Transcript Nutrigenomics

Cancer
from
Nutrigenomics
point of veiw
M. H Javanbakht MD, PhD
Department of cellular & molecular nutrition,
Faculty of Nutritional Sciences & Dietetics, TUMS.
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 Nutrition-Gene Interaction
1. Direct interactions
Nutrients, sometimes after interacting with a receptor,
behave as
transcription factors that can bind to DNA and acutely
induce gene
expression
2. Epigenetic interactions
Nutrients can alter the structure of DNA so that gene
expression is
chronically altered
3. Genetic variation
Common genetic variations such as single-nucleotide
polymorphisms
(SNPs) can alter the expression or functionality of genes
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Transcription-factor pathways
mediating nutrient-gene interaction
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Nutritional
Genomics
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Nutrigenomics vs. Nutrigenetics
Nutrigenomics
 “Nutrigenomics refers to
the application of
genomics in nutrition
research, enabling
associations to be made
between specific nutrients
and genetic factors, e.g. the
way in which food or food
ingredients influence
gene.” Chadwick R. (2004)
Proceedings of the Nutrition Society
63:161-166.
Nutrigenetics
 “Nutrigenetics is the study
of individual differences at
the genetic level
influencing response to
diet. These individual
differences may be at the
level of single nucleotide
polymorphisms rather
than at the gene.” Chadwick R.
(2004) Proceedings of the Nutrition
Society 63:161-166.
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Nutrigenomics
 “Nutrigenomics attempts to
study the genome-wide
influences of
nutrition…[and] aims to
identify the genes that
influence the risk of dietrelated diseases on a
genome-wide scale, and to
understand the mechanisms
that underlie these genetic
predispositions.” Muller M &
Nutrigenetics
 “Nutrigenetics examines the
effect of genetic variation on
the interaction between diet
and disease or on nutrient
requirements. Genetics has
a pivotal role in determining
an individual’s risk of
developing a certain
disease.” Muller M & Kersten S.
(2003) Nature Reviews Genetics 4:315322.
Kersten S. (2003) Nature Reviews
Genetics 4:315-322.
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Nutrigenomics
Nutrigenetics
 “Nutrigenomics describes the use of
functional genomic tools to probe a
biological system following a
 “Nutrigenetics embodies the science
of identifying and characterizing
gene variants associated with
nutritional stimulus that will permit
an increased understanding of how
nutritional molecules affect
metabolic pathways and
homeostatic control.” Mutch D, et
al. (2005) FASEB Journal 19:16021616.
differential responses to nutrients,
and relating this variation to disease
states.” Mutch D, et al. (2005) FASEB
Journal 19:1602-1616.
 “Nutrigenomics focuses on the
effect of nutrients on the genome,
proteome, and metabolome.”
Ordovas J & Mooser M. (2004)
Current Opinion in Lipidology 15:101108.
 “Nutrigenetics examines the effect
of genetic variation on the
interaction between diet and
exercise. This includes…gene
variants associated with, or
responsible for, differential
responses to nutrients.” Ordovas J &
Mooser M. (2004) Current Opinion
in Lipidology 15:101-108.
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Nutrigenomics & Nutrigenetics:
Two Sides of a Coin
Mutch D, et al. (2005) FASEB Journal 19:1602-1616.
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Vitamin D
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System and Tissue Distribution of Nuclear
Vitamin D Receptors (VDR)
System
Tissue
Immune
Thymus, bone marrow, macrophages, B cells, T cells
Gastrointestinal
Esophagus, stomach, small intestine, colon, rectum
Cardiovascular
Endothelial cells, smooth muscle cells, myocytes
Respiratory
Lung alveolar cells
Hepatic
Liver parenchyma cells
Renal
Proximal and distal tubules, collecting duct
Endocrine
Parathyroid, thyroid, pancreatic beta cells
Exocrine
Parotid gland, sebaceous gland
CNS
Brain neurons, astrocytes, microglia
Epidermis/appendage Skin, breast, hair follicles
Musculoskeletal
Osteoblasts, osteocytes, chondrocytes, striated muscle
Connective Tissue
Fibroblasts, stroma
Reproductive
Testis, ovary, placenta, uterus, endometrium, yolk sac
Vitamin D Deficiency
Rickets, Osteomalacia
Influenza, Tuberculosis
MS, RA, SLE, Type I diabetes
Hypertension, CAD, PVD, CHF
Syndrome X, Type 2 Diabetes
Chronic Fatigue, SAD,
Depression
Cataracts, Infertility
Osteoporosis
Cancer
Endocrine, paracrine and intracrine functions of
Vitamin D
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25-OHase
24-Ohase (CYP24A1)
1-OHase
Deeb et al (2007) Nature Reviews Cancer 7, 684-700
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Vitamin D and Cancer
 May influence both incidence and mortality
 Linked with GI cancer, prostate and breast cancers,
lymphomas, endometrial and lung cancers
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Something New Under the Sun?
Apperly FL. The relation of solar radiation to cancer
mortality in North America.
Cancer Research.1941(1):191-195
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Northern vs. Southern U.S.
30 – 40 extra
deaths for other
major cancers
(per 100,000)
1 – 2 extra
skin cancer
deaths (per
100,000)
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1979 - 1981
 Vitamin D receptors found in malignant melanoma
cells and myeloid leukemia cells
 1,25(OH)2D inhibited melanoma cell proliferation and
induced myeloid cell differentiation
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1998
 Serum levels of 1,25(OH)2D are tightly controlled by
the kidneys & don’t vary by sun exposure so how could
vitamin D contribute to the north-south gradients and
African-American excess in cancer rates?
 Non-renal cells discovered to hydroxylate 25(OH)D
and synthesize 1,25(OH)2D locally.
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19 Vitamin D-Sensitive Cancers (from several ecological
and observational studies)
 Vitamin D-sensitive cancers with moderate-to-strong
support after accounting for other factors:
 Gastrointestinal: colon, esophageal, gallbladder,
gastric, pancreatic, rectal
 Urinary: bladder, kidney; Male: prostate
 Female: breast, cervical, endometrial, ovarian,
vulvar
 Blood: Hodgkin’s and non-Hodgkin’s
lymphoma, leukemia
 Miscellaneous: melanoma
Vitamin D & Cancer
 Environmental: sunlight & diet
 Calcitriol (hormonal form of vitamin D) controls the
differentiation of many cells that possess vitamin D
receptors (VDR)
 Induce cell differentiation and apoptosis of cancer cells
while inhibiting cell proliferation, angiogenesis, and
metastasis
 Genetic: VDR polymorphisms
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Vitamin D Implications in Cancer
Lung
Colon
Breast
Pancreas
Prostate/Ovarian
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Dietary Vitamin D and Colorectal Cancer
Garland 1 989
Bostick 1 993
Kearney 1 996
Martinez 1 996
Pritchard 1 996
Marcus 1 998
Pietinen 1 999
J arvinen 2001
McCollough 2003
All
0.1
0.2
0.5
1 .0
2.0
5.0
1 0.0
Odds ratio
Gorham E., et al. J Steroid Biochem Mol Biol. 97:179-94, 2005
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June, 2007 American Journal of Clinical
Nutrition
 Women who regularly took vitamin D3 and calcium
had a 60% reduction in all-cancer incidence compared
with a group taking placebo and a 77% reduction when
the analysis was confined to cancers diagnosed after
the first 12 months.
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Lung cancer
1,25(OH)2D:
 Inhibits proliferation and induces differentiation of
lung cancer cell lines (Higashimoto, et al., 1996, Guzey,
et al., 1998)
 Inhibits metastatic growth and locoregional
recurrence of lung cancer cells in mice (Wiers, et al.,
2000)
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Lung cancer
 456 patients with early stage NSCLC
 Median age – 69
 96% Caucasian
 Data collection:
 Season of surgery
 Food frequency questionnaire
 Recurrence free survival (RFS)
 Overall survival (OS)
Zhou, et al., 2005
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Lung cancer
 Patients who had surgery during summer with the
highest vitamin D intake had better RFS than patients
who had surgery during winter with the lowest vitamin
D intake.
 Similar associations were seen for overall survival.
Zhou, et al., 2005
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Breast cancer
1,25(OH)2D:
 inhibits cell proliferation, induces differentiation &
apoptosis, and inhibits angiogenesis in normal and
breast cancer cells (Colston, et al, 1989, Saez, et al,
1993, Mantell, et al., 2000)
 suppresses high-fat diet-induced mammary
tumorigenesis in rats (Jacobson, et al., 1989, Xue,
1999)
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Breast cancer
 Inverse association between vitamin D & calcium
intake and breast density
 Inconclusive results in studies looking at VDR
genetic polymorphisms and breast cancer
 Inverse association between high sunlight exposure
and breast cancer risk
 Association may be stronger for premenopausal
than postmenopausal women due to interactions
between vitamin D, the VDR, estrogen and insulinlike growth factor-I (IGF-I)
Cui & Rohan, 2006
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Breast cancer
 Case-control study – 972 women with newly-
diagnosed breast cancer & 1,135 healthy controls
 Interviews regarding vitamin D-related exposures, e.g.
outdoor activities, use of sunscreen, dietary
contributions
Knight, 2007
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Breast cancer
 More frequent sun exposure during adolescence was
associated with a 35% reduction in breast cancer risk
later in life
 Lower risk also linked to cod liver oil and milk intake >
10 glasses / week
 Milder protection seen for people age 20 – 29
 No protection for people over age 45
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Breast cancer
 Epidemiologic study of different regions of
Norway, each with a different annual UV exposure
 Prognosis 15 – 25% better for women diagnosed /
treated in the summer vs. winter
<Breast Cancer Research and Treatment,
May>Knight , 2007
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Endometrial cancer
Is ultraviolet B irradiance inversely associated with
incidence rates of endometrial cancer: an ecological
study of 107 countries.
Mohr, et al, 2007
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Endometrial cancer
 Objective: perform an ecological analysis of the
relationship between low levels of ultraviolet B
irradiance and age-standardized incidence rates of
endometrial cancer by country, controlling for known
confounders
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Endometrial cancer
 107 countries:







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UVB irradiance
cloud cover
intake of energy from animal sources
proportion overweight
skin pigmentation
cigarette consumption
health expenditure
total fertility rates
 vs. age-standardized incidence of endometrial
cancer
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Endometrial cancer
 Association found between endometrial cancer
incidence rates and:
 Low UVB irradiance
 High intake of energy from animal sources ( IGF-I?)
 Per capital health expenditure
 Proportion of population overweight
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Pancreatic cancer
 Prospectively collected diet and lifestyle data
 Nurses’ Health Study – 75,427 women
 Health Professionals Follow-up Study – 46,771 men
 Pancreatic cancer risk 41% lower among those who
consumed > 600 IU of vitamin D / day vs. those
who consumed < 150 IU / day
Skinner, et al., 2006
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Cancer Survival
 Summer / Fall (vs. Winter / Spring) diagnosis
associated with improved survival in:
 Colorectal cancer
 Hodgkin’s lymphoma
 NSCLC
 Breast cancer
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Cancer Survival
 Intermittent sun exposure associated with
increased survival following a diagnosis of
melanoma.
Berwick, et al., 2005
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Vitamin D Overview
 It is a fat soluble vitamin.
 Not just a vitamin it is a prehormone
 Found in some food and made in the body after
exposure to UV rays
 Major biological function is to maintain normal
blood levels of Ca and Po4
 Other tissues like macrophages, prostrate tissue
also have vit D receptor
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History of Vitamin D
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Existed over 500 million years
Industrial revolution : rickets
Cod liver oil: common folklore medicine
Discovery of Vit D as the antirachitic factor in cod liver oil(1920)
Discovery of conversion of 7-dehydrocholesterol in the skin to vit D
(1937)
Antirachitic property in food
Fortification of food with vitamin D was patented
Complete eradication of rickets in US
US public service issuing warnings about sun-induced health risk
Over next 30 yrs skin cancer hazard of excessive sun exposure became
well established
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Food Sources of Vitamin D
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Cod liver oil – 1 TBS

Salmon 3.5 oz.

Mackerel 3.5 oz.

Tuna, canned, in oil, 3 oz.

Sardines 3.5 oz.

Milk (fortified) 8 oz.

Ready to eat cereal (fortified) ¾ -
1 cup
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 Egg 1 whole

 Liver, 3.5 oz.

 Cheese, swiss 1 oz.
1,360 IU
360
345
200
250
98
40
20
15
12
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Annual Number of Vitamin D Publications
Listed at Pubmed
4500
4000
Vitamin D publications
3500
3000
2500
2000
1500
1000
1985
1990
1995
2000
Year
2005
2010
2015
Infants
48
Children
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Adolescents
50
Adults
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Pregnant &
lactating women
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Treatment with Sunshine
Thanks
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