Use of Proteins as Biomarkers and Their Role in Carcinogenesis

Introduction

In previous experimental and epidemiological research, the role of the dietary fiber and fat in cancer development was the focus of study, while the influence of protein intake in carcinogenesis was barely understood. Research by Visek et al. ⁷ focused on the quantity of certain types of protein and amino acid content rather than its source. Later, an analysis in several studies on dairy products and tumor development indicated the importance of dietary milk proteins in cancer prevention.

Whey protein is a component of milk and constitutes approximately 20% of the bovine milk proteins (with casein constituting the other 80%). Whey protein is also concentrated in the whey, the liquid bi-product of cheese manufacture, and can be isolated from these sources. The whey proteins including α-Lactalbumin, β-lactoglobulin, lactoferin, lactoperoxidase, immunoglobulins, and glycomacropetide offer a wide range chemical, physical and functional properties ⁸ as well as anti-cancer properties.⁹ Importantly, the proteins can survive digestion, which allows it create a physiological effect both inside and outside of the digestive system. Specifically, these anti-carcinogenic properties are tied to the substrate amino acid cysteine, which with glutamate forms γ-glutamylcysteine, and subsequently with glycine forms the antioxidant glutathione (figure (figure1).1). In fact, cysteine is a limiting residue in glutathione synthesis, which can be readily supplied by whey protein, allowing for glutathione formation. Glutathione is important in protecting against oxidative stress from Reactive Oxygen Species (ROS). In addition it plays a role in cell growth, differentiation and apoptosis. These properties are thus protective against cancer formation.

Great emphasis in cancer prevention and treatment has been given to soy proteins. These proteins contain various compounds that have been have been proven to inhibit tumors in rats, and thought to prevent the formation of tumors in humans. isoflavones, a class of plant-based compounds that act as phytoestrogens, and various studies examine their individual action, as well as their interaction with cancer medication. Other agents such as Protease Inhibitors, specifically BBI, and Protein Kinase Inhibitors have been proven effective in tumor growth restriction or reversal. Also, Methionine Deficiency has been studied as the mechanism of tumor inhibition.

The Shanghai Breast Cancer Survival Study was a large, population-based cohort study of 5042 female breast cancer survivors in China. The conclusion of this study was that soy food consumption was significantly associated with a decreased risk of recurrence and death in female breast cancer patients.

Lectins are phytochemicals present in plant foods, and are also found in almost all organisms, including plants, invertebrates, bacteria and viruses.⁵ Lectins have an active components which alters cancer initiation, promotion and progression.³^,⁴ In fact, previous epidemiological studies proved that the consumption of a diet based on plants is associated with a reduced risk of developing certain types of cancer.² Furthermore, several different types of lectins exist, and have been showed to reduce the malignant potential of cancer cells. In addition, lectins have been characterized as a useful tool in biochemistry, cell biology, immunology and in diagnostic and therapeutic purposes in cancer research. ⁶

CPTP, a recently discovered protein, has been shown to transport ceramide-1-phosphate (C1P), a lipid that helps regulate cell growth, survival, migration and inflammation. Specifically, C1P increases the production of pro-inflammatory eicosanoids, which are powerful signalling molecules that contribute to chronic inflammation, and thus diseases such as cancer, asthma, atherosclerosis and thrombosis. The discovery of CPTP thus shines light on the cellular mechanisms that contribute to these diseases, ¹⁵ and their potential role as biomarkers and agents for targeted therapy.

Interleukin-6 (IL-6) is a glycoprotein consisting of 184 amino acids and has a molecular weight of 26 kilodaltons (kDa). It is known as a multifunctional cytokine which, in addition to its more known roles as a proinflammatory and sclerotic agent, also affects the activity of cancer cells. Studies have indicated that it is involved in tumor growth and in distinction between benign cells and malignant cancer cells. ¹⁶^,¹⁷ It is shown that the levels of Interleukin-6 are elevated in advanced cancer and that elevated levels are associated with an increased risk of cancer.¹⁸ Because of that, IL-6 has been characterized as a prognostic marker of cancer disease. High levels of IL-6 have been linked up with increased risk of lung cancer in non-smoking women with asthma, whereas reducing IL-6 levels, by administering estrogen, has been observed to have a protective role against metastasis from hepatocellular carcinoma.

The CCN family of proteins, composed of CCN1 (CYR61), CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2), and CCN6 (WISP-3), is a set of cysteine-rich regulatory proteins. It is believed that these matricellular proteins are involved in a wide range of functional pathways such as cellular adhesion, mitogenesis, chemotaxis, cell survival, and wound healing. CCN proteins are also able to modulate the signals of several proteins, including integrins, Wnt, Norch and bone morphogenetic protein (BMP) which may also influence skeletal development and angiogenesis.²⁰ Many of the functions of these proteins are thus also related to tumor growth. In fact, either overexpression or underexpression of CCN proteins has been tied to cancer development. Furthermore, estrogen seems to play an interactive role with CCN proteins in the development of cancer, especially that of breast and ovarian cancer.

S100 proteins participate in a variety of intracellular processes, including calcium homeostasis, energy metabolism, proliferation and differentiation. In addition, it is involved in inflammation, and apoptosis, as well as migration and invasion. Therefore, S100 plays a role in the healthy cell regulation, as well as cancer development. These proteins are subclassified into S100A and S100 B, and interact with a variety of other proteins, such as cytoskeletal components, enzymes, receptors, as well as transcription factors and nucleic acids.