**1. Introduction**

Circulating lipoproteins perform vital functions, including the transport of fatty acids and cholesterol from intestine and liver throughout the body. However, in well-fed Western societies, elevated concentrations of lipoproteins in blood have long been recognized to convey increased risk for cardiovascular disease. High fat diets, obesity, and heredity can all contribute to hyperlipidemia. More recently, there has been concern for the possible effects of hyperlipidemia on risk for or progression of cancers, which have a far greater demand for lipids than normal tissues. For example, obesity is now an established risk factor for certain types of cancer and is also found to affect the prognosis for cancer patients (Calle and Kaaks 2004; Cleary and Grossmann 2009). While the association of obesity with cancer is complex, higher circulating lipids may be a contributing element. Similarly type 2 diabetes, a condition of multiple co-morbidities including hyperlipidemia, is associated with the incidence of and mortality from cancer (Faulds and Dahlman-Wright 2012).

**Figure 1.** Cytoplasmic lipid droplets consist of an oily core of TAG and CE surrounded by a phospholipid monolayer, specific coat proteins, and other proteins.

© 2012 Antalis and Buhman, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The association of hyperlipidemia with cancer began with early observations of an accumulation of cholesterol in tumors (reviewed, (Mulas, Abete et al. 2011)). Higher levels of cholesterol and cholesteryl esters (CE) in malignant compared to less malignant tumors and normal tissues were first measured chemically (Yasuda and Bloor 1932). The accumulation of lipids in tumors was subsequently noted in tumor sections through histological examination and staining for lipid droplets (also called lipid bodies) (Freitas, Pontiggia et al. 1990). Lipid droplets are cellular organelles that store neutral lipids triacylglycerol (TAG) and CE (**Fig. 1**). Adipocytes store lipids in a single, large lipid droplet. Most other cell types have fewer, smaller lipid droplets except under pathological conditions when increased numbers and amounts of lipid may be present (Bozza and Viola 2010). Lipid droplets were detected *in vivo* in tumors with proton magnetic resonance (Delikatny, Chawla et al. 2011), and more recently, *in vivo* and *in vitro* with coherent anti-Stokes Raman scattering microscopy (Le, Huff et al. 2009). Unlike adipocyte lipid droplets, tumor cell lipid droplets contain significant quantities of CE (Tosi and Tugnoli 2005); therefore as these tumors grow and accumulate cholesterol, they may be expected to affect whole body cholesterol homeostasis and circulating cholesterol levels.

The observation of changes in plasma cholesterol in cancer patients constitutes the second line of evidence in the association of lipoproteins with cancer. It appeared in multiple studies over many years that lower plasma cholesterol was associated with a higher risk of cancer (Rose and Shipley 1980). This was a concern because lowering plasma cholesterol is a goal in cardiovascular disease prevention. The relationship between plasma cholesterol and cancer was examined in many population-based studies. Although total plasma cholesterol (total-C) measurements were used in many studies, determinations of individual lipoprotein cholesterol fractions were increasingly included. Plasma cholesterol resides primarily in low density lipoproteins (LDL) and high density lipoproteins (HDL), the lipoproteins that transport cholesterol to cells and collect excess cholesterol from cells, respectively. High HDL-C is a protective factor against atherosclerosis, while high LDL-C is positively associated with risk of atherosclerosis.

Two trends ultimately emerged from the data. First, total-C concentrations were lower two to six years prior to a cancer diagnosis, suggesting reverse causation: i.e., the early stages of the tumor led to lower circulating cholesterol (Sharp and Pocock 1997). Second, the plasma cholesterol fraction associated with tumor-caused decreases was primarily HDL-C, although the trend was detectable in total-C values also (Ahn, Lim et al. 2009). These conclusions were supported by data showing an increase in HDL-C when the patient was in remission (Dessi, Batetta et al. 1995).

The observations above suggest that in some types of cancer, tumor cells accumulate cholesterol as CE in lipid droplets and efflux less cholesterol to HDL, resulting in lower circulating HDL-C, detectable even before the tumor can be diagnosed. There is also some indication that low HDL-C levels may contribute to the development of cancer (Mondul, Weinstein et al. 2011). HDL has antioxidant and anti-inflammatory properties in addition to its role in reverse cholesterol transport (Kwiterovich 2000), and low HDL-C is a defining characteristic of the metabolic syndrome which has already been linked to cancer risk (Faulds and Dahlman-Wright 2012). Although lower HDL-C can have multiple etiologies, it can be one indicator of the presence of a tumor. If some tumors accumulate cholesterol, then it might be reasonable to ask if LDL-C fuels the development of this type of tumor.

624 Lipoproteins – Role in Health and Diseases

associated with risk of atherosclerosis.

(Dessi, Batetta et al. 1995).

The association of hyperlipidemia with cancer began with early observations of an accumulation of cholesterol in tumors (reviewed, (Mulas, Abete et al. 2011)). Higher levels of cholesterol and cholesteryl esters (CE) in malignant compared to less malignant tumors and normal tissues were first measured chemically (Yasuda and Bloor 1932). The accumulation of lipids in tumors was subsequently noted in tumor sections through histological examination and staining for lipid droplets (also called lipid bodies) (Freitas, Pontiggia et al. 1990). Lipid droplets are cellular organelles that store neutral lipids triacylglycerol (TAG) and CE (**Fig. 1**). Adipocytes store lipids in a single, large lipid droplet. Most other cell types have fewer, smaller lipid droplets except under pathological conditions when increased numbers and amounts of lipid may be present (Bozza and Viola 2010). Lipid droplets were detected *in vivo* in tumors with proton magnetic resonance (Delikatny, Chawla et al. 2011), and more recently, *in vivo* and *in vitro* with coherent anti-Stokes Raman scattering microscopy (Le, Huff et al. 2009). Unlike adipocyte lipid droplets, tumor cell lipid droplets contain significant quantities of CE (Tosi and Tugnoli 2005); therefore as these tumors grow and accumulate cholesterol, they may be expected to affect

The observation of changes in plasma cholesterol in cancer patients constitutes the second line of evidence in the association of lipoproteins with cancer. It appeared in multiple studies over many years that lower plasma cholesterol was associated with a higher risk of cancer (Rose and Shipley 1980). This was a concern because lowering plasma cholesterol is a goal in cardiovascular disease prevention. The relationship between plasma cholesterol and cancer was examined in many population-based studies. Although total plasma cholesterol (total-C) measurements were used in many studies, determinations of individual lipoprotein cholesterol fractions were increasingly included. Plasma cholesterol resides primarily in low density lipoproteins (LDL) and high density lipoproteins (HDL), the lipoproteins that transport cholesterol to cells and collect excess cholesterol from cells, respectively. High HDL-C is a protective factor against atherosclerosis, while high LDL-C is positively

Two trends ultimately emerged from the data. First, total-C concentrations were lower two to six years prior to a cancer diagnosis, suggesting reverse causation: i.e., the early stages of the tumor led to lower circulating cholesterol (Sharp and Pocock 1997). Second, the plasma cholesterol fraction associated with tumor-caused decreases was primarily HDL-C, although the trend was detectable in total-C values also (Ahn, Lim et al. 2009). These conclusions were supported by data showing an increase in HDL-C when the patient was in remission

The observations above suggest that in some types of cancer, tumor cells accumulate cholesterol as CE in lipid droplets and efflux less cholesterol to HDL, resulting in lower circulating HDL-C, detectable even before the tumor can be diagnosed. There is also some indication that low HDL-C levels may contribute to the development of cancer (Mondul, Weinstein et al. 2011). HDL has antioxidant and anti-inflammatory properties in addition to its role in reverse cholesterol transport (Kwiterovich 2000), and low HDL-C is a defining

whole body cholesterol homeostasis and circulating cholesterol levels.

In this chapter, we will review the evidence that LDL-C, which is usually highly correlated to total-C, is positively associated with the risk of some types of cancer. We will also review the growing body of data on what mechanisms may be involved in tumor cholesterol accumulation and what markers may be useful to identify tumors that are stimulated by cholesterol. We will address the questions: does higher circulating cholesterol increase the risk of or prognosis for certain cancers, and should lowering LDL-C be a goal in the prevention or management of some types of cancer?
