Download cancer questions - Joan

Nutrition 577: Nutritional Problems in the United States, Fall 2012
Review Questions: Cancer 100 points
Joan Temmerman
Answer the following questions as thoroughly & succinctly as possible. Use your assigned readings and other
relevant resources. Assignment is due on November 19, 2012.
1. (12 points) Tumor development (2 Scientific American articles; Lecture notes)
a) 6 pts: Briefly describe the multi-step process of tumor development from initiation through
metastasis. The development of cancer is a multistep process that takes years. A carcinogen
produces a genetic mutation that transforms normal cells into cancerous, immortal cells
(tumorigenesis). During tumor initiation, a genetic mutation occurs which allows a cell to multiply
(promotion). Additional mutations occur (transformation) and cell offspring become abnormal,
producing dysplastic tissue and a tumor (progression). If the tumor hasn’t breached tissue
boundaries, it is called in situ cancer. Mutations may continue, allowing the tumor to become
malignant and invade underlying tissue, the bloodstream or the lymphatics. Cells may spread and
produce tumors elsewhere in the body (metastases).
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b) 6 pts: Briefly describe the 6 “diabolical superpowers of cancer.” Healthy cells are programmed to
die (apoptosis). Cancerous cells are immortal. Numerous reparative and regulatory systems have to
be breached for malignant transformation to occur. The superpowers of cancer are: 1. uncontrolled
proliferation without growth signals; 2. uncontrolled growth despite “stop” signals by neighboring cells;
3. Evasion of programmed cell death (apoptosis); 4. angiogenesis: the formation of new blood
vessels to provide nutrients and oxygen; 5.cell immortality (unlimited division); and 6. ability to invade
nearby tissues and metastasize to distant sites (most lethal consequence)
2. (14 points) Oncogenes and tumor suppressor genes
a) 6 pts: What are oncogenes and tumor suppressor genes, and what general role does each play in
cancer development? Proto-oncogenes normally direct cell differentiation and proliferation.
Oncogenes are proto-oncogenes that are mutated or activated, allowing the uncontrolled growth of
cancer. Oncogenes can be inherited, but are usually acquired by carcinogens. Tumor suppressor
genes control cell division, cell death, and DNA repair. Mutated tumor suppressor genes are missing
or inactivated by mutation, which allows cells to grow uncontrolled.
b) 2 pts: Identify at least 2 specific oncogenes: ras and myc.
2 specific tumor suppressor genes: BRCA1, RB
.
c) 2 pts: For each gene listed above, indicate the specific cancer(s) each has been linked to. ras
carcinomas of the colon, pancreas, lung. Myc: malignancies of blood-forming tissues. BRCA1:
breast and ovarian cancers; RB: retinoblastoma, bone, bladder, breast, and small cell lung cancers.
d) 4 pts: For the genes listed above, briefly describe the cellular function that each is involved with.
Ras oncogenes disturb the protein signaling cascade in the cytoplasm. Normal ras genes encode
proteins that transmit stimulatory signals from growth factor receptors to other proteins. Mutant ras
genes signal continuously, without input from growth factor receptors. Myc oncogenes alter
transcription factors in the nucleus, Myc transcription factors are normally made by cells after
stimulation by growth factors on the cell surface. In many types of cancer, myc levels are constantly
high, without being stimulated by growth factors. The cellular location of proteins coded by BRCA1
gene is not clear. The RB gene codes for the pRB protein in the cytoplasm, which is a master brake
of the cell cycle.
You can write this as one answer; this is just the grading rubric.
3. (11 points) Obesity & cancer (Calle & Kaaks Review; McCullough & Giovannucci Review)
a) 3 pts: List at least 6 cancers that have been linked to obesity. Breast (postmenopausal women),
colon, gastric, pancreatic, liver, kidney, endometrial, esophageal, and gallbladder cancers.
b) 8 pts: Describe how: 1) growth hormone & IGF-1 and 2) endogenous sex steroids may
contribute to obesity-related cancers. Identify at least 1 cancer that may be linked to each
mechanism.
1. Excess levels of insulin are associated with several cancers, including colon, breast, endometrial,
and pancreatic cancers. One mechanism may be through growth hormones. Insulin promotes the
synthesis and activity of insulin-like growth factor 1 (IGF1), which is an anabolic hormone that
regulates cellular proliferation and many metabolic processes. Growth hormone stimulates production
of IGF1 in the liver. In overnourished states and in patients with T2DM, insulin and IGF1 levels are
increased. Although IGF1 levels are higher in overweight and obese people, levels are paradoxically
decreased in the highest obesity ranges. Increased blood levels of IGF1 are related to an increased
risk of breast cancer (especially premenopausally), prostate and colorectal cancer.
The IGF axis includes binding proteins and receptors, as well as various growth hormones. It is a
complex multicomponent cellular signaling network that is involved in many physiological and
pathologic processes (angiogenesis, mitogenesis, transformation, differentiation, anti-apoptosis, and
cell motility). IGFs influence carcinogenesis, tumorigenesis, and metastases. Deregulation of the
IGF axis is associated with tumor initiation and progression. Moreover, a chronic excess energy
balance, mediated by insulin and the IGF pathway, is thought to play a central role in the
development of many cancers.
2. Endogenous sex hormones-estrogens, androgens, and progesterone-are affected by excess fat.
Adiposity increases circulating estrogen levels, through peripheral conversion of androgen precursors
in adipose tissue. Both endometrial cancer and breast cancer in post-menopausal women are
strongly associated with excess weight, largely because of increased estrogen. Obesity increases
rates of breast cancer in postmenopausal women by 30-50%. Regardless of menopausal status,
adiposity affects survival and recurrence in women with breast cancer. Women with severe obesity
have a 3-fold increased mortality, compared to very lean women. Endometrial cancer rates also
show a linear relationship with increasing BMI in both pre and postmenopausal women.
Obesity and its resultant insulin resistance causes excess androgen and decreased progesterone
levels. Insulin affects the bioavailability and synthesis of androgens, estrogens and progesterone.
Chronic hyperinsulinemia, androgen excess and progesterone deficiency are the basis of polycystic
ovarian syndrome (PCOS), which is linked with an increased risk for endometrial cancer in
premenopausal women. Excess adipose tissue increases insulin and IGF1, which decreases sexhormone binding globulin (SHBG). Decreased SHBG increases estrogen and androgen availability in
women.
4. (10 points) Cancer and meat intake (McCullough & Giovannucci Review)
a) 4 pts: Briefly explain the association between meat intake and cancer risk. Excessive meat
consumption, especially processed and red meats, has consistently been associated with colon,
rectal, and prostate cancers. The AICR reports convincing evidence that regular red and processed
meat consumption is causally related to a 20% increase in colorectal cancer. The risk dose-related:
studies have reported up to a 24% increased risk with each 120 g increment of red meat intake, and
up to a 49% increased risk for each 25 g intake of processed meats (one slice).
b) 2 pt: Name at least 2 cancers besides colorectal cancer that may be involved. Prostate, bladder,
breast, lung, stomach, pancreas.
c) 4 pts: What are some of the possible mechanisms that could support the association? What
other dietary factors could confound the relationship between red meat and cancer? Cooking
methods may foster the formation of carcinogens. Mutagenic heterocyclic amines (HCAs) are formed
during cooking at high temperatures, which produces pyrolysis of proteins and amino acids.
Polycyclic aromatic hydrocarbons (PAHs) are formed when meat or tobacco burn incompletely.
Nitrates and nitrates use used as preservatives in meats and curing. Nitrate can interact with dietary
amines or amides to produce mutagenic N-nitroso compounds (NOC) (nitrosamines and
nitrosoamines), which are potent carcinogens. Heme iron in meat appears to stimulate endogenous
NOC production; moreover heme damages colonic mucosa and stimulates epithelial proliferation.
Tea, garlic, and cruciferous vegetables, may inhibit the formation of endogenous NOCs. This
protective effect of fruit and vegetables (and vitamin C) on NOC formation may largely explain the
role of F & V in lowering cancer risk. Unfortunately consumption of diets high in red meat is
frequently associated with less vegetable intake and additional unhealthy lifestyle behaviors.
5. (25 points) Choose 5 of the following food components/nutrients, and identify the specific types (or
sites) of cancer that each has been associated with. Briefly discuss the possible mechanism(s)
through which each component may influence cancer risk. Each is worth 5 points.
a) folate: folate is a coenzyme in many cellular reactions that require the transfer of methyl groups. It
is especially important in DNA synthesis, repair, and stability. Folate modulates DNA methylation,
which is an important epigenetic determinant in gene expression, DNA stability and integrity,
mutations and chromosomal modifications. Folate deficiency impairs DNA methylation and repair,
and causes strand breaks and mutations. Low folate can cause inappropriate activation of protooncogenes, or inactivation of tumor-suppressor genes. However, high folate may facilitate
proliferation and growth of neoplastic cells. Folate inhibits tumor initiation but enhances tumor
promotion and progression. Folate deficiency is linked with breast, uterine, cervical, and most
especially colorectal cancers. Long term folate supplementation is associated with a 30-75% reduced
risk of colon cancer.
b) alcohol: Most epidemiological studies have found that breast cancer risk increases with
alcohol consumption. The relationship is dose-dependent for premenopausal and
postmenopausal breast cancer regardless of the type of alcoholic beverage. Regular alcohol
consumption as low as one or two drinks/day has been associated with modest but significant
increases in breast cancer risk. About one in eight women (13.3%) in the U.S. will develop
breast cancer at some point in their lifetime. Although there are many risk factors for breast
cancer, alcohol consumption is one of only a few modifiable risk factors.
Heavy alcohol consumption is consistently and dose-dependently associated with increases in
risk of cancers of the mouth, throat, larynx, esophagus, as well as breast. Moreover, the
combining smoking and alcohol results in even more dramatic increases in cancer risks. Longterm heavy alcohol consumption is associated with an increased risk of liver cancer, which may
be related to alcoholic cirrhosis of the liver or increased susceptibility to cancer caused by viral
hepatitis. Although less consistent, there is evidence that the risk of colorectal cancer is
increased with heavy alcohol consumption, especially in the presence of inadequate folate
intake
Alcohol interferes with the absorption, transport, and metabolism of folate, which is required for
DNA methylation and DNA repair. Alterations in these processes may result in mutations or
altered gene expression, which increase the risk for cancer.
d) vitamin D: Vitamin D is a hormone that participates in numerous physiologic and pathologic
processes, and vitamin D receptors are found in most tissues. Vitamin D is an important
regulator of gene expression, cellular proliferation, differentiation, apoptosis, and angiogenesis.
Epidemiological studies have demonstrated lower rates of breast, colon and prostate cancer in
populations with greater UV light exposure and presumably higher vitamin D levels. Higher
serum levels of the main circulating form of vitamin D, 25-hydroxyvitamin D, 25(OH)D, are
associated with much lower incidence rates of colon, breast, ovarian, renal, pancreatic,
aggressive prostate and other cancers. It is projected that Intake of 2,000 IU/day of vitamin D3
daily would lead to 25% reduction in incidence of breast cancer and 27% reduction in incidence
of colorectal cancer, and would also prevent three fourths of deaths from breast and colorectal
cancer in the United States and Canada (1).
e) vitamin C: A large number of studies have shown that increased consumption of fresh fruits
and vegetables is associated with a reduced risk for most types of cancer. These are the basis
for the dietary guidelines endorsed by the USDA and the National Cancer Institute (eating at
least five servings of fruits and vegetables per day.). Epidemiological studies have shown an
inverse relationship between dietary vitamin C and cancers of the mouth, throat, stomach,
esophagus, pancreas, lung, colorectum, and cervix, with significant cancer risk reductions in
people consuming at least 80 to 110 mg of vitamin C daily. Vitamin C is the main water-soluble
antioxidant in humans. Vitamin C can interfere with nitrosamine formation (NOC) (carcinogen)
in the stomach. Vitamin C also interferes with heme iron activity, which can produce adverse
effects (see above #c).
h) dietary fat: High fat intake has been implicated in elevated risk for breast, prostate and colorectal
cancers. Some studies have shown conflicting results. Possible confounders include difficulty of
isolating the effects of fat alone from extra energy intake or obesity, and differentiating fat from other
components of meat and dairy products. Distinguishing between the types of fat (total or saturated)
may also be problematic. Fats from red meat and dairy products are linked to a higher risk for
prostate cancer. Likewise, animal fats appear to increase the risk for breast cancer. The mechanism
may be the influence of saturated fat on sex hormone levels. A higher fat intake may promote
colorectal cancer by stimulating mutagenic bile acid secretion. Moreover, diets high in saturated fat
and trans fat are pro-inflammatory, and chronic inflammation is a component of some cancers.
6. (10 points) Discuss xenobiotic transformations. Be sure to include:
2 pt: the site (organ, organelle) where most transformations occur;2 pts: their purpose
4 pts: the specific types of chemical reactions that occur in the 2 phases of xenobiotic transformations
2 pts: an example of 1 detrimental xenobiotic transformation (with respect to cancer).
Xenobiotics are foreign chemicals that can cause cell damage by reacting with cells, proteins,
and DNA. Xenobiotics may include dietary factors, toxins, carcinogens, mutagens,
pharmaceuticals, and pollutants. Xenobiotics include chemicals that are nonreactive, but
become reactive through cellular transformation.
Xenobiotic transformation or metabolism (XT) occurs by a series of enzymatic reactions that
convert a foreign chemical compound (not easily excreted) into an inert compound (more polar
and hydrophilic) that can be safely excreted in urine or feces. These enzymes are located at
sites that have 1st exposure to foreign compounds, but extensive XT occurs mainly in the liver:
smooth endoplasmic reticulum (ER) and cytosol. There are 2 phases of XT:
Phase 1: activation: ER primarily liver: series of enzymatic reactions to create more polar,
hydrophilic molecules that are water soluble and easily excreted: hydrolysis (addition of water to
break bonds), reduction (addition of hydrogen), oxidation (loss of hydrogen, addition of oxygen).
These reactions involve the microsomal enzymes associated with the smooth ER and cystosol,
reducing equivalents such as NADH, and the cytochrome P450 (CYPs) enzymes in the ER and
mitochondria. CYPs contain heme, are part of electron transport, are involved in hormone
metabolism, and help metabolize xenobiotics. Most are membrane proteins of ER/mitochondria
and are monooxygenases. Various substances (drugs, grapefruit juice) can affect CYP activity
and XT. Additional enzymes involved in phase 1 metabolism are peroxidases, aldehyde
oxidase, and xanthine oxidases. Products of phase 1 are very reactive can cause cell injury or
carcinogenesis unless excreted or metabolized further.
Phase 2: transformations: cytosol, liver: further detoxification reactions including conjugation
(with glucuronate, sulfate, glutathione, and various amino acids), acylation, acetylation, and
methylation. The result is a large increase in water solubility which facilitates excretion.
XT are biotransformations designed to detoxify harmful substances, but XT can increase
carcinogenicity, such as converting a procarcinogen to a carcinogen. Direct carcinogens don’t
require metabolic activation. Other compounds, such as dietary PAHs, NOCs from meat
(discussed above), heavy metals (nickel, cadmium, chromium, arsenic), and aflatoxin (a liver
carcinogen produced by certain species of fungus found in moldy grains and legumes) may be
converted in the liver to reactive metabolites that can interact with DNA and cause cancer.
7. (8 points) Isoflavones & other compounds
1 pt: Name the 2 main isoflavones found in soy: Genistein and daidzein.
2 pts: Why are these compounds considered phytoestrogens? Isoflavones are a class of
phytoestrogens—plant-derived compounds with estrogenic activity. Isoflavones have a similar
structure to the mammalian estrogen estradiol, and exhibit weak estrogenic activity via binding to
estrogen receptors.
3 pts: Briefly describe the molecular mechanism that might explain the antiproliferative effects of
these compounds. Soy isoflavones and other phytoestrogens can bind to estrogen receptors,
mimicking the effects of estrogen in some tissues and blocking the effects of estrogen in others. Antiestrogenic effects in reproductive tissue may help reduce the risk of hormone-associated cancers
(breast, uterine, and prostate). Moreover, Soy isoflavones and their metabolites also have biological
activities that are unrelated to their interactions with estrogen receptors By inhibiting the synthesis
and activity of certain enzymes involved in estrogen metabolism, soy isoflavones may alter the
biological activity of endogenous estrogens and androgens. Soy isoflavones have also been found to
inhibit tyrosine kinases (enzymes that play critical roles in the signaling pathways that stimulate cell
proliferation). Additionally, isoflavones can act as antioxidants.
2 pt: Briefly explain how cruciferous vegetables might lower breast cancer risk. Cruciferous
vegetables are rich sources of glucosinolates, sulfur-containing compounds. Chopping or
chewing cruciferous vegetables results in the formation of bioactive glucosinolate hydrolysis
products, such as isothiocyanates and indole-3-carbinol. Glucosinolate hydrolysis products may
alter the metabolism or activity of sex hormones in ways that could inhibit the development of
hormone-sensitive cancers such as breast. Some studies have reported that high intakes of
cruciferous vegetables can shift estrogen metabolism (the endogenous estrogen 17beta-estradiol can be
irreversibly metabolized to 16alpha-hydroxyestrone (16aOHE1) or 2-hydroxyestrone (2OHE1). In contrast to 2OHE1,
16aOHE1 is highly estrogenic and has been found to enhance the proliferation of estrogen-sensitive breast cancer
cells in culture. It has been hypothesized that shifting the metabolism of 17beta-estradiol toward 2OHE1, and away
from 16aOHE1, could decrease the risk of estrogen-sensitive cancers like breast cancer. In a small clinical trial,
increasing cruciferous vegetable intake of healthy postmenopausal women for four weeks increased urinary
Limited evidence suggests an inverse association between cruciferous
vegetable intake and breast or prostate cancer in humans, but genetic differences may
influence the effect of cruciferous vegetables on human cancer risk.
2OHE1:16aOHE1 ratios) (2).
8. (10 points) Dietary calcium and vitamin D and cancer
6 pt. Discuss the roles of dietary calcium and vitamin D in colorectal cancer. Be sure to include the
magnitude of the effect (provide an interpretation of the RR and whether effects are significant). In
many large epidemiologic studies, calcium and vitamin D appear to exert a protective role against
colorectal carcinogenesis. Calcium and vitamin D functions are intertwined: vitamin D is essential for
calcium absorption and utilization, and high calcium reduces circulating calcitriol, which increases
vitamin D degradation and decreases vitamin D. It is difficult to separate their relative effects.
Active vitamin D inhibits proliferation and differentiation of cells. Observational studies cannot prove
causation, but recent prospective randomized studies have shown that higher vitamin D intakes and
serum 25-hydroxyvitamin D levels are associated with reductions in colorectal cancer risk. This
appears to be dose-related. In the Multiethnic Cohort Study (12), calcium intake was inversely
associated with colorectal cancer risk in both men (multivariate-adjusted RR 0.70) and women (RR
0.64). Total vitamin D intake was inversely associated with cancer risk in men (RR 0.72), but not in
women (RR 0.89), although women in the highest quintile of dietary vitamin D had a significantly
lowered risk (RR 0.78).
The RR predicts risk, where <1 is protective, and > 1 is causative. Substantive relationships are
indicated by RR >2 and < 0.7. Many studies have been significantly limited by the inability to quantify
the dose of vitamin D, using suboptimal doses of vitamin D, and not determining vitamin D blood
levels*. One recent dose-response analysis estimated that 1,000 IU of oral vitamin D daily would
lower one's risk of colorectal cancer by 50% (14). I do believe that a very significant relationship
exists between vitamin D status and colorectal cancer.
2 pt. Are the same effects seen in men and women? What possible mechanism(s) might be involved.
Several large epidemiologic studies have found that total vitamin D intake was inversely associated
with the risk of colorectal cancer in men but not in women. However, women tend to take more
vitamin and calcium supplements, which may misclassify the actual dose of vitamin D intake and
obscure the study results. Also, differences in sex hormones may affect .the relationship between
colorectal cancer and vitamin D in women, since the vitamin D receptor and estrogen receptor
systems have been linked. Moreover, many studies have had significant limitations (see preceding
question*). For example, in the Nurses Health Initiative, the vitamin D in the treatment arm (400 IU) was inadequate,
baseline vitamin D status was not measured, women were allowed to continue taking calcium supplements, the placebo arm
was allowed to take vitamin D supplements, and adherence was very poor (< 60%).
2 pt. Why might dietary intake of vitamin D NOT be a good predictor of vitamin D status? Foods are
only one source of vitamin D. Photosynthesis of vitamin D in the skin and supplements/fortification all
contribute to available vitamin D. Vitamin D includes D2 (plant source) or D3 (produced by sun
exposure or diet). Vitamin D is converted in the liver to 25(OH)D, the main circulating form, which is
biologically inactive. 25(OH)D must be converted in the kidneys to 1,25(OH)2D, the biologically active
form.
Resources
1. Garland CF, Gorham ED, Mohr SB, Garland FC. Vitamin D for cancer prevention: global perspective.
Ann Epidemiol. 2009 Jul;19(7):468-83.
2. Oregon State University. Linus Pauling Institute. Macronutient Information Center; Nutrition and
Inflammation. Accessed 11/15/12 at: http://lpi.oregonstate.edu/infocenter/inflammation.html
3. Wilson T, Bray, GA, Temple NJ, Struble M. Nutrition Guide for Physicians. New York, NY: Humana
Press, 2011.
4. Heidegger I, Pircher A et al. Targeting the insulin-like growth factor network in cancer therapy. Cancer
Biol Ther. 2011 Apr 15;11(8):701-7.
5. Temmerman JC. Vitamin D and cardiovascular disease. J Am Coll Nutr. 2011;30(3):167-170.
6. Weinburg RA. How cancer arises. Sci Am. Sept. 1996; 62-70.
7. Gibbs WW. Untangling the roots of cancer. Sci Am. July 2003; 57-65.
8. Calle EE, Kaaks R. Overweight, obesity and cancer: Epidemiological evidence and proposed
mechanisms. Nat Rev Cancer 2004;4:579-591.
9. Chao A, Thun MY et al. Meat consumption and risk of colorectal cancer. JAMA 2005;293(2):172-182.
10. McCullough ML, Giovannucci EL. Diet and cancer prevention. Oncogene 2004;23:6349-6364.
11. Ronnenberg A. Spring 2011. Cancer. University of Massachusetts, Amherst.
12. Park SY, Murphy SP et al. Calcium and vitamin D intake and risk of colorectal cancer: The Multiethnic
Cohort Study. Am J Epidemiol. 2007;165:784-793.
13. Lappe JM, Travers-Gustafson D et al. Vitamin D and calcium supplementation reduces cancer risk:
results of a randomized trial. Am J Clin Nutr. 2007:85:1586-91.
14. Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J Steroid
Biochem Mol Biol. 2005;97(1-2):179-194.