Targeting the SR-B1 Receptor as a Gateway for Cancer Therapy and Imaging

Abstract

Malignant tumors display remarkable heterogeneity to the extent that even at the same tissue site different types of cells with varying genetic background may be found. In contrast, a relatively consistent marker the scavenger receptor type B1 (SR-B1) has been found to be consistently overexpressed by most tumor cells. Scavenger Receptor Class B Type I (SR-BI) is a high density lipoprotein (HDL) receptor that facilitates the uptake of cholesterol esters from circulating lipoproteins. Additional findings suggest a critical role for SR-BI in cholesterol metabolism, signaling, motility, and proliferation of cancer cells and thus a potential major impact in carcinogenesis and metastasis. Recent findings indicate that the level of SR-BI expression correlate with aggressiveness and poor survival in breast and prostate cancer. Moreover, genomic data show that depending on the type of cancer, high or low SR-BI expression may promote poor survival. This review discusses the importance of SR-BI as a diagnostic as well as prognostic indicator of cancer to help elucidate the contributions of this protein to cancer development, progression, and survival. In addition, the SR-B1 receptor has been shown to serve as a potential gateway for the delivery of therapeutic agents when reconstituted high density lipoprotein nanoparticles are used for their transport to cancer cells and tumors. Opportunities for the development of new technologies, particularly in the areas of cancer therapy and tumor imaging are discussed.

Keywords: Drug Delivery Systems; SR-B1; gateway for theranostics; individual therapy; tumor imaging.

FIGURE 1

The physiological role of HDL is to clear the excess tissue cholesterol through the liver. (A) In phase 1, the cholesterol-rich HDL is captured by the SR-B1 receptor on the surface of the cell. (B) In phase 2, HDL delivers its cholesteryl ester cargo through SR-B1 directly into the cytoplasm. (C) In phase 3, the depleted HDL particle is released into the blood. The majority of cancer patients have lower than normal blood cholesterol especially HDL (or good) cholesterol. Images courtesy of Andras Lacko; full animation video is available at https://www.youtube.com/watch?v=q0YiPqmsXRg.

FIGURE 2

SR-B1 signaling pathway for normal hypoxia-induced angiogenesis. Interaction of HDL and SR-B1 activates the PI3K/Akt pathway leading to HIF-1α translocation to the nucleus and transcription of VEGF. HDL treatment and over-expression of SR-B1 has been shown to activate the PI3K/Akt pathway in tumor cells and stimulate proliferation and migration.