A Critical Role for the Inflammatory Response in a Mouse Model of Preneoplastic Progression

Abstract

The tumor microenvironment, which includes inflammatory cells, vasculature, extracellular matrix, and fibroblasts, is a critical mediator of neoplastic progression and metastasis. Using an inducible transgenic mouse model of preneoplastic progression in the mammary gland, we discovered that activation of inducible fibroblast growth factor receptor-1 (iFGFR1) in the mammary epithelium rapidly increased the expression of several genes involved in the inflammatory response. Further analysis revealed that iFGFR1 activation induced recruitment of macrophages to the epithelium and continued association with the alveolar hyperplasias that developed following long-term activation. Studies using HC-11 mammary epithelial cells showed that iFGFR1-induced expression of the macrophage chemoattractant osteopontin was required for macrophage recruitment in vitro. Finally, conditional depletion of macrophages inhibited iFGFR1-mediated epithelial cell proliferation and lateral budding. These findings show that inflammatory cells, specifically macrophages, are critical for mediating early events in an inducible transgenic mouse model of preneoplastic progression.