Chemotherapy induces secretion of exosomes loaded with heparanase that degrades extracellular matrix and impacts tumor and host cell behavior

Abstract

We find that anti-myeloma chemotherapy dramatically stimulates secretion of exosomes and alters exosome composition. Exosomes secreted during therapy contain high levels of heparanase on their surface that can degrade ECM and also can be transferred to both tumor and host cells, altering their behavior in ways that may enhance tumor survival and progression.

Forty Years of Basic and Translational Heparanase Research

“…Moreover, chemoexosomes stimulated macrophage migration and this effect was blocked by H1023, a monoclonal antibody that inhibits heparanase enzymatic activity. These data suggest that antimyeloma therapy ignites a burst of exosomes having a high level of heparanase that remodels ECM and alters tumor and host cell behaviors that likely contribute to chemoresistance and eventual patient relapse [103]. * [103].…”

Heparanase in health and disease: The neglected housekeeper of the cell?

“…These HPSE-mediated processes have been demonstrated to play a pivotal role in cell adhesion, migration, and invasion in different cell types. More recently, HPSE has been also shown to regulate exosome production [4,9,10] and autophagy [11]. Low density lipoprotein (LDL) receptor-related proteins and mannose 6 phosphate receptors mediate the uptake of secreted proHPSE [12]; intracellular HPSE can localize to autophagosomes, where it positively stimulates the autophagic process through a non-enzymatic mechanism that involves downregulation of mTOR1 activity [6,11].…”

Combatting Fibrosis: Exosome‐Based Therapies in the Regression of Liver Fibrosis

“…Another enzyme, heparanase, is expressed on the surface of exosomes and has been shown to degrade heparan sulfate within the ECM and to participate in an inflammatory response. (99) Further, exosomes from hypoxia-induced endothelial cells have increased collagen crosslinking activity in the ECM through upregulation of LOXL2, whereas knockdown of LOXL2 in endothelial-derived exosomes in both normal and hypoxic conditions reduced activity of exosomes. (40) (Figure 1 & Table 1) Therefore, exosomes have been implicated in the regulation of both inflammation and ECM remodeling.…”

“…Thus, a dynamic mechanism of forming adhesion interactions and breaking interactions by exosomal enzymes and components of the ECM is involved in wound healing and inflammation. Another enzyme, heparanase, is expressed on the surface of exosomes and has been shown to degrade heparan sulfate within the ECM and to participate in an inflammatory response . Further, exosomes from hypoxia‐induced endothelial cells have increased collagen crosslinking activity in the ECM through up‐regulation of LOXL2, whereas knockdown of LOXL2 in endothelial‐derived exosomes in both normal and hypoxic conditions reduced activity of exosomes .…”