Nancy B. Kuemmerle

Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids

One of the most important metabolic hallmarks of cancer cells is enhanced lipogenesis. Depending on the tumor type, tumor cells synthesize up to 95% of saturated and mono-unsaturated fatty acids (FA) de novo in spite of sufficient dietary lipid supply. This lipogenic conversion starts early when cells become cancerous and further expands as the tumor cells become more malignant. It is suggested that activation of FA synthesis is required for carcinogenesis and for tumor cell survival. These observations suggest that the enzymes involved in FA synthesis would be rational therapeutic targets for cancer treatment. However, several recent reports have shown that the anti-tumor effects, following inhibition of endogenous FA synthesis in cancer cell lines may be obviated by adding exogenous FAs. Additionally, high intake of dietary fat is reported to be a potential risk factor for development and poor prognosis for certain cancers. Recently it was reported that breast and liposarcoma tumors are equipped for both de novo fatty acid synthesis pathway as well as LPL-mediated extracellular lipolysis. These observations indicate that lipolytically acquired FAs may provide an additional source of FAs for cancer. This review focuses on our current understanding of lipogenic and lipolytic pathways in cancer cell progression.

Lipoprotein lipase links dietary fat to solid tumor cell proliferation.

Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, in addition to synthesis, cancer cells may obtain preformed, diet-derived FA by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake. We find that selected breast cancer and sarcoma cells express and secrete active LPL, and all express CD36. We further show that LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of these cells. Providing LPL to prostate cancer cells, which express low levels of the enzyme, did not augment growth, but did prevent the cytotoxic effect of FA synthesis inhibition. Moreover, LPL knockdown inhibited HeLa cell growth. In contrast to the cell lines, immunohistochemical analysis confirmed the presence of LPL and CD36 in the majority of breast, liposarcoma, and prostate tumor tissues examined (n = 181). These findings suggest that, in addition to de novo lipogenesis, cancer cells can use LPL and CD36 to acquire FA from the circulation by lipolysis, and this can fuel their growth. Interfering with dietary fat intake, lipolysis, and/or FA uptake will be necessary to target the requirement of cancer cells for FA. Mol Cancer Ther; 10(3); 427–36. ©2011 AACR.

Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis?

Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested.

Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered

Brisk fatty acid (FA) production by cancer cells is accommodated by the Warburg effect. Most breast and other cancer cell types are addicted to fatty acids (FA), which they require for membrane phospholipid synthesis, signaling purposes, and energy production. Expression of the enzymes required for FA synthesis is closely linked to each of the major classes of signaling molecules that stimulate BC cell proliferation. This review focuses on the regulation of FA synthesis in BC cells, and the impact of FA, or the lack thereof, on the tumor cell phenotype. Given growing awareness of the impact of dietary fat and obesity on BC biology, we will also examine the less‐frequently considered notion that, in addition to de novo FA synthesis, the lipolytic uptake of preformed FA may also be an important mechanism of lipid acquisition. Indeed, it appears that cancer cells may exist at different points along a “lipogenic‐lipolytic axis,” and FA uptake could thwart attempts to exploit the strict requirement for FA focused solely on inhibition of de novo FA synthesis. Strategies for clinically targeting FA metabolism will be discussed, and the current status of the medicinal chemistry in this area will be assessed. J. Cell. Physiol. 231: 2128–2141, 2016.

THRSP (thyroid hormone responsive)

Review on THRSP (thyroid hormone responsive), with data on DNA, on the protein encoded, and where the gene is implicated.

Abstract 5607: Lipoprotein lipase binds to the surface of cancer cells and facilitates uptake of lipoproteins.

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