Download Food, Nutrition, Physical Activity and the

NUTRITION AND CANCER:
BEFORE, DURING AND AFTER
Andrew D. Nish MD
NUTRITION AND CANCER: BEFORE,
DURING AND AFTER
A simple question:
IS CANCER A PREVENTABLE DISEASE?
Basic Concepts of Cancer
• 5-10% of cancers result directly from inheriting genes
associated with cancer
• The majority of cancers involve alterations or damage
accumulated over time to the genetic material within cells
• The causes of damage are both endogenous (internal) and
exogenous (environmental)
• FOOD, NUTRITION AND PHYSICAL ACTIVITY ARE
IMPORTANT ENVIRONMENTAL FACTORS IN THE
DEVELOPMENT OF CANCER
• The hallmark of cancer is unregulated cell growth and/or
cell death
Basic Concepts of Cancer
Basic Concepts of Cancer
Concepts of Cell Function and Obesity
• The normal functioning of all biological processes depends
on the availability of substrates and nutrients.
• Good nutrition – appropriate provision of food and
nutrients from the level of the whole organism to the
cellular and intracellular level- is needed for normal
structure and function.
• When a person is not suitably nourished, either through
under- or overnutrition, this impacts the tissue
microenvironment, compromising both structure and
function.
• Overall dietary patterns can indirectly influence cell growth
by way of changes in general metabolic, regulatory and
endocrine effects.
Concepts of Cell Function and Obesity
• The prevalence of obesity has doubled globally over
the past 30 years. Today 65% of the population lives in
countries where obesity kills far more people than
underweight ( WHO fact sheet 311. Obesity and Overweight;2011)
• The prevalence of adult obesity in the US 2011-2012 –
34.9% and youth 17% (JAMA.2014;311(8) 806-814)
• CDC estimates that 75 million Americans have
metabolic syndrome – this is truly astounding!!!
Concepts of Cell Function and Obesity
Concepts of Cell Function and Obesity
• So what?
• Why are we talking about metabolic syndrome? I
thought we are suppose to be talking about cancer
• Well, metabolic syndrome increases cancer risk
through metabolic disturbances that promote genetic
instability (increased risk in 75 million people)
• The inflammatory state associated with obesity and
metabolic syndrome is one mechanism that promotes
cancer
Energy Excess and Cancer
• When energy intake exceeds energy expenditure, the
resulting state of nutrient excess can trigger responses in
many cell types – endothelial cells, hepatocytes, myocytes,
adipocytes and macrophages
• Nutrient excess can lead to the production of reactive
oxidative species (molecules generated during fuel
production by the mitochondria)
• Excessive production of these molecules creates “oxidative
stress” which can damage cellular structures and trigger an
inflammatory response
Energy Excess and Cancer
• Nutrient excess can also impair functioning of the
endoplasmic reticulum giving rise to unfolded proteins
which can itself induce inflammation
• A third response to nutrient excess is the accumulation
of long-chain fatty acyl coenzyme A molecules (driven
mainly by fructose) further increasing inflammation
Energy Excess and Cancer
• Inflammation can limit further exposure to nutrients by blocking
the action of insulin
• The binding of insulin or IGF-1 to cell surface receptors activates the
PL3K/Akt pathway leading to downstream activation of the mTOR
complex, a central regulator of cell growth and mitogenesis.
• Data strongly suggests that endogenous hyperinsulinemia may be
one obesity-related factor enhancing cancer growth and metastases
• In women with breast cancers a worse prognosis has been noted in
those with higher circulating levels of insulin.
Energy Excess and Cancer
Energy Excess and Cancer
Factors associated with cell growth, carcinogenesis
and tumor promotion:
Hormones and growth factors – insulin,
insulin derived growth factor1 (IGF1),
vascular endothelial growth factor (VGEF)
estrogen
Immune cells and inflammatory factors Macrophage infiltration, cytokines
Energy Excess and Cancer
• Clinical and epidemiologic evidence suggests that
elevated levels of circulating insulin or C-peptide
(cleavage product of proinsulin) are associated
with increased risk and/or poor prognosis of
endometrial, pancreatic, renal, prostate, colon
and pre and postmenopausal breast cancer
• Data strongly suggests that endogenous
hyperinsulinemia may be one obesity-related
factor enhancing cancer growth and metastases
(Hursting et al Cancer Prevention Research 2012;5:12601272)
Energy Excess and Cancer
• High circulating levels of insulin also upregulate the hepatic
synthesis of insulin derived growth factor-1 (IGF-1) which
is a major endocrine and paracrine regulator of tissue
growth and metabolism as it both suppresses apoptosis
and initiates cell cycle progression from G1 to S phase.
• Epidemiologic evidence supports the hypothesis that
increased circulating IGF-1 is associated with increased risk
and/or worse prognosis for several types of human cancers
(Hursting et al Cancer Prevention Research 2012;5:1260-1272)
Energy Excess and Cancer
• Vascular Endothelial Growth Factor (VGEF) production is
induced by insulin and IGF-1 and mediates cancer cell
proliferation and tumor growth by inducing angiogenesis
• Produced by both adipocytes and tumor cells higher levels
of VEGF are seen in obese animals and humans and
decrease with weight loss
• A growing body of evidence in humans suggests strong
associations between VGEF levels and aggressive cancers
(Hursting et al Cancer Prevention Research 2012;5:1260-1272)
Energy Excess and Cancer
• Estrogens stimulate cell proliferation and inhibit apoptosis and can
also induce VEGF and angiogenesis
• Estrogens can also be metabolized into DNA-reactive metabolites
that potentially induce mutagenesis
• In postmenopausal women a major contributor to estrogen
production is adipose tissue, where the enzyme aromatase converts
adrenal androgens into estrogen
• Tamoxifen, a selective estrogen receptor inhibitor, has been shown
to significantly reduce the development of postmenopausal breast
cancer (Hursting et al Cancer Prevention Research 2012;5:1260-1272)
Energy Excess and Cancer
• Leptin: an adipocytokine secreted by adipose tissue. As body fat
stores increase, circulating levels of leptin increase. In vitro studies
have shown that leptin can stimulate cell proliferation and survival
in colon, breast, endometrial and prostate cancer cells. Leptin can
modulate tumor growth by increasing the expression of VEGF
• Adiponectin: an adipocytokine secreted by adipose tissue. As fat
stores increase levels of adiponectin decrease. In vitro studies have
shown that adiponectin induces apoptosis and inhibits cell growth
and proliferation in breast, colon, endometrial and prostate cancer
cells. It has also been shown to inhibit angiogenesis by inducing
apoptosis of endothelial cells. Higher adiponectin concentrations
have been associated with a lower risk of post-menopausal breast
cancer and endometrial cancer
Energy Excess and Cancer
• Chronic inflammation has long been associated
with cancer development and progression and
increases the risk of multiple tumor types
• Obesity leads to subclinical inflammation in
visceral and subcutaneous white fat and is
characterized by macrophages surrounding
necrotic adipocytes
Energy Excess and Cancer
• Increasing obesity has been positively associated with inflammation
• Increased adipose tissue produces inflammatory cytokines including
tumor necrosis factor (TNF), monocyte chemoattractant protein
(MCP1) and C-reactive protein (CRP), all of which enhance local
macrophage infiltration
• Through intracellular signaling pathways inflammatory molecules
induce gene expression associated with cell proliferation, apoptosis
and angiogenesis, leading to increased proliferation and
differentiation, inhibition of apoptosis and induction of
angiogenesis. (Hursting et al Cancer Prevention Research 2012;5:12601272)
Energy Excess and Cancer
• In mice, tumor cells transplanted into underfed mice did
not grow as rapidly as in those fed more abundantly
• An excess in nutrients causes an imbalance in energy
leading to oxidative stress and abnormalities of fatty acid
metabolism that foster inflammation and insulin resistance.
This results in a number of processes that underlie cancer
initiation and promotion including DNA damage, cell
division, delayed cell death, an increase in blood vessel
formation and cell migration ( An Integrated View of Obesity.
Science 318: 928-929)
Energy Excess and Cancer
Energy Balance, Obesity and Cancer
• How many of us are obese?
34.9% of adults over 20 are obese-defined as a BMI greater than 30
(JAMA. 2014;311(8):806-814)
• Another third of people are overweight – BMI 25-29.9
• That means that fully 2/3rds of the US population is
overweight or obese and carries an increased risk of
cancer!!
Energy Balance, Obesity and Cancer
Is this the new normal?
Energy Balance, Obesity and Cancer
• Is there evidence between obesity and
increased risk of cancer?
Energy Balance, Obesity and Cancer
• There is a convincing link of obesity to the following
cancers:
Endometrial
Colorectal
Esophageal
Kidney
Pancreas
Post-menopausal breast
Gallbladder
Liver
Thyroid
Ovarian
Early and aggressive prostate
Energy Balance, Obesity and Cancer
Lancet 2014;384:755-765
Energy Balance, Obesity and Cancer
• How bad is the problem?
It has been estimated that up to 1/3 of
cancers are related to overweight or
obesity, physical inactivity and/or poor
nutrition
(AICR/WRCF, Policy and Action for Cancer Prevention 2009)
How Did We Get Here?
• By substituting natural protein, fat and
carbohydrate sources for high caloric, poorly
nutritious manufactured food, fast food and
sugary beverages – THE WESTERN DIET
• The largest medical disaster of the past 100 years
has been the recommendation of the low
fat/high carbohydrate diet – a public health
experiment which has been an utter and
complete failure!!!
How Did We Get Here?
• What happened??
• In the 1950’s and 60’s there was an all out war on heart
disease and the lipid heart hypothesis was born – the
thought that saturated fat and cholesterol were the
cause of heart disease.
• This led to National guidelines (USDA, AHA, NHLBI,
NIH) in the 1970’s promoting a low fat/high
carbohydrate diet.
• Let’s see how that worked out…..
How Did We Get Here?
Here is what we are eating. Convenient - yes, nutritious – NO!!
How Did We Get Here?
How Did We Get Here?
How Did We Get Here?
How Did We Get Here?
How Did We Get Here?
• So the question becomes is the increase in obesity due
to increased caloric intake and decreased physical
activity (calories in vs calories out) or is it because of
the composition of the food we are eating and the
biochemical and hormonal response to this food
(response to simple carbohydrates and sugar)??
• I want you to think about the following statement
before you contemplate your answer.
• We have an epidemic of obese 6 month olds
How Did We Get Here?
So what happened??
• We replaced highly nutritious fats and plant based carbohydrates
with sugar and highly refined, nutrient poor processed
carbohydrates. Our consumption of protein has stayed about the
same.
• At the same time our caloric consumption increased. Adult males
are eating 187 calories more per day and adult females are eating
335 calories more per day than they were 20 years ago. ALL THE
EXTRA CALORIES ARE IN THE FORM OF SUGARY BEVERAGES AND
PROCESSD CARBOHYDRATES, NOT FAT (in fact fat consumption has
decreased).
FOODS, TOXINS AND CANCER:
IS THERE A LINK?
• Arsenic: inorganic arsenic is a human
carcinogen found in drinking water and there
is convincing evidence linking arsenic
contamination to an increased risk of lung
cancer and possibly skin and esophagus
cancer.
• Coffee: there is no convincing evidence that it
increases the risk of pancreas or kidney
cancer.
FOODS, TOXINS AND CANCER:
IS THERE A LINK?
• Supplements: there is convincing evidence
that high dose beta carotene supplements in
tobacco smokers increases the risk of lung
cancer.
No specific vitamin or mineral
supplementation is recommended for
cancer prevention
FOODS, TOXINS AND CANCER:
IS THERE A LINK?
• Processed meat and domesticated red meat:
there is convincing evidence for an increased
risk of colorectal cancer.
• Alcohol: there is convincing evidence for an
increased risk of mouth, pharynx, larynx,
esophageal, colorectal in men and breast
cancer in women and liver cancer related to
cirrhosis without distinction as to the type of
alcoholic beverage consumed.
RECOMMENDATIONS FOR CANCER
RISK REDUCTION
So what do we do?
• It is really quite simple – we need to eat fewer and
more nutritionally dense calories. In many cases we
have replaced 30-40% of potentially nutritious foods
with SUGAR – a substance with absolutely NO
nutritional value. In fact, sugar is a chronic toxin!!
• RESTRICTION OF ENERGY INTAKE FROM FOOD IS THE
MOST EFFECTIVE SINGLE INTERVENTION FOR
PREVENTING CANCER IN EXPERIMENTAL ANIMALS!!
RECOMMENDATIONS FOR CANCER
RISK REDUCTION
• Limit consumption of energy dense foods and
eliminate ALL sugar sweetened and diet
beverages as well as all fast food:
Energy dense foods are those containing
225-275 kcal per 100g. This includes most
processed and fast food. Energy dense
processed food and sugary beverages
promote weight gain and obesity
=
=
RECOMMENDATIONS FOR CANCER
RISK REDUCTION
• Limit intake of red meat and processed
meats:
Limit the consumption of domesticated
red meat to 18oz per week and try to
eliminate all processed meats.
• Limit consumption of alcohol:
No more than 2 drinks per day for
men and 1 drink per day for women
RECOMMENDATIONS FOR CANCER
RISK REDUCTION
• Non-starchy fruits and vegetables: there is
probable evidence that these protect against
cancers of the mouth, pharynx, esophagus
and stomach with limited evidence for
protection against lung, colon, endometrial
and ovarian cancers.
That being said these foods are high in
fiber and nutrients and low in energy
density thus being the foundation
of any diet.
RECOMMENDATIONS FOR CANCER
RISK REDUCTION
• Eat mostly plant based foods:
Consume 5 servings of non-starchy vegetables
(14 oz) daily as well as 2 servings of fruit,
preferably those lower in sugar – berries
If eating grains consume unprocessed grains
• Nuts and seeds:
Good source of fiber, essential fatty
acids and vitamins and minerals
RECOMMENDATIONS FOR CANCER
RISK REDUCTION
• Physical activity: there is convincing evidence
physical activity protects against colon cancer
and probable evidence that it protects against
post-menopausal breast cancer and
endometrial cancer.
RECOMMENDATIONS FOR CANCER
RISK REDUCTION
• Maintain a lean body mass - BMI between 19
and 25 from childhood through adulthood
• Be physically active – perform some sort of
physical activity equivalent to 30 minutes of
brisk walking daily. Avoid sedentary activities
such as television watching.
RECOMMENDATIONS FOR CANCER
SURVIVORS
• Cancer survivors should follow the recommendations for
healthy weight, diet and physical activity as recommended
for cancer prevention.
• Current evidence suggests that there are health benefits
from physical activity during cancer survivorship with
breast cancer survivorship having been the most studied
Energy Balance, Obesity and Cancer
In animal models a 20-40% reduction in total energy intake relative to an unrestricted
comparison group is one of the most potent and broadly acting dietary interventions for
preventing or reversing weight gain and inhibiting cancer in experimental tumor models
Hurstig et al; Cancer and Metabolism 2013, 1:10
Energy Balance, Obesity and Cancer
• How does this translate into humans??
• CALERIE trial – Comprehensive Assessment of Long
Term Effects of Reducing Intake of Energy – preliminary
reports indicate that many of the same metabolic and
endocrine changes observed in rodents and monkeys
are also occurring in humans in response to calorie
restriction.
Energy Balance, Obesity and Cancer
• Woman at high risk for breast cancer showed reduction
in inflammatory and growth factor signaling pathways
with either total caloric restriction or carbohydrate
calorie restriction for 2 days/week. Imayama et al; Cancer Research
2012, 72:2314-2326
• Each increase in energy intake of 238kcal/day during
childhood was associated with a 20% increase in adult
cancers unrelated to smoking Frankel et al: BMJ 1998, 316:499
Energy Balance, Obesity and Cancer
What is the bottom line ??
• We are too fat
• We consume the wrong calories – sugar and
refined carbohydrates
• We consume too many calories – increased
caloric consumption mainly as refined
carbohydrates and sugar
• We consume a diet rich in calories but
extraordinarily poor in nutrients
• We are too sedentary
• We want a pill to make it go away
Energy Balance, Obesity and Cancer
Is Cancer a Preventable Disease??
• The resounding answer is YES. With appropriate
dietary intervention, increased exercise, smoking
cessation and appropriate vaccinations it has
been estimated that up to 60% of cancers could
be prevented!!!
Energy Balance, Obesity and Cancer
ARE WE NEXT ?
NUTRITION AND CANCER: BEFORE,
DURING AND AFTER
In addition to the references quoted in
this power point there is a terrific
reference on the link between food,
nutrition, physical activity and the
prevention of cancer:
Food, Nutrition, Physical Activity and
the Prevention of Cancer: A Global
Perspective: World Cancer Research
Fund and American Institute for Cancer
Research 2007
This is the most comprehensive
publication on the subject to date –
537 pages worth!