OBESITY AND CANCER

 The Cancer Prevention Study II (CPS II) examined the risk of cancer mortality in obese men and women in the U.S. They reported that obesity is associated with a significant increase in mortality from multiple cancers, including esophageal, colorectal, liver, gallbladder, pancreatic, breast, endometrial, cervical, ovarian, renal, brain, kidney, and prostate cancer; non-Hodgkin lymphoma; and multiple myeloma.

 It has been estimated that overall overweight and obesity cause approximately 20% of all cancer cases.  International Agency for Research on Cancer has reported that obesity causes 39% of endometrial cancer cases.

Asia-Pacific Cohort Collaboration set out to to specifically examine the association of cancer mortality with BMI. They reported a significant increase in the risk of mortality from colon, rectal, postmenopausal breast, ovarian, cervical, and prostate cancer and leukemia in overweight and obese individuals from this population.

The CPS II study examined the association between diabetes and cancer mortality in 467,922 men and 588,321 women in the U.S. After 16 years of follow-up, they found a significantly increased risk of mortality from bladder, colon, pancreatic, and liver cancer in men and from pancreatic, colon, and breast cancer in women with diabetes. In the CPS II study, an inverse association was found between diabetes and prostate cancer mortality.

After 26 years of follow-up, in addition to finding an increased risk of mortality from bladder, pancreatic, breast, liver, and colon cancers, they reported that diabetes was associated with an increased risk of oral and pharyngeal cancer, breast cancer in men, and endometrial cancer in women.

The Metabolic Syndrome and Cancer Project (Me-Can) cohort in Austria, Sweden, and Norway is examining the association between the metabolic syndrome as a whole and its individual components on the risk of cancer. From this cohort, the investigators have reported that higher glucose levels were associated with an increased risk of liver, gallbladder, respiratory, and thyroid cancer and multiple myeloma in men, and pancreas, bladder, endometrial, cervical, and stomach cancer in women.

Syllogisms aside, if infections cause inflammations, by Giuseppe Peano’s logic, cancer must to some degree come from an infection.

A more apt question would be; does inflammation promote cancer? The answer to this statement is more apt to be a yes.

The most well-known is the disease Ulcerative Colitis. In this disease there is generalized inflammation of the colon.  This constant inflammation leads to intestinal crypt deformation and a 43% chance of colon cancer within 25-35 years.

PMNs produce enzymes/cytokines to evoke the inflammatory and immune response. The immune cells are provoked via a protein product liberated by the (TAM1) or T cell activated Macrophages. This product is called TNFa. TNFa promotes another agent called NFkB that sends signals to the immune system via IL6 (a cytokine). This signal essentially motivates the immune system with an “intruder alert” warning.

In the immune system, the NFkB is designed to eradicate the potential for injury but in the tissues the mischief it creates is a whole different ballgame.

This leads to the continuous inflammatory response and further production of the TNFa and by shared cross-talk the production of NFkB in the infected tissue cells. 

The overabundance of the NFkB leads to signaling via the STAT3 and IL6. The latter agent induces COX2, which stimulates the Prostaglandin E or PGE. This final agent then provokes the inflammatory response. The continued inflammation leads to a constant provocation of the tissue cells and a self-sustained vicious cycle of cytokine production that induces the cells to grow or proliferate. Somewhere in that confluence of this potpourri of enzymes, a genetic mutation lives or occurs and a cancer is born.

It appears that the NFkB causes about 500 different reversible and irreversible actions within the cellular DNA through epigenetics (Modulating the gene function by virtue of minor or major pressures from micro RNA, Histones etc. imposed on the genome) So not only is this cascade in flow, but other mechanisms are also being cumulated and promoted.

Specific COX-2 inhibitors (Celexecob) including aspirin and other NSAIDs (Advil. Aleve etc.) the increased incidence of polyp formation and cancer is reduced many-fold in patients with ulcerative colitis, in Familial Polyposis Coli and Inflammatory Bowel Disease.

Interestingly, the mitochondria undergo stresses via infection and inflammation by releasing Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS). 80% of all ROS is produced by the mitochondria. These reactive or nascent radical elements (when released within the mitochondria) lead to damage to the mitochondrial DNA (mtDNA), which leads to loss of energy needed for cell growth and function, cell senescence and finally cell death. In the aging process, mtDNA damage occurs over decades. While in infection-inflammation scenario the time is shorter. These ROS and RNS liberations are directly related to the TNFa and NFkB production.

Breast Implants: Recent studies have shown a higher risk of Malignant Lymphoma arising in the breasts of patients with breast implants. Questions remain as to the inflammatory link as the probable causality.

Mutation of the c-Myc and the K-Ras genes lead to the production of TNFa and NFkB, both within the tissue cells and the mitochondria spontaneously thus liberating the ROS and RNS (Oxidative Stressors)

Aspirin. A large meta-analysis of eight studies done by Rothwell et al revealed that those individuals talking daily aspirin had a 60% lower risk of colo-rectal cancer and a 30% lowered risk of other solid malignancies.

Natural agents: Fruits, vegetables, legumes and spices are notable in their ability to reduce inflammatory response.

Curcumin used in curry has been shown to decrease the levels of Y+TNFa and NFkB in the blood of individuals consuming curcumin when exposed to inflammatory provocations. In addition there was a reduction by 40% of abnormal crypt formation in the intestines of patients with inflammatory bowel disease (IBD), which also is proof positive.

Green Tea, Red wine, grape juice and other bioflavonoid also reduce the ROS liberation and the inflammatory response.

Hippocrates: “Let food be thy medicine and medicine be thy food.”

Potential mechanisms:

Increased insulin secretion from the pancreas into the portal circulation may lead to increased hepatic growth hormone–mediated synthesis of IGF-1. High-normal levels of insulin, C-peptide, and IGF-1 have been associated with an increased risk of certain cancers in epidemiological studies.

An analysis of 12 prospective studies reported that men with serum IGF-1 levels in the highest quintile of the population range had an odds ratio of 1.38 for developing prostate cancer, compared with men with the lowest IGF-1 levels not all studies have reported positive findings.

In vitro, both IGF-1 and insulin stimulate the proliferation of tumor cells lines. In vivo animal studies have demonstrated that endogenous hyperinsulinemia increases the growth and metastasis of mammary tumors, while increased circulating IGF-1 levels increased the growth and metastases of colon cancers in mice.

Many tumors are known to overexpress the IR, and some studies have reported that higher expression of the IR is associated with a worse prognosis.

Therefore, in obesity, diabetes, and the metabolic syndrome, glucose may be playing a role in concert with hyperinsulinemia, inflammation, adipokines, and altered estrogen levels.

Estrogen:

Similarly, increased endogenous estrogen levels have been reported to increase the risk of postmenopausal breast cancer twofold. Obesity has long been known to be associated with increased circulating estrogen levels, due to increased aromatase activity in adipose tissue. In addition, insulin-resistant women have suppressed hepatic production of sex hormone–binding globulin, leading to increased levels of free estrogen. More recent studies have also demonstrated that obese women express increased levels of aromatase in breast stromal tissues, the expression of which is increased by inflammatory mediators including TNF-α, IL-1β, prostaglandin E2, and cyclooxygenase-2 (COX-2)

The estrogen receptor (ER) and IGF-1R are known to have significant cross-talk in the normal mammary gland and breast cancer.

Cytokines:

Obesity is considered a state of chronic inflammation. In obesity, adipocytes increase in size and have a greater number of macrophages. Adipose tissue macrophages secrete a number of inflammatory molecules including IL-6 and TNF-α.

Increased IL-6 levels have been implicated in the pathogenesis of hepatocellular carcinoma and ovarian, prostate, and breast cancer.

IL-6 has also been implicated in the development of breast cancer metastases by inducing changes in cells that lead them to have greater invasive and migration properties: a phenomenon known as epithelial-mesenchymal transition. TNF-α has also been seen to play a role in tumor promotion. TNF-α is associated with increased colon tumor growth in animal models and with more aggressive prostate cancer and in breast adipose tissue has been shown to increase the expression of aromatase. 

Studies have demonstrated cross-talk between IL-6 and epidermal growth factor receptor signaling in epidermal growth factor receptor–driven breast cancer.

Knocking down IL-6 was also associated with a decrease in the number of tumor-associated macrophages. Tumor-associated macrophages are a source for cytokines and TNF-α and may contribute to tumor growth and metastases.

Low adiponectin levels and high leptin have been associated with an increased risk of colorectal cancers in a cohort study nested within the Women’s Health Initiative cohort. Leptin is also a proangiogenic factor and increases the expression of matrix metalloproteases (MMP-2 and MMP-9) that are important for cell invasion.

The bottom line is simple: Obesity is linked with chronic Inflammation and the latter drives the wheel of misfortune (cancer).

"Live Long and Prosper: Eat less (consider fasting a few days a month a prelude to healthy living), Exercise more (Walking daily for an hour) and De-stress a bit (don't take everything seriously)."

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