UCSF

Abstract Tumor progression is influenced by the dynamic interplay between the genetically-modified epithelium and the associated microenvironment. We previously showed that the extra-cellular matrix (ECM) progressively stiffens as mammary tumors evolve, and that stiffening the ECM promotes malignant transformation while inhibiting ECM stiffening reduces tumor progression (Levental et al., 2009; reviewed in Butcher et al., 2009). Yet breast cancers also exhibit elevated influx of inflammatory cells and tissue inflammation promotes tumor progression by fostering angiogenesis and enhancing tumor cell growth and motility (Ruffell et al., 2011). Tumor-associated macrophages additionally stimulate stromal fibroblasts, implying that tissue inflammation could promote malignancy by stiffening the ECM. To address this possibility, we explored the relationship between ECM tension and macrophages in human breast cancer and during mammary tumor development in transgenic mice. Using fresh and archived tissue samples, we quantified a progressive increase in ECM remodeling and stiffening as human breast tumors and mouse mammary cancers developed. We found that the ECM associated with triple negative breast cancers was almost twice as stiff as the ECM adjacent to ER+/PR+ tumors and that ECM stiffness correlated significantly with increased numbers of infiltrating activated macrophages. Consistently, we established a positive correlation between tumor progression, elevated mechanosignaling, ECM stiffness and tissue inflammation in both human and mouse tissue. However surprisingly, when macrophages were depleted from the mammary glands of MMTV-PyMT tumors, ECM tension did not change. Instead we found that inhibiting lysyl oxidase activity to decrease collagen cross-linking and ECM stiffness reduced the activation state of the macrophages within the mammary glands of 14-week old mice. Consistently, in vitro studies showed that ECM tension potentiates the expression of pro-inflammatory chemokines and increases levels of phosphoStat3 and that ECM tension directly modifies macrophage polarity. These findings suggest that ECM tension may promote malignancy either by directly regulating macrophage activity or indirectly through enhancing expression of pro-inflammatory chemokines. Further studies are now underway to explore these findings and to clarify their impact on tumor progression and response to therapy. Acknowledgements: supported by W81XWH-05-1-0330 and R01 CA138818-01A1 to VMW, 1U01 ES019458-01 to VMW and ZW, and P50 CA 58207 to JG, VW, SH and LC, U54CA143836-01 to JL and VW, and Susan G. Komen for the Cure PSF12230246 to IA. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S2-06.