The Role of Fructose in Pancreatic Cancer Cells

Inhaltsverzeichnis

TITLE PAGE

CERTIFICATION

DEDICATION

ACKNOWLEDGEMENT

CONTENTS

LIST OF TABLES AND FIGURES

SUMMARY

CHAPTER ONE
1.0 Introduction
1.1 Background
1.2 Prevalence and Morbidity

CHAPTER TWO
2.0 Overview of Pancreatic Cancer
2.1 The Pancreas
2.1.1 Exocrine gland
2.1.2 Endocrine gland
2.2 Types of Pancreatic Cancer
2.2.1 Pre-cancerous growth in the pancreas
2.2.2 Pancreatic Exocrine Tumours
2.2.3 Pancreatic Endocrine Tumours

CHAPTER THREE
3.0 Fructose Metabolism and Pancreatic Cancer
3.1 Chemical Structure
3.2 Metabolism
3.3 Glycolytic Pathway and Pancreatic Cancer
3.4 The Non-oxidative Pentose Phosphate Pathway
3.5 Uric Acid Production in Pancreatic Cancer
3.6 Effect of Fructose in other cancer cells
3.6.1 Liver Cancer
3.6.2 Breast Cancer
3.6.3 Colon Cancer
3.6.4 Cancer of the Small Intestine

CHAPTER FOUR
4.0 Fructose Mechanism in Pancreatic Cancer Cells
4.1 Cancer Mechanisms
4.2 Insulin Relation to Pancreatic Cancer Cells
4.3 Oxidative Stress, Insulin Resistance and Inflammation in pancreatic cancer
4.4 Pancreatic Cancer and Diabetes Mellitus
4.5 Pancreatic Cancer and Obesity
4.6 Body Mass Index and Physical Activity in Relation to Pancreatic Cancer
4.7 Recent Advances in the Role of Fructose Metabolism and Mechanisms in Pancreatic Cancer Cells

CHAPTER FIVE
5.0 Dietary Factors in Relation to Pancreatic Cancer
5.1 High Fructose Corn Syrup (HFCS) in Relation to Pancreatic Cancer
5.2 Fruit and Fruit Juices in Relation to Pancreatic Cancer
5.3 Phytochemicals and Antioxidants in Fruits in Relation to Pancreatic Cancer
5.4 Glucose in Relation to Pancreatic Cancer
5.5 Other Dietary Factors and Pancreatic Cancer
5.5.1 Vegetables
5.5.2 Dietary Meat and Fat
5.6 Conclusion

REFERENCES

LIST OF TABLES AND FIGURES

Table 2.1 Differences between benign and malignant tumours

Fig 2.1 Parts of a human Pancreas

Fig 3.1 Different chemical structures of glucose and fructose.

Fig 3.2 Glucose and fructose metabolic pathways in the liver.

Fig 3.3 Fructose metabolism in the liver

Fig 3.4 Differences in the metabolic pathways of glucose [A] and fructose [B] in pancreatic cancer cells

Fig 3.5 Fructose breakdown in pancreatic cells

Fig 3.6 Fructose metabolism to uric acid

Fig 4.1 The mechanism showing how fructose promotes carcinogenesis and cancer growth...

Fig 4.2 The mechanism showing how fructose supports the up regulation of fatty acid synthesis and the triglyceride synthesis

Fig 4.3 Fructose causes Hepatic Insulin Resistance from the synthesis of triglycerides.

Fig 4.4 Potential mechanisms for fructose induced insulin resistance.

Fig 5.1 Effect of natural antioxidants on pancreatic cancer.

Fig 5.2 Metabolic pathways that are altered by the oncogene Kras

DEDICATION

I dedicate this work to God Almighty, my parents, Mr & Mrs I.O. Adjekukor, my brothers: Davis, Christian and Cyril for their unending love and support throughout the preparation of this seminar report.

ACKNOWLEDGEMENT

I acknowledge God Almighty, my parents Mr and Mrs Adjekukor, my siblings, and my ever-able supervisor Dr T.M. Dokunmu for her time and commitment. I also acknowledge the head of the department Prof A.A. AJAYI, biochemistry programme coordinator Dr E.O. Omotosho and biochemistry seminar coordinator Dr T.M. Dokunmu.

SUMMARY

Pancreatic cancer occurs when abnormal cells grow out of control in the pancreas, it is the fourth leading cause of cancer deaths in the United States. Over the past years, the consumption of fructose especially in its principal form, High-Fructose Corn Syrup has drastically increased along as the same time as nutrition-linked chronic diseases. Fructose has been linked to carcinogenesis and cancer growth of the pancreas. This occurs by the up-regulation of de novo lipogenesis, reactive oxygen species generation, hepatic insulin resistance, chronic inflammation and cellular oxidative stress, which can lead to the promotion of deoxy ribonucleic acid damage. Due to the differences in chemical structure of fructose and glucose, they both exhibit distinct metabolic properties. Fructose is preferentially used to glucose in the non-oxidative pentose phosphate pathway that produces 85% of ribose for deoxy ribonucleic acid synthesis in cancer cells. Fructose has similar effects in proliferating human breast cancer, liver cancer cells and other cancers. Michaud and colleagues reported that fructose may also increase pancreatic cancer risk in obese or overweight individuals, with a high body mass index, low physical activity and in susceptible individuals. Although fruits contain high levels of fructose, it is believed that fruits possess natural antioxidants and phytochemicals, which are thought to inhibit the deleterious effects of fructose in carcinogenesis. The biochemical mechanisms and the roles of high consumption of refined fructose in the progression of pancreatic cancers are discussed.

CHAPTER ONE

1.1 BACKGROUND

The word ‘cancer’ is used to describe any disease in which the cells are abnormal, grow out of control, and can spread. Thus, pancreatic cancer occurs when abnormal cells grow out of control in the tissue of the pancreas and form tumour. Tumours are mass of tissues formed from the build up of extra cells. Tumours may be benign or malignant and just as other living cells they possess the potential for proliferation, differentiation, cell cycle arrest and apoptosis. Due to this, macromolecule synthesis pathways directly determine the survival of these cells by providing energy and substrates necessary for cells to function under different pathophysiologic condition (Boros et al., 2002).

Carbohydrate metabolism through glycolysis and tricarboxylic acid (TCA) cycle is very important for cancer growth and increased consumption of refined carbohydrate promotes cancer survival. Fructose stimulates the up regulation of De novo Lipogenesis (DNL), which contributes to cancer risk by increasing oxidant stress and com- promising cellular antioxidant defense mechanisms (Port et al., 2012). It does this by increasing depleting NADPH, which is not only required in large amounts for fatty acid synthesis but is also a major cofactor in maintaining the reduced state level of glutathione and thioreductase (Port et al., 2012). This is associated with many negative health consequences, including development of insulin resistance, non alcoholic fatty liver, diabetes, hypertension and kidney disease, which could increase cancer risk by elevating levels of insulin, glucose, inflammation and oxidant stress (Port et al., 2012).

Recently, fructose intake contributed directly to oxidative stress in hamster islet tumour cells. It plays a vital role in the risk of pancreatic cancer and also may act as a marker of high-sugar diet, studies have shown that pancreatic cancer was inhibited by the drug metformin, which reduces insulin resistance in a hamster pancreatic adenocarcinoma model (Michaud et al., 2002). Also, the studies demonstrated that the pancreatic ductal cancer either arises from islet cells or from some common progenitor cells that could give rise to both islet and duct cells (Pour, 1978). Peripheral insulin resistance is associated hyperactivity and proliferation of islet cells because of this; fructose may be involved in promoting pancreatic cancer (Michaud et al., 2002).

1.2 PREVALENCE AND MORBIDITY

Pancreatic cancer is the fourth leading cause of cancer related death in the United States (Siegel et al., 2013). In 2012, it was the twelfth most common cancer worldwide (World Cancer Research Fund International, 2016). In Japan it is the fifth most common cause of cancer death, preceded in males by lung, stomach, liver and large bowel, and in females by stomach, large bowel, lung and breast (Lowenfels and Maisonneuve, 2004). Also, Pancreatic cancer is the 9th most common cancer in Western Europe and 19th in Middle Africa (World Cancer Research Fund International, 2016).

By 2030, it is expected to be the second leading cause of cancer death. Only 5% of individuals who develops pancreatic adenocarcinoma survive five years after diagnosis, and most patients live for less than 12 months (Wolpin et al., 2013). Fructose consumption has increased over the past years and this has been linked to various diseases including obesity, diabetes, cardiovascular diseases and cancer. The third National Health and Nutrition Examination Survey reported that over 10% of Americanapolis daily calories come from fructose of which the largest part comes from sugar sweetened beverages (30%), followed by grains (22%) and fruit or fruit juices (19%) (Vos et al., 2008). The principal form of this fructose is the High Fructose Corn Syrup (HFCS, 10-53% glucose and 42-90% fructose) (Tappy et al., 2010), which has been implicated in pancreatic tumour progression.

This review elicits the roles of fructose in pancreatic cancers and other cancers, giving a biochemical understanding, the implications and ways of managing pancreatic cancers in a developing world.

CHAPTER TWO OVERVIEW OF PANCREATIC CANCER

2.1 THE PANCREAS

The pancreas is an important digestive organ that is about 6 inches long, located deep in the abdomen between the stomach and the spine (back bone). The liver, intestine, and other organs surround the pancreas (Figure 2.1). The pancreas is made up of three parts: the head (is closest to the small intestine), the body (middle section) and tail (the thinnest part).

2.1.1 Exocrine

gland makes pancreatic juices, which contains enzymes that help in digestion of food and releases them into the intestine.

2.1.2 Endocrine gland

also known as islet of Langerhans make important hormones, such as insulin and glucagon and release them directly into the bloodstream.

2.2 TYPES OF PANCREATIC GROWTH

2.2.1 Pre-cancerous growth in the pancreas

Serous cystic neoplasm (also known as Serous Cystadonomas): they are usually benign tumours that have sacs (cyst) filled with watery fluid.

Mucinous cystic neoplasm (also known as Mucinous Cystadonomas): they are slow growing tumours in the body or tail of the pancreas that have cyst filled with a jelly-like substance called mucin. Intraductal papillary mucinous neoplasm: are benign tumours, which make mucin that grow in pancreatic ducts

2.2.2 Pancreatic Exocrine Tumours

Exocrine cancer is the most common type of pancreatic cancer. More than nine out of ten people (95%) have this type. They include:

Pancreatic adenocarcinoma: 95% of pancreatic cancer type is the pancreatic adenocarcinoma. They usually begin in the ducts (gland cells) of the pancreas but sometimes they develop from the cells that make the pancreatic enzymes in which case they are called acinar cell carcinomas. Solid pseudopapillary neoplasm: these are rare, slow growing tumours that almost always occur in young women.

Less common type of cancer: adenosqua carcinomas, squamous cell carcinomas, signet cell carcinomas, different carcinomas and undifferentiated with giant cells.

Ampullary cancer (carcinoma of the ampulla of vater): this cancer starts at the ampulla of vater which is where the bile ducts and pancreatic duct come together and empty into the small intestine.

2.2.3 Pancreatic Endocrine Tumours

They include:

a) Functioning tumours: they make hormones that are released into the blood and cause symptoms

Gastrinomas: about half of gastrinomas are cancers. It comes from cells that make gastrin.

Insulinomas: most insulinomas are benign. It comes from cells that make insulin.

Glucagonomas: most glucagonomas are cancers. It comes from cells that make glucagon.

Somatostatinomas: most somatostatinomas are cancerous. It comes from cells that make somatostatin.

VIPomas: most VIPomas are cancerous. It comes from cells that make Vasoactive Intestinal Peptide (VIP).

PPomas: most PPomas are cancerous. It comes from cells that make Pancreatic Polypeptide (PP).

b) Non functioning tumours: they are more likely to be cancerous than functioning tumours because these tumours does not make enough excess hormones to cause symptoms, they can grow quite large before they are found.

c) Carcinoid tumours: they rarely start in the pancreas, although they are much common in other parts of digestive system. This tumour often makes serotonin (also called 5-HT) or its precursor 5-HTP. Note: metastasis is when cancer cells often travel to other parts of the body, where they begin to grow and form new tumours that replace normal tissue. It happens when cancer cells get into the lymph nodes or bloodstream of the body. Tumours can be either malignant or benign. Table 2.1 shows a comparison between malignant and benign tumours.

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Figure 2.1 Parts of a human pancreas (National Cancer Institute, 2010).

Table 2.1. Differences between benign and malignant tumours

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CHAPTER THREE FRUCTOSE METABOLISM AND PANCREATIC CANCER

3.1 CHEMICAL STRUCTURE

Although glucose and fructose have identical chemical formulas (C6H1206) (figure 3.1), the difference in their chemical structure result in completely distinct absorptive and metabolic properties, which have fundamental implications for cellular functions and disease (Varman, 2011).

3.2 METABOLISM

The disaccharide (i.e. sucrose) components of the food we consume are cleaved in the gut into smaller glucose and fructose units. Fructose is absorbed in the small intestine by the fructose specific transporter, glucose transporter 5 (GLUT5) while glucose is absorbed through the gut by sodium-dependent glucose transporter (Bray, 2013). The liver is the major site of metabolism, which removes up to 70% of the portal fructose, leaving the 30% for metabolism by other tissues (kidney, musculoskeletal, testes, fat and brain). In contrast, the glucose is transported to hepatocytes and most other cell types using the glucose specific insulin-dependent transporter, GLUT4 (figure 3.2). Once in the hepatocytes, some of the glucose is absorbed while others goes into glycolysis and other metabolic pathways. During elevated concentration of glucose the pancreatic hormone, insulin, is released from the beta cells to regulate the glucose levels in the bloodstream. It should be noted that GLUT5 does not respond to insulin, thus leaving fructose uptake uninhibited. Fructose is independent of insulin and uses GLUT5 transporter, while glucose is regulated by insulin and uses the GLUT4 transporter (Charrez et al., 2015).

Figure 3.3 shows that a small amount of fructose goes into gluconeogenesis for the immediate production of glucose. The green pathway is related to the phosphorylation of fructose by fructokinase and the by- product of this is uric acid. Down to the left is an aldehyde pathway, which is the concept, used for the production of alcohol. The yellow pathway leads to the production of Insulin receptor substrate-1 (IRS-1),

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Figure 3.1 Different chemical structures of glucose and fructose (A) The hemiacetal group of glucose is substituted to a hemiketal group for fructose. (B) Representation of the open ring structure of glucose and fructose (Charrez et al., 2015).

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Figure 3.2 Glucose and fructose metabolic pathways in the liver (Charrez et al., 2015).

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Figure 3.3 Fructose metabolism in the liver (http://www.nofructose.com/introduction/metabolism/ Sourced on 08/05/2016).

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