NIH Meetings: Nutril Genomics/Proteomics Ca Prevention (MORE)

Nutritional Genomics and Proteomics in Cancer Prevention

September 5-6, 2002

by Ann Fonfa

This meeting was held on the campus of the National Institutes of Health, Bethesda, MD.

John A. Milner, Chief, Nutritional Science Research Group, Div of Cancer Prevention, NCI, NIH made the statement that "we will learn how genes influence the metabolism of diet". A paper of his is shown below.

Michael Wargovich, Ph.D., South Carolina Cancer Ctr, Univ of South Carolina School of Medicine spoke about "Diet, Individual Responsiveness, and Cancer Prevention". His abstract follows:

During the early 1980's, dietary recommendations to the American public were formulated based on international epidemiological observations comparing the dietary patterns of low-risk populations for the major cancers to populations at high risk for these cancers. Initiatives such as the "5 A Day" program have increased awareness among Americans of the potential benefits of a low-fat, increased fruit and vegetable diet; however, intervention trials have yielded mixed results.

Clinical trials incorporating either increases in cereal fiber or the combination of an increase in fruit and vegetables have been unsuccessful in modifying risk for cancer (i.e. precancer). While differences in dietary composition may explain differences at the group level, it may not at the level of the individual.

Genetic polymorphisms may preclude some from the benefit of a "healthy" diet, while others with a favorable polymorphic profile might benefit more from dietary change.

In this light, it may be time to re-evaluate new genetic/protein targets for nutritional effects on cancer. Modern lifestyles depart from the cyclic nature of "feast and famine" characterizing all but the last century of our development. The advent of electrification and of the global, fast access, food delivery system have created a constant state of abundance.

Cancer may be reviewed as a process evolving out of a persistent "feast" environment at the cellular and molecular level. Discovery of the subcellular mechanisms by with tumors co-opt and circumvent growth controls may lead to a new understanding of the impact of modern diet on cancer. The bio consequence of this switch also includes seasonal/diurnal disruptions.

Dr. Wargovich mentioned the NCI Polyp Prevention Trial as one of the studies that had failed to show a modification of risk. However, he did state that the participants achieved 3.5 fruits/vegetables per day. This is below the NCI suggestion of "5 A Day". Perhaps a cohort (group) that achieves at least 5 a day might show more benefit.

He suggested that it is still unclear how much diet affects cancer in the world citing 10-70% as possible but 30-50% as more likely. There are different risk factors in various countries, i.e. gastric (Japan), thought to be salt-related; liver (China), thought to be aflatoxin-related; skin cancer, thought to be related to sun exposure in warmer climate countries, etc.

Surveys show that up to 35% of Americans have heard of the "5 A Day" program but the serving portion concept is still confusing. I explained to my young nephews that a portion is about the size of a baseball. (I believe that came from AICR).

Americans may be choosing lower fat diets but not lower calories.

Ann's NOTE: The whole movement toward lower fat completely disregarded healthy fats and this has mattered. Even tomato sauce available in the health food stores, removed olive oil to call themselves 'fat free'.

Dr. Wargovich suggested that diet/gene interaction may involved P450 cytochromes(activation of PAH, nitrosamines, HCA's-all potentially carcinogenic). Also folate metabolism, glutathione S transferases, N-acetyl transferases, etc.

He said that individual responsiveness may be a function of different genes governing metabolic activation and detoxification pathways, DNA repair, and antioxidants.

He mentioned inflammation as important for cancer prevention research, specifically mentioning prostaglandins and Cox-1 and Cox-2. Anti-inflammation phytochemicals include Ginseng, Green tea, Milk thistle, Astralagus, Cat's claw, Chamomile, Cordyceps (mushroom), Saw Palmetto, Reishi (mushroom), Uva Ursi, Schisandra (Chinese herb), Grape Seed and more.

Dr. Wargovich mentioned too, that there is a theory that states our genes are still in the late Paleo age (pre-hunter-gatherer) and sedentary food is abundant.

For the future, he suggests developing ways to assess polymorphisms linking diet and cancer; looking at diurnal rhythms and feast/famine; looking at individual and combinations of dietary elements that may influence pathways for cancer prevention; and determining feasibility of genomic/proteomi profile for dietary risk reduction strategies.

Ann's NOTE: This researcher spoke to one of the main points I brought to this meeting - combining dietary/nutritional elements in study.

Jeffrey E. Greene, M.D., Laboratory of Cell Regulation and Carcinogenesis, CCR, National Cancer Institute, National Institutes of Health, Bethesda, MD spoke about "The Use of Genetically Altered Mice for Nutrition Studies".

He believes that these mice "may be utilized for testing of particular chemopreventive, nutritional and therapeutic agents". And "the effects of nutritionally derived compounds on gene expression profiles from normal and tumor tissue may also be assessed to better define modes of action of these compounds".

Dr. Greene mentioned that giving DHEA to these animals has shown a lower number of tumors (drop of about 50%). He also mentioned the benefits shown for calorie restriction.

Interestingly, he said that estrogen receptor expression (useful in breast cancer experimentation) is lost early in mice, even before they develop DCIS (ductal carcinoma in situ), so this limits their usefulness for hormonal research.

Dr. Greene discussed some specific areas of research:

Growth factor receptors, diet, IGF and Vitamin D

Cell cycle, genistein and selenium

Apoptosis (programmed cell death), genistein, selenium, butyrate

Differentiation, DHEA and retinoic acid (RA, vitamin A)

Cyclo-oxogenase, COX-2 inhibitors and selenium

Angiogenesis, endostatin, VEGF II

Metabolism, carcinogens, antioxidants, DFMO and selenium

Leonard H. Augenlicht, Ph.D., Albert Einstein Cancer Center, Bronx, NY spoke about "Application of Gene Expression Profiling to Colon Cell Maturation, Transformation and Chemoprevention".

The opening line of his abstract:

"The processes by which colon cells undergo cell cycle arrest, lineage specific differentiation, and cell death are complex and involve the interaction and coordination of a large number of genes and pathways".

In his talk he mentioned that there is evidence for genetic/dietary considerations for colon cancer. Calcium, Vitamin D, Folate, Choline, Methionine and Fiber have all shown prevention value.

Yuri Lazebnik, Ph.D., Cold Spring Harbor Laboratory, gave a talk on "Oncogenic Transformation as a Cause of Apoptosis".

This was a true scientific researcher-oriented talk. I did not understand much of what was said, although the speaker was funny and clever in his delivery. He sent me an email stating that he agreed with some of the statements I made during the conference, so apparently he understood my remarks far better than I did his.

Hasan Mukhtar, Ph.D., Department of Dermatology, University of Wisconsin, spoke on "Prostate Cancer Chemoprevention by Green Tea: Cell Cycle Dysregulation, Induction of Apoptosis, and Inhibition of Metalloproteases".

He had told me prior to his talk that he was the first to research green tea (JNCI 89:1881-1889, 1997).

From the abstract:

"In recent years, green tea has gained considerable attention as an agent that could reduce the risk of several cancer types. The cancer chemopreventive effects of green tea appear to be mediated by its major polyphenolic constituent, (-) epigallocatechin-3-gallate (EGDCG). Employing a TRAMP mouse prostate cancer (CaP) model that mimics a progressive form of human prostatic disease, we recently showed that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a humanly achievable dose (equivalent to six cups of green tea a day), significantly inhibits CaP development and its metastasis and resulted in an increased cancer-free and overall survival (PNAS, 98:10350-10355, 2001). "

Ann's NOTE: Of course this does what I least appreciate, that is look for the 'major polyphenolic constituent' as though the 'minor' ones are not important. I strongly believe that it is not only all the entire contents of green tea that matter, but that green tea should be looked at in the context of many other dietary compounds.

Dr. Mukhtar suggested that green tea is a stronger antioxidant than Vitamin C, although I do not recall any evidence as to this thesis.

JoEllen Welsh, Ph.D, Department of Biology, University of Notre Dame, spoke on "Role of Mitochondria and Caspases in Vitamin D-Mediated Apoptosis of MCF-7 Breast Cancer Cells".

From the abstract:

"Collectively, these studies support the concepts that the VDR (vitamin D3 receptor) is a nutritionally modulated growth regulatory gene in mammary cells and that strategies to enhance VDR signaling may prove beneficial in the prevention or treatment of human breast cancer".

Ann's NOTE: Even though I am very interested in vitamins and in breast cancer, there is not much more I can say about her talk. It went over my head for the most part. What I understand generally is that vitamin D3 is a negative growth regulator for both normal and abnormal mammary cells. It can stop growth and induce cell death (desirable traits).

Fazlul H. Sarkar, Ph.D., Department of Pathology, Wayne State University School of Medicine, Detroit, MI spoke on "Translocation of Bax to Mitochondria Induces Apoptotic Cell Death in Indole-3-Carbinol (I3C) Treated Breast Cancer Cells".

From the abstract:

"Indole-3-carbinol (I3C), a natural component of Brassica vegetables, has been found to be a promising cancer preventive agent. However, the precise molecular mechanism(s) through which I3C exerts its inhibitory effects on cancer cells has not been fully elucidated. We investigated the molecular mechanism(s) of action of I3C during apoptotic processes in breast epithelial cells.

Nontumorigenic and tumorigenic breast epithelial cells were exposed to I3C, and growth inhibition, apoptosis and expression of genes involved in apoptotic processes were measured. Translocation of Bax to the mitochondria was assessed by confocal imaging. Mitochondrial potential and cytochrome c release also were measured.

We found that I3C inhibits the growth of breast cancer cells with G1 arrest and induced apoptosis in these cells, concomitant with upregulation of p21 WAF1 and Bax, and downregulation of Bcl-2, Bcl-xl and Bax. I3C induces translocation of Bax to the mitochondria in both tumorigenic and nontumorigenic cells, but concomitant loss of mitochondrial potential, release of cytochrome c, and induction of apoptosis was observed only in cancer cells.

I3C exerts its effects by regulating cell cycles and by altering the expression of genes involved in apoptotic pathways. The translocation of Bax to the mitochondria alone was not sufficient during I3C-induced apoptosis. Translocation of Bax followed by mitochondrial depolarization and cytochrome c release was necessary, which may be responsible for selective induction of apoptosis in cancer cells, supporting the potential preventive and/or therapeutic benefit of I3C against cancers."

Dr. Sarkar discussed the need for studies in cancer patients and said they will be doing some. He felt that epidemiological studies suggest that I3C may be responsible (in part) for the lower breast cancer incidence in Asians. He also said it acted in more than one way.

He stated that there had been significant progress using I3C with head/neck cancers.

Ann's NOTE: Vitamin A analogues have also been used in head/neck as has PDT (photodynamic therapy). In private conversation with Dr. Sarkar (someone I met during my stint as a DOD reviewer), he said he thought I3C would function as well or better than Tamoxifen.

Roger J. Davis, Ph.D., F.R.S., Howard Hughes Medical Institute and University of Massachusetts Medical School, spoke on "Signal Transduction by JNK: Role of JNK in Tumor Development".

Ann's NOTE: The only thing I wrote down about this talk was that JNK was not required for proliferation and that it regulates leukemia.

Catherine A. O'Brian, Ph.D, Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, spoke on "Resveratrol: A Nutritional Suppressor of EGFR-Dependent Erk 1/2".

From the abstract:

"Resveratrol is a dietary polyphenol that is notable for its high abundance in commonly consumed food products (e.g. grapes) and its healthful effects, which include cancer preventive activity and protective cardiovascular effects. We hypothesize that resveratrol may be particularly valuable in prostate cancer (PRCA) prevention. Resveratrol may prevent PRCA through three independent mechanisms.

They are inhibition of multistage carcinogenesis, scavenging of incipient androgen-dependent PRCA cell populations through androgen-receptor antagonism, and scavenging of incipient androgen-independent (AI) PRCA cell populations by short-circuiting EGFR-dependent autocrine loops in the cells.

Dr. O'Brian stated that since resveratrol has both estrogenic and anti-estrogenic effects, she was not sure if it was safe for women. However resveratrol can limit tumor initiation, promotion and progress as well as having anti-inflammatory effect. It has been shown to inhibit Cox-1 and Cox-2.

She further said that as resveratrol is 10% of grapeskin biomass, it is most likely non toxic.

Snorri S. Thorgeirsson, M.D., Ph.D., Laboratory of Experimental Carcinogenesis, NCI, NIH, "Vitamin E Reduces Chromosomal Damage and Inhibits Hepatic Tumor Formation in a Transgenic Mouse Model".

From the abstract:

"We have shown that vitamin E (VE), a potent free radical scavenging antioxidant, is able to protect liver tissue against oxidative stress and suppress the tumorigenic potential of c-myc oncogene. Dietary supplementation with VE, starting from weaning, decreased ROS generation coincident with a marked inhibition of hepatocyte proliferation, while increasing the chromosomal as well as mtDNA stability in the liver.

Similarly, dietary VE reduced liver dysplasia and increased viability of hepatocytes. At 6 months of age, VE treatment decreased the incidence of adenomas by 65% and prevented malignant conversion. These results indicate that ROS generated by overexpression of c-myc and TGF alpha in the liver are the primary carcinogenic agents in this animal model. Furthermore, the data demonstrate that dietary supplementation of VE can effectively inhibit liver cancer development.

Ann's NOTE: Apparently liver cancer develops in known stages (as does colon cancer). The start is often HBV/HCS (viral), then chronic hepatitis/cyrrhosis, then phenotypically-altered hepatocytes, then dysplastic hepatocytes, then neoplasia. Dysplasia can last 3-5 years while neoplasia is usually less than 5 years.

Steven Kliewer, Ph.D., Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, TX, "Nuclear Receptors and Lipid Physiology"

From the abstract:

"Members of the nuclear receptor family of ligand-activated transcription factors play important roles in protecting the body against the accumulation of potentially toxic concentrations of lipophilic chemicals including cholesterol, bile acids, and fatty acids. Over the past several years, we have shown that Pregnane X Receptor (PXR) is an integral component of the body's defense mechanism against xenobiotics.

PXR is activated by a broad spectrum of lipid xenobiotics, including several widely used prescription drugs and hyperforin, the psychoactive constituent of the herbal antidepressant St. John's Wort. PXR regulates a large program of genes, including those encoding phase I and phase II enzymes and transporters that are involved in the metabolism and excretion of toxic substances from the body.

Although PXR evolved to protect the body, its activation by drugs represents the molecular basis for an important class of drug-drug interactions."

Dr. Kliewer told the audience that this xenobiotics receptor (foreign chemicals) involved cyp3A (cytochrome P450) liver/intestine mechanism for protecting the body from anything absorbed inhaled, ingested or synthesized. The receptor also works for endobiotics or chemicals produced by the body and thus causes those drug-drug interactions. The body cannot tell good xenobiotics from harmful ones.

What Dr. Kliewer referred to as the 'dark side' is more than 50% of all cancer and immunosuppressive drugs, including doxirubicin, taxol, indinavir, cyclosporin, camptosar, hyperforin (St. John's Wort), phenobarbitol, lithocholic acid and more.

Gary Firestone, Ph.D., Department of Molecular and Cell Biology, University of California at Berkeley, "Indole-3-carbinol Signaling Controls Cell Cycle Gene Transcription in Human MCF-7 Breast Cancer Cells by Regulating Promoter-Sp1 Transcription Factor Interactions".

From the abstract:

"Indole-3-carbinol (I3C), a compound naturally occurring in Brassica vegetables such as cabbage and broccoli, can induce a G1 cell cycle arrest of human MCF-7 breast cancer cells that is accompanies by the selective inhibition of cyclin dependent kinase 6 (CDK6) expression and stimulation of p21 (Waf1/Cip1) gene expression...

In indole treated cells, a fraction of [3H]I3C was converted into its natural diindole product, [3H]DIM, which accumulated in the nucleus, suggesting that DIM may have a role in the transcriptional activities of I3C."

Dr. Firestone spoke about the synergy between estrogen and I3C. He suggested that I3C virtually blocks the 's' phase.

Luigi M. De Luca, Ph.D., Laboratory of Cellular Carcinogenesis and Tumor Promotion, NCI "Carcinogens Interfere with the Expression of Retinoic Acid Receptors".

From the abstract:

"Retinoids are essential for the maintenance of epithelial differentiation in adult organisms. Carcinogens disrupt epithelial differentiation and induce a phenotype that resembles what was caused by the condition of retinoid deficiency and termed "squamous metaplasia" of mucus secretory epithelia. Exposure to retinoids prevents the formation of carcinogen-induced squamous metaplasia in organ cultures of hamster tracheas.

Further, in the two-stage mouse skin carcinogenesis system, topical as well as systemic retinoic acid inhibit carcinoma development. In this system, malignant progression is characterized by a loss of expression of the retinoic acid receptors (RARs) and is without effect on the RXRs.

Introduction of RAR expression 'normalizes' malignant behavior of certain neoplastically transformed cultured mouse keratinocytes. The knockout of the carcinogen receptor aryl hydrocarbon receptor (AHR) is characterized by a 2-3 fold increase in liver retinoids and liver fibrosis; both are reversed by the induction of nutritional retinoid deficiency.

Increased liver retinoids are accompanied by increased liver TGFbetas and their receptors, TRI and TRII, which are reversed in mice fed a vitamin A-deficient diet. This work is consistent with the interpretation that retinoid signaling is interfered with by carcinogens at several levels, eventually contributing to neoplastic transformation, and that exposure to retinoids under the right conditions may prevent or inhibit carcinogenesis".

Ann's NOTE: In our section called Ann's Bio, I explain my personal experiences using vitamin A as a treatment for chest wall recurrent tumors.

Juanita Merchant, Ph.D., M.D., Department of Internal Medicine and Physiology, Division of Gastroenterology, University of Michigan, Ann Arbor, "p53-Independent Cell Cycle Arrest and Apoptosis Via Butyrate-Inducible ZBP-89".

From the abstract:

"Together, these findings demonstrate that ZPB-89 also plays a critical role in butyrate-mediated growth arrest and apoptosis, in part through preferential cooperation of ZPB-89 with p300".

Ann's NOTE: I have no notes taken during this talk because I did not understand its relevance. Sorry.

William Isaacs, Ph.D., Department of Urology, Johns Hopkins University School of Medicine, "Gene Expression Profiling of Human Prostate Cancer: Identification of Transcriptionally Distinctive Genes in Prostate Cancer, BPH, and Normal Prostate".

From the abstract:

"This work suggests that investigation of the transcriptional networks of prostate cancer reveals distinct gene expression profiles among normal prostate, BPH, and low grade and high grade prostate tumors and can provide much-needed molecular markers for prognostic and diagnostic use.

At lease a subset of these markers provides etiologic clues, implicating dietary constituents as factors associated with prostate carcinogenesis".

David Feldman, M.D., Stanford University School of Medicine, "Pathways of Vitamin D Action to Inhibit Prostate Cancer Cell Growth".

From the abstract:

"Vitamin D is emerging as an important dietary factor that affects the incidence and progression of a number of malignancies. Our research is directed at understanding the mechanism of vitamin D action on normal and malignant prostate cells with the goal of developing chemoprevention and treatment strategies to improve prostate cancer therapy.

We have studied primary cancer cell lines (e.g. LNCap, PC-3 and DU145) to elucidate the molecular pathways through which vitamin D inhibits cell growth. To mediate its biological actions, vitamin D is converted to an active hormonal form, 1,25-dihydroxyvitamin D (1,25D). 1,25D regulates target genes by binding to its nuclear receptor, the vitamin D receptor (VDR).

Its main actions are to inhibit proliferation and stimulate differentiation of prostate cancer cells. Recent studies have indicated new pathways through which vitamin D activity is modulated. 1,25D is catabolized by the enzyme 24-hydroxylase, which is induced by 1,25D. Inhibition of this degrading enzyme enhances 1,25D action and allows resistant prostate cancer cells (DU145) to become more sensitive.

IGFBP-3 is induced by 1,25D. Inhibition of IGFBP-3 by immunoneutralization or antisense abrogates 1,25D action in LNCaP cells, indicating this action is essential for growth inhibition.

We have used cDNA microarray analysis to identify additional target genes regulated by 1,25D in normal and prostate cancer cells. Ongoing research will verify these new targets and evaluate their potential role in 1,25D action to inhibit prostate cancer growth or for use in chemoprevention.

Dr. Feldman told us that vitamin D is antiproliferative, immunosuppressive and promotes differentiation. The classic view is that it maintains mineral homeostasis and bone density through calcium maintenance.

Prostate cancer is inversely related to sunlight exposure in that a little more sun can be beneficial. There is some evidence that a deficiency can be a problem for the prostate.

Vitamin D inhibits epithelial cancer, its work is multifactorial (many different ways). It may be chemopreventive if from dietary sources or administered as a supplement, although 1,25D is an unlikely treatment.

There is a human trial against stage A/B minimally recurrent disease. Most patients stabilized, that is slowed the rate of PSA rise. However, 2 patients developed kidney stones. Future studies might include low calcemic vitamin D analogues.

Myles Brown, M.D., Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, "Molecular Determinants for the Tissue Specificity of SERMS".

From the abstract:

"Since the discovery of the first estrogen receptor (ER) associated proteins, it has been hypothesized that coregulators play an important role in determining the spectrum of transcriptional responses to ER and its ligands in various target tissues...

SERMS mimic estrogen action in certain tissues while opposing it in others. The therapeutic effectiveness of SERMS, such as tamoxifen and raloxifene in breast cancer, depends on their antiestrogenic activity. However, the clinical utility of tamoxifen is limited to some degree by its estrogenic activity in the uterus.

We find that both tamoxifen and raloxifene induce the recruitment of corepressors to target gene promoters in mammary cells. In endometrial cells, tamoxifen, not raloxifene acts like estrogen by stimulating the recruitment of coactivators to a subset of genes. This depends on the specific pattern of coregulator expression. Thus, cell type and promoter specific differences in coregulator recruitment are determinants of the spectrum of responses to SERMS".

Ann's NOTE: I asked the speaker what he thought about the fact that two animal species had developed ovarian cancer with raloxifene. He did not know about it at all. He told me privately that his wife is a well-known breast cancer doctor. In retrospect, I am a bit horrified that he did not know this information. He said he would explore it. I may email to make sure he follows up with this. I would love to know what he thinks. Many breast cancer advocates may recall a talk given at the 2000 NBCC (National Breast Cancer Coalition, advocacy conference on this very topic.

Dr. Brown pointed out that at relapse after endocrine therapy (recurrence), the ER is rarely mutated, suggesting other mechanisms at play.

Nutritional Genomics & Proteomics-Part II

Summary of 9/5-9/6/02

Molecular Targets for Nutrients/Prevention

Nutrition & Cancer

Eat Fruits & Vegetables;Prevention

National Cancer Institute Newscenter, 11/02

J Nutrition, Supplement, 7/03

LINK to all abstracts from this meeting

Critical Sulfhydrul Switches, Diet & Cancer Prevention Workshop

Summary from NIH, 8/03

Lycopene/Tomato Supplementation & Cancer Prevention

Summary from NIH February 17-18, 2005

Session 1: Epi Evidence for Role of Lycopene in Ca Prevention
Session II: Typical Lycopene Exposure & Metabolomic Response
Session III: Model Systems for Lycopene
Session IV: What Have We Learned From Clinical Trials
Literature Cited: Lycopene NIH Meeting
Listening & Learning Together: Building A Bridge of Trust

National Cancer Institute DCLG

Nutrient Interactions with Human Genes

June 1-2, 2007 Workshop NIH

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