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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