Obesity and Cancer

             
              
   

                         P.R.Jayawickrama
       
                              

Obesity

Obesity is a disorder of body weight regulatory systems characterized by an accumulation of excess body fat (1). In early ages in human civilizations, in which day today life required a high level of physical activity and food was only available intermittently, a genetic tendency favoring storage of excess calories as fat had a survival value. But, in modern era the abundance of food has encouraged people to eat much. This,with the combination of less activity levels found in developed countries,caused in a tendency for the sustained deposition of fat.The prevalence of obesity increases with age. As the obesity in the world has increased so the risk of developing associated diseases, such as diabetes mellitus, hypertension, and cardiovascular disease and also it increase the risk of cancer.

Markers of the Obesity (1)

1) Body mass index

2) Body fat percentage

With the development of medicine they invented a standard scale for measuring obesity.so in these days BODDY MASS INDEX (BMI) uses as the surrogate marker for body fat content, it is calculated as:

B M I = ( weight in kg ) / ( height in meters ) ²
                or

 B M I = ( weight in lb ) / ( height in inches ) ²  ×  703

In use, The healthy range for the BMI is between 19.5 and 25.0.
BMI between 25 and 29.9 kg/m2 is called overweight,  and a BMI higher than 30 kg/m2 is called obese(2). But BMI is not a direct estimate of adiposity and doesn’t take consider the fact that some individuals have a high BMI due to a high amount of muscle mass. Because of this, the much better way to define obesity is to actually measure the percentage of total body fat. Obesity is usually defined as 25 per cent or greater total body fat in men and 35 per cent or greater in women.

METHODS OF ESTIMAING THE BODY FAT PERCENTAGE
1)measuring skin-fold thickness,
2)bioelectrical impedance,
3)underwater weighing,
 but above methods are very rarely used in general practice,and also there are debates on methods like measuring skin fold thickness(3) ,so BMI is commonly used to assess obesity in clinics..

CAUSSES FOR OBESITY

1. Greater Energy Intake than Energy Expenditure.

The main cause for obesity is Greater Energy Intake than Energy Expenditure(4).When greater quantities of energy (in the form of food and drinks) enter the body than the amount that expended, the body weight rises,so most of the excess energy is stored as fat in the adipose tissues,mainly in the form of triacylglecerols(5).so,excessive adiposity (obesity) is caused by energy intake in excess of energy output. For each 9.3 Cals of excess energy that uptake to the body, approximately 1g of fat is stored in adipose tissues.Fat is stored mainly in adipocytes in subcutaneous tissue and in the intraperitoneal cavity in the abdomen, although the liver and other tissues of the body also store high amounts of lipids in obese individuals. also the amount of adipocytes are also rises with the weight gain.as a example an extremely obese person may have as many as four times as many adipocytes, each containing twice as much lipid, as a lean person.when a person has become obese and a stable weight is gained,the energy uptake again equals to the energy output.so if a person need to lose weight,he or she should maintain energy intake lesser than the energy expenditure.

2. Decreased Physical Activity and Abnormal Feeding Regulation as Causes of Obesity.

Though genes play a vital role in determining food uptake and energy utilization,lifestyle and environmental issues also play the major role in many obese people.The rapid rise in the prevalence of obesity in the past few decades show the important role of lifestyle and environmental issuses.Because genetic changes couldnt have occurred so fast.

3. Sedentary Lifestyle Is a Major Cause of Obesity.

Regular physical training and physical exercises are known to increase muscle mass and reduce body fat mass,so inadequate physical activity is generally associated with reduce muscle mass and increased lipid content of the body.

4. Psychological Factors Which are Contribute to Abnormal Feeding.

For example, people often gain large amounts of weight during or after stressful situations,such as the death of a parent, a severe illness or even mental depression.

5. Childhood Over nutrition.

6. Neurogenic Abnormalities as a Cause of Obesity.

Individuals with hypophysial tumors that encroach on the hypothalamus often develop progressive obesity.
7. Genetic Factors as a Cause of Obesity(6).

We can often identify obese people within the same family background.though it has been difficult to determine the exact role of genetics in contributing to obesity,scientists suggest that 20% to 25% of cases of obesity may be caused by genetic factors.

Genes can contribute to obesity by causing abnormalities of:

 (1) One or more of the pathways that regulate the feeding centers.

 (2) Energy expenditure and fat storage. There are three monogenic (single-gene) causes of    obesity.they are:

   (1) Mutations of MCR-4 -the most common monogenic form of obesity discovered thus far. 

   (2) Congenital leptin deficiency caused by mutations of the leptin gene-which are very rare

   (3) Mutations of the leptin receptor-also very rare.

but these monogenic forms of obesity account for only a few percentage of obesity. It is understandable that the many gene variations interact with environmental factors to influence the total amount and distribution of body fat.

As discribed in the above obesity become a major health issue in the world, and it causes and enhance the ill effects of  many disease conditions like
*diabetes mellitus(DM)(7).
*high blood pressure and other cardiovascular diseases,
*strokes.
* cancers.
in the following segment im going to illustrate what are the co-relations between obesity and cancers.


The relationship between obesity and cancer

 According to modern researches obesity is associated with high risks of many cancer types, like:

1 ) breast cancers(mainly post menopause).

2 ) cancers in the oesophagus.

3 ) cancers in the pancreas.

4 ) cancers in the colon and the rectum.

5 ) cancers in the endometrium.

6 ) cancers in the kidney.

7 ) cancers in the tyhyroid.

8 ) cancers in the gallbladder.

to understand the co-relation between the cancer and obesity,there is a set of possible mechanisms have been suggested by the scientists,they are;

1 ) Adipose tissue manufactures high amounts of estrogen, high levels of which have been co-related with the risk of breast(8),endometrial, and some other cancers.

2 ) Fatty people usually have high levels of insulin and insulin-like growth factor-1 (IGF-1) in their plasma(this condition known as insulin resistance),this condition may help the development of certain tumors(9).

3 ) Adipocytes manufacture hormones,known as adipokines,these hormones may stimulate or inhibit cell growth and function.as a example, leptin, which can find in higher amounts in fatty people, seems to promote cell proliferation.

4 ) Adipocytes can have direct and indirect effects on other tumor growth regulators, including mammalian target of rapamycin (mTOR) and AMP-activated protein kinase.

5 ) Fatty individuals usually have chronic low-level, or “sub acute,” inflammation, which may associated with higher risk of cancer.

      Also there are other possible mechanisms like,

             1 ) altered immune responses.

             2 ) effects on the nuclear factor kappa beta system.

             3 ) oxidative stress.


in the following section I will discuss how the above pathophysiological mechanisms give rise to cancers.

Dysfunctional Adipose Tissue

Though the main function of the adipose tissue is to store lipids but also they are highly functioning endocrine and metabolic tissues.these tissues are consists of many cell types, such as adipocytes, pre-adipocytes, macrophages,fibroblasts,and also blood vessels.these different cells   product number  of  adipokines, such as leptin, adiponectin, vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-α), interleukin (IL) -6.  ,and plasminogen activator inhibitor (PAI)-1. As adipose tissue grow,the adipocytes grow bigger and these adipose tissues start to manufacture above factors in high amounts.

These obesity- corelted changes of adipose tissue metbolism are  play a main role in the development of insulin resistance & the production of leptin which is a major co-relation between obesity and cancer,except that these factors also cause type 2 diabetes, and obesity-related cardiovascular diseases.

 Insulin Resistance

Insulin resistance and the insulin-like growth factor (IGF) -1 system may explain in part the link between obesity and cancer. In insulin resistance, which is commonly associated with obesity,plasma insulin levels increase.Insulin enhance the effect of growth hormone (GH) receptors in the liver,and this causes a stimulation in production of IGF-1.

Both insulin and insulin-like growth factor (IGF) -1 are play a vital role in cancer development through binding with the insulin receptor (IR) and IGF-1 receptor (IGF-1R). Insulin-like growth factor-1 can inhibit apoptosis and aid cell growth and development through several mechanisms(9).

Also this unbalanced tissue environment aids the stepwise accumulation of genetic mutations and it helps the carcinogenesis.

modern studies have shown that individuals with high levels of insulin-like growth factor-1 have an high risk of several cancer types,including postmenopausal breast cancer,prostate cancer,colorectal cancers. high levels of serum insulin is also a risk factor for breast cancer in women and also increases the risk of colorectal cancer and endometrial cancer.Further more, diabetes mellitus (D.M.), which is characterized by insulin resistance,is also associated with high risk of breast,pancreatic,colorectal cancers(9).So the Insulin resistance is play a prominent role in carcinogenesis(9) , and it is one of the major mechanisms shows the co-relation between obesity and cancer(9).

Adipokines

Adipose tissue cells manufactures a variety of biochemical substances which act like hormones and cytokines,which are known as adipokines.Adipose tissue dysfunction as a result of obesity unbalanced the serum levels of adipokines,this may cause to obesity-related carcinogenesis.

Leptin

Leptin is a protein hormone,it is secreted by adipocytes in the adipose tissuses, and plays a major role in regulating the energy balance,by regulating the metabolic rate.Levels of leptin are higher in obese individuals,. Though the findings of sciencetific studies of the relationship between systemic leptin levels and breast or prostate cancer are inconsistent, but an association reported for colorectal cancer and for the endometrial cancer.Also many cancers such as colorectal, breast, and endometrial cancers overexpress the leptin receptor ObR.studies have shown that leptin has mitogenic actions in the cancer cell lines,it vary one from other by the type of cancer.it stimulates the growt and development of the breast,the oesophagus, and the prostate cancer,But inhibits the growth of the malignent cells in pancreatic tissue.

Though Mitogenic and anti-apoptotic functions of leptin described in both colon and prostate mlignent cells,represion of MAPK and PI3-K inhibited these effects,this shows that these pathways underlie the growth-encouraging effects of leptin.



In the above section we  discussed how the obesity related pathophysiological mechanisms give rise to cancers in a general aspect.in the following section I consider how the obesity cause for cancers in specific sites in the body.


Co-relation between obesity and breast cancer.
Modern studies have shown that overweight and obesity are associated with a moderate increase in risk of postmenopausal breast cancer in women. and mainly in women who have never used menopausal hormone therapy(MHT) and for tumors that express both progesterone and estrogen receptors.

The correlation between obesity and breast cancer may be affected by the age of her life in which she gain weight and becomes obese.Weight gain during adult life, most frequently from about age eighteen to between the ages of fifty and sixty, has been consistently associated with higher risk of breast cancer after menopause.

The higher risk of postmenopausal breast cancer is thought to be due to higher levels of estrogen in obese  individuals.After the menopause,the ovaries stop producing hormones,and then the adipose tissue becomes the most important source of estrogen.As a result of obese women have more adipose  tissue,their estrogen levels are higher,and probably leading to faster growth of estrogen-responsive breast tumors(8).

 According to the sciencetific studies the correlation between obesity and breast cancer risk may also vary by ethnicity and race. There is rare evidence that the risk associated with overweight and obesity may be less among African American and Hispanic women than among white women.


 Co-relation between obesity and colorectal cancers.

In men,who have higher BMI is closely associated with elevated risk of colorectal cancer.The distribution of body fat appears to be an important factor in here,as a example people with abdominal obesity,show the strongest co-relation with colon cancer risk.

A co-relation between BMI and abdominal obesity with colon cancer risk is also identified in women, but it is weaker than in men.May be the use of menopausal hormone therapy (MHT) modify the association in postmenopausal women.

Many mechanisms have been proposed to account for the co-relation between obesity with increased colon cancer risk.One such mechanism is that elevated levels of insulin or insulin-related growth factors in fatty individuals may uphold colon cancer development.also the free adipokines , free fatty acids and many other proinflammatory chemokines which released  from the  adipose tissue are known as factors which  act a major role in regulating carcinogenesis(10). 

Though obesity is also related with rectal cancer risk,the increase in risk is lesser than the colon cancer risk.


Co-relation between obesity and endometrial cancers.

Overweight and obesity is clearly related with endometrial cancers,which is cancer of the lining of the uterus in females.Obese and overweight females have 2 to 4 times greater risk of developing this disease than female with a normal BMI.

Many reacherchs  have also show that the risk of endometrial cancer is higher with elevated weight gain in adultlife because some studies shows that there is a higher risk of having  a endometrial cancer when a patient develop insulin resistance(11) specially in obese individuals ,and among women who do not use menopausal hormone therapy(MHT).

Although it hasn’t yet been determined 100% how the obesity is a risk factor for endometrial cancer,some other studies shows the possibility in combination with low levels of physical activity and elevated levels of estrogen manufactured by adipose tissue is co related with endometrial cancer.


Co-relation between obesity and kidney cancers.

Obesity and having high BMI has been markedly related with renal tissue cell cancer,according to the national cancer institute of  USA  it is the most commonly found species of kidney cancer, in both males and females.The way that the obesity related to the renal cell cancers is not cleared.But the high blood pressure is regarded as a risk factor for renal cell cancer,but according to the modern studies the co-relation between obesity and overweight with kidney cancer is not dependent on blood pressure status.May be the high levels of insulin,which found in  obese   people play a important role in the development of the renal cancers.


Co-relation between obesity and oesophageal cancers.

people with higher BMI are about two times as likely as people who have normal BMI to suffer from a oesophageal cancer type known as oesophageal adenocarcinoma.But many studies have observed no elevated risk, or even a decrease in risk, with high BMI for the other major type of oesophageal cancer,which is known as squamous cell cancer.

The mechanisms by which high BMI may develop the risk of oesophageal adenocarcinoma are not well defined, but according to some studies there are links between IGF-1, high levels of estrogen (12)  with oesophagieal cancers(13).
Also people who are with high BMI are more likely than people with normal BMI to have a record of gastroesophageal reflux disease/Barrett esophagus.And they are related with an higher risk of oesophageal adenocarcinoma.



Co-relation between obesity and pancreatic cancers.

Modern studies have identified a little increase in risk of pancreatic cancer among individuals with high BMI than the normal individuals. But the mechanism is not clear how the co-relation of overweight and obesity with pancreatic cancer development.
also some studies shows that there is an increase in mortality rate with pancreatic cancer patients who are obese(14) .



Co-relation between obesity and thyroid cancers.

Individuals with high BMI has been found to be associated with higher risk of thyroid cancer. It is not clear how this association develops.



Co-relation between obesity and gallbladder cancers.

The risk of gallbladder cancer is higher when the BMI is higher than the healthy range(15). The increase in risk may be due to the higher frequency of having gallstones in obese people this is a risk factor for gallbladder cancers(15).


Co-relation between obesity and other types of cancers.

The link between having high BMI and prostate cancer has been studied in deep, so when the statistical data from numerous studies are pooled, analyses present that obesity may be associated with a very little increase in the risk of having prostate cancers due to obesity.

the bio medical link between the risk of prostate cancer and obesity is the higher levels of some hormones and growth factors, a major example is IGF-1.

Also some other studies have shown a poor link between obesity and risk of having an ovarian cancer, specially in premenopausal females, But other studies haven’t found an link between them. As like as some other cancers, the link between ovarian cancer and increased BMI may explained with the increased levels of estrogens.Also there are suspicions for association of obesity to liver cancers and to some species of  leukemia and lymphoma.


so now we can understand that there is a clear link between obesity and the cancer risk.the next problem is how to overcome this and how to reduse the cancer risk.as result of thousands of studies in this field medical professionals suggest that, it is a possibility                         of reducing cancer risk by reducing obesity.in the following section I will what are the treatments for obesity.


 Treatments for Obesity

Treatments for obesity mainly depend on reducing energy input below energy loss and making a relatively sustained negative energy balance until the needed weight loss is gained,or simply reducing energy uptake or increasing energy loss. To reduce energy uptake, most "reducing diets" are created to contain big quantities of “bulk”,that typically consist of non-nutritive cellulose or other substances which are cannot be digested.

 also ther are various drugs for reduce the degree of hunger and appetite as a treatment of obesity.The most commonly used drugs are the amphetamines (or amphetamine derivative),these drugs directly inhibit the feeding centers in the human brain.One such drug in use for treating obesity is sibutramine, it is a sympathomimetic which decrease food uptake and also increases energy wastage.But ther is a dark side in using these drugs,because these drugs can overexcite the central nervous system(CNS), making the patient nervous and rising the blood pressure.Also,when the time passes patients adapt for the drug, so that weight reduction is usually a less amount,not  higher than 5% to 10%. Also there is a another group of drugs effect on lipid metabolism.As a example,orlistat,this is a lipase(enzyme that digests lipids) inhibitor, decrease the intestinal digestion of lipids.As result of this a considerable portion of the taken lipids with food is loss with the feces and as a result decreases the energy uptake.but this drug also has some disadvantages,as a example fat loss with fecal matter may result in unpleasant gastrointestinal side effects, also there is a waste of fat-soluble vitamins( vit - A , vit - D , vit - E , vit - K  ) with the feces.

Also a patient can achieve a significant weight loss by increasing physical activity. The morephysical exercise one gets, the energy expenditure become greater and as a result obesity reduce. Therefore,physical exercise is an essential part of any treatment for obesity.So the modern clinical methods for the treatment of obesity highlights that the 1st step be lifestyle changes which includes increased physical exercises combined with a decrease in energy (food) intake. For morbidly obese patients with BMIs higher than fourty, or for patients with BMIs greater than thirty-five and with complications such as type II diabetes or hypertension that predispose them to other serious disease  conditions,there are variety of surgical methods are to use  for reduce the fat mass of the body or to reduce the quantity  of food that a person can taken at each meal. Two of the most common surgical procedures used in the world as a treatment for morbid obesity are

                 1 ) Gastric bypass surgery.

                 2 ) Gastric banding surgery.

 Though these surgeries produce a considerable weight loss in obese and over weight patients,these are major operations, and also there may be long-term effects on overall health.

Summary
obesity is a major health problem in the modern world and it causes many ill effects on human life. As there are clear connections between obesity and other diseases obesity plays a major role in carcinogenesis. So we can reduce cancer risk in society by controlling obesity  and adapting to a healthy lifestyle.












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 Acknowledgement
I wish to thank our dear sir Dr.Mahinda Kommalage for  all the advices and
 his valuable time in completing this analytical essay.