Abstract 1256: A role for lipoprotein lipase in fatty acid acquisition by breast, prostate and liposarcoma tumors
Authors: Kuemmerle Nancy B. , Rysman Evelien , Lombardo Portia S. , Flanagan Alison J. , Lipe Brea C. , Fricano Catherine , Wells Wendy A. , Pettus Jason R. , Froehlich Heather , Morganelli Peter M. , Memoli Vincent A. , Swinnen Johannes V. , Timmerman Liuika A. , Chaychi Leila , Eisenberg Burton L. , Coleman William B. , Kinlaw William B. 
Published: June 2012

The importance of de novo fatty acid (FA) synthesis for tumor cell growth is well established, and we have now examined the hypothesis that the uptake of exogenous FA provides an alternative FA fuel source for tumors.

Background: Many tumor cells utilize FA as a major energy source, and they do not survive if the supply is interrupted. In order to obtain lipids, tumors can synthesize fatty acids from glucose-derived precursors using fatty acid synthase (FASN), or they could potentially hydrolyze diet-derived triglycerides from circulating lipoproteins using the enzyme lipoprotein lipase (LPL), and take up the free fatty acids using the cell surface channel CD36. It is also conceivable that they could obtain lipids by receptor-mediated endocytosis, using syndecan (Sdc1) and LPL. The latter two of these three mechanisms have not been examined.

Methods: We employed cDNA microarray and quantitative RT-PCR to study mRNA expression, measured secreted LPL enzyme activity, and produced a monoclonal antibody for LPL protein analysis and immunohistochemistry (IHC). We also assessed cellular uptake of fluorescently labeled very low density lipoproteins (VLDL). We studied cell lines and/or tumor tissues for expression of FASN, Spot 14 (a nuclear protein that drives FASN expression), LPL, CD36, and Sdc1.

Results:

1. By RT-PCR, FASN and Spot14, a driver of FASN gene expression, are expressed in all cell lines (45 breast cancer, 1 liposarcoma, 1 cervical carcinoma, 3 prostate cancer) and tumor tissues (160 breast cancer, 24 liposarcoma, 10 prostate cancer) examined.

2. By RT-PCR and enzyme activity assays, LPL is expressed only in liposarcoma and triple-negative breast cancer cell lines. Prostate cancer cells secrete negligible LPL.

3. Addition of exogenous LPL and triglyceride substrate to culture media enhanced the growth of breast cancer and liposarcoma cell lines, but not prostate cancer cell lines.

4. Provision of exogenous LPL, however, rescued prostate cancer cell lines from the cytotoxicity of FASN inhibition.

5. siRNA-mediated knockdown of LPL impaired the growth of HeLa cells,

6. In contradistinction to observations in cell lines, IHC demonstrated brisk expression of LPL in all liposarcomas, prostate tumors, and breast cancer tumors examined, irrespective of ER/PR or HER2/neu status.

7. CD36 is expressed in the majority of tumors examined by IHC, including 98% of breast cancers.

8. Sdc1 and CD36 are expressed in triple-negative DU4475 breast cancer cells, but they did not endocytose labeled VLDL particles.

Conclusions: These data demonstrate that, in addition to de novo FA synthesis, tumors can utilize diet-derived fat, and that this can fuel their growth. Our findings provide a mechanism, namely lipolysis by LPL and uptake by CD36, for the link between dietary fat intake and tumor progression. Inhibition of lipolysis, as well as lipogenesis, may be a necessary strategy to target the FA requirement of aggressive tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1256. doi:10.1158/1538-7445.AM2011-1256