development and progression of tumours (27)(28)(29)(30)(31). In addition, numerous studies have suggested that increased tissue MVD and Ki-67 proliferation index, which were individually assessed, were correlated with a poor prognosis in PDACP (21,22).…”

NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development

“…Therefore, we expanded our analysis generating additional Gdf- 15- (15,16) that also stably expressed a luciferase reporter gene that was used for bioluminescence imaging (17) (Figure 3A). KPC control or KPC Gdf-15-knockdown clones were then orthotopically injected into the tail of the pancreas of C57BL/6 albino mice, and tumor development was visualized.…”

Inflammation and pancreatic cancer: disease promoter and new therapeutic target

“…Analysis of a pancreatic cancer model mouse revealed the contribution of mast cells during pancreatic carcinogenesis, and detailed mechanisms of their activation were examined thereafter. Co-culture of mast cells with PSCs led to mast cell activation, characterized by tryptase and tumor necrosis factor-a release in the culture supernatant [91]. In turn, mast cell-derived IL-13 and tryptase promoted the proliferation of PSCs, leading to further fibrogenesis.…”