Abstract 5607: Lipoprotein lipase binds to the surface of cancer cells and facilitates uptake of lipoproteins.
Authors: Kuemmerle Nancy Benton , Lupien Leslie E. , Smits Nicole C. , Davis Wilson L. , Kinlaw William B. 
Published: August 2014

We examined the hypothesis that some cancer cells have surface-bound lipoprotein lipase (LPL), and we postulate that this membrane-bound LPL facilitates the acquisition of fatty acids (FA) from circulating triglyceride-rich lipoproteins. This deployment of the enzyme links the growth of tumors to dietary fat.

Background: Recent studies have explored the association of dietary fat and obesity with increased incidence and aggressiveness of certain cancers. Tumor cells require FA for synthesis of membranes and thus for growth. Cells can acquire lipids through de novo synthesis from glucose and glutamine using fatty acid synthase (FASN) or by acquisition of pre-formed FA using LPL. LPL is a secreted enzyme synthesized by some cancer cell lines and all tumors examined to date (n = 181). It facilitates the uptake of very low density lipoproteins (VLDLs) by extracellular hydrolysis of triglyceride-rich particles such as VLDLs in the circulation or lipoprotein endocytosis followed by intracellular hydrolysis. In previous work, we demonstrated a heparin-releasable pool of LPL, consistent with tumor cell surface-associated LPL binding to a heparan sulfate proteoglycan (HSPG).

Methods: We used immunocytochemistry and flow cytometry to demonstrate LPL on the surface of HeLa, BT474 and DU4475 breast cancer, and LiSa-2 liposarcoma cells. Confocal microscopy with fluorophore-labeled VLDLs enabled us to follow the endocytosis of VLDLs.

Results: We have demonstrated that cancer cells can acquire lipoprotein particles (VLDLs) from their environment by endocytosis, and that this is mediated by cell-surface LPL bound to a specific HSPG motif. Major findings include:

1) Cell surface LPL is detectable by immunocytochemistry and flow cytometry.

2) The binding of LPL to the cell surface is abrogated by heparin.

3) LPL binding is likewise disrupted by NS4F5, a novel antibody to the specific proteoglycan motif which binds LPL to the surface of vascular endothelial cells.

4) Cancer cells endocytose VLDL particles, and this is abrogated by heparin or NS4F5.

5) VLDL particles accelerate the growth of LPL-expressing cancer cells.

Conclusions: This work demonstrates of the use of endocytosis for the acquisition of diet-derived FA by cancer cells, and that this is mediated by cell-surface LPL bound to a specific HSPG motif. Thus endocytosis is a new mechanistic link between dietary lipoproteins and tumor cell growth. Further, these findings suggest that abrogation of LPL binding to the cell surface presents an opportunity for non-cytotoxic, therapeutic intervention.

This work was supported by a grant from the Sarcoma Foundation of America (NBK) and a Prouty grant from Norris Cotton Cancer Center (WBK) and NIH Grant RO1CA126618 (WBK).

Citation Format: Nancy Benton Kuemmerle, Leslie E. Lupien, Nicole C. Smits, Wilson L. Davis, William B. Kinlaw. Lipoprotein lipase binds to the surface of cancer cells and facilitates uptake of lipoproteins. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5607. doi:10.1158/1538-7445.AM2013-5607