Hyaluronan, Inflammation, and Breast Cancer Progression

Abstract

Breast cancer-induced inflammation in the tumor reactive stroma supports invasion and malignant progression and is contributed to by a variety of host cells including macrophages and fibroblasts. Inflammation appears to be initiated by tumor cells and surrounding host fibroblasts that secrete pro-inflammatory cytokines and chemokines and remodel the extracellular matrix (ECM) to create a pro-inflammatory "cancerized" or tumor reactive microenvironment that supports tumor expansion and invasion. The tissue polysaccharide hyaluronan (HA) is an example of an ECM component within the cancerized microenvironment that promotes breast cancer progression. Like many ECM molecules, the function of native high-molecular weight HA is altered by fragmentation, which is promoted by oxygen/nitrogen free radicals and release of hyaluronidases within the tumor microenvironment. HA fragments are pro-inflammatory and activate signaling pathways that promote survival, migration, and invasion within both tumor and host cells through binding to HA receptors such as CD44 and RHAMM/HMMR. In breast cancer, elevated HA in the peri-tumor stroma and increased HA receptor expression are prognostic for poor outcome and are associated with disease recurrence. This review addresses the critical issues regarding tumor-induced inflammation and its role in breast cancer progression focusing specifically on the changes in HA metabolism within tumor reactive stroma as a key factor in malignant progression.

Keywords: CD44; RHAMM/HMMR; breast cancer; hyaluronan; inflammation; macrophage; tumor microenvironment.

Figure 1

Hyaluronan induces receptor-mediated signaling through interaction with cell-surface HA binding proteins. Interaction of HA with CD44 and RHAMM induces CD44 receptor clustering and intracellular RHAMM-regulated MAPK activation, resulting in ERK phosphorylation and downstream activation of the transcription effectors AP-1 and NFκB. Active transcription of AP-1 and NFκB target genes ultimately result in the induction of directed cell migration and release of inflammatory cytokines. Abbreviations: MEK, MAPK ERK kinase; ERK, extracellular regulated kinase; RHAMM, receptor for hyaluronan-mediated motility; CD44, cluster of differentiation 44; AP-1, activator protein 1; RTK, receptor tyrosine kinase; NFκB, nuclear factor kappa B.

Figure 2

Effects of HA on various cell types within the tumor microenvironment. HA is synthesized by HAS enzymes in breast cancer cells (shown) or in stromal cells (not shown) and extruded to the extracellular space. HA can be fragmented by hyaluronidases (Hyal) or reactive oxygen species within the tumor microenvironment. HA, full length and fragmented, can act through cell-surface receptors, including CD44 and RHAMM, on various cell types to regulate the indicated cell functions.