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The Low-Density Lipoprotein Receptor–Related Protein Regulates Cancer Cell Survival and Metastasis Development

Departments of ¹ Pathology and ² Anesthesiology, University of California San Diego School of Medicine, La Jolla, California

Requests for reprints: Steven L. Gonias, University of California San Diego School of Medicine School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0612. Phone: 858-534-1887; Fax: 858-534-0414; E-mail: sgonias{at}ucsd.edu.

Low-density lipoprotein receptor-related protein-1 (LRP-1) is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. In this study, we show that LRP-1 is abundantly expressed in severe combined immunodeficient (SCID) mouse xenografts by various human cancer cell lines that express very low or undetectable levels of LRP-1 when cultured in 21% O₂ in vitro (standard cell culture conditions). To test whether LRP-1 expression in vivo may be explained by hypoxia in the xenografts, CL16 cells, which are derived from the MDA-MB-435 cell line, were cultured in 1.0% O₂. A substantial increase in LRP-1 expression was observed. To test the activity of LRP-1 in cancer progression in vivo, LRP-1 expression was silenced in CL16 cells with short hairpin RNA. These cells formed tumors in SCID mice, in which LRP-1 expression remained silenced. Although LRP-1 gene silencing did not inhibit CL16 cell dissemination from the primary tumors to the lungs, the pulmonary metastases failed to enlarge, suggesting compromised survival or growth at the implantation site. In cell culture experiments, significantly increased cell death was observed when LRP-1–silenced CL16 cells were exposed to CoCl₂, which models changes that occur in hypoxia. Furthermore, LRP-1–silenced cells expressed decreased levels of vascular endothelial growth factor in response to 1.0% O₂. These results suggest mechanisms by which LRP-1 may facilitate the development and growth of cancer metastases in vivo. [Cancer Res 2007;67(20):9817–24]

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