Manipulating Exosome Signaling to Inhibit Tumor Metastasis

摘要

Over the past decade significant advancements have been made across the field of cancer biology resulting in transformative new therapies. Despite these advancements, treatments for metastatic cancer remain relatively ineffective. Metastasis is coordinated by various types of "healthy" stromal cells in addition to the tumor cells themselves. This requires a means by which the tumor cells can communicate with stromal cells. Exosomes are 30--150 nm nanovesicles that function as the primary endogenous intercellular delivery vehicle. During cancer progression, cancer cells package pro-tumorigenic RNAs, proteins and DNA into exosomes and subsequently release them into circulation. After release, exosomes traffic to the sites of metastasis, prior to the arrival of circulating tumor cells, where they initiate phenotypic changes, notably immunosuppression, that support the colonization and survival of metastasis. Collectively, the microenvironment generated by these exosomes has been called the pre-metastatic niche.;In this project, we were first interested in understanding the effects of exosomes released from non-metastatic cancer cells. It is well established that exosomes from aggressive cancer cells promote metastasis, but the functions of non-aggressive cancer cell exosomes are not understood. We discovered that exosomes from non-metastatic melanoma cells drive the expansion of a Ly6C lo monocyte population called patrolling monocytes (PMo). These monocytes trafficked to the metastatic sites where they cleared circulating tumor cells preventing metastasis formation in mouse models of melanoma. The expansion in the PMo population was stimulated by pigment epithelial derived factor (PEDF), a multifunctional anti-tumor protein carried in the exosomes of non-metastatic melanoma cells. Importantly, exosomes isolated from the serum of patients with primary melanoma that did not recur had higher PEDF content compared to exosomes from patients with highly aggressive metastasis. Ultimately, this study demonstrated that exosomes from non-metastatic tumors can carry triggers like PEDF that active innate immune responses against cancer preventing metastatic spread.;Additionally, due to the metastasis promoting functions of tumor exosomes, we were interested in developing a technology to specifically inhibit the uptake of cancer exosomes by target cells. Exosome uptake is dependent on cholesterol-rich lipid raft regions of the cell membrane. Our laboratory has developed high-density lipoprotein-like nanoparticles (HDL NP) that specifically efflux cholesterol from cells that express scavenger receptor-type B1 (SR-B1). By modulating cholesterol flux at lipid rafts, HDL NPs effectively inhibit the uptake of melanoma exosomes by multiple cell types that play important roles in the pre-metastatic niche including endothelial cells, macrophages and tumor cells themselves. This work provides a crucial step in developing a cancer therapy that functions by inhibiting the uptake of exosomes.;The development of HDL NPs led us to test their efficacy as a cancer therapeutic in a wide array of applications. We discovered that HDL NPs can function to inhibit metastasis independent of inhibiting exosome uptake, as well. Myeloid-derived suppressor cells (MDSCs) promote tumor progression by suppressing T cell mediated clearance of cancer cells. We demonstrated that HDL NPs target SR-B1 expressed by MDSCs resulting in a significant inhibition of their suppressive activity. HDL NP treatment led to increased T cell proliferation and, most importantly, significantly reduced tumor growth, metastatic tumor burden, and increased survival due to an enhanced adaptive immunity. Overall, HDL NPs have the potential to be developed into a novel multifunctional immunotherapy that can inhibit the activity of MDSCs, as well as block the uptake of exosomes in SR-B1 expressing cells.