Curcumin extract inhibits metastasis

Curcumin inhibition of STEM cells 

Kim HI¹, Huang H, Cheepala S, Huang S, Chung J.

Author information

Abstract

(integrin (alpha6beta4) - dependent breast cancer cell motility and invasion and reverts cells to apoptosis (normal growth) including HER2)

Curcumin, a polyphenol natural product isolated from the rhizome of the plant Curcuma longa, has emerged as a promising anticancer therapeutic agent. However, the mechanism by which curcumin inhibits cancer cell functions such as cell growth, survival, and cell motility is largely unknown. We explored whether curcumin affects the function of integrin alpha(6)beta(4), a laminin adhesion receptor with an established role in invasion and migration of cancer cells. Here we show that curcumin significantly reduced alpha(6)beta(4)-dependent breast cancer cell motility and invasion in a concentration-dependent manner without affecting apoptosis in MDA-MB-435/beta4 (beta(4)-integrin transfectants) and MDA-MB-231 breast cancer cell lines. Further, curcumin selectively reduced the basal phosphorylation of beta(4) integrin (Y1494), which has been reported to be essential in mediating alpha(6)beta(4)-dependent phosphatidylinositol 3-kinase activation and cell motility. Consistent with this finding, curcumin also blocked alpha(6)beta(4)-dependent Akt activation and expression of the cell motility-promoting factor ENPP2 in MDA-MB-435/beta4 cell line. A multimodality approach using curcumin in combination with other pharmacologic inhibitors of alpha(6)beta(4) signaling pathways showed an additive effect to block breast cancer cell motility and invasion. Taken together, these findings show that curcumin inhibits breast cancer cell motility and invasion by directly inhibiting the function of alpha(6)beta(4) integrin, and suggest that curcumin can serve as an effective therapeutic agent in tumors that overexpress alpha(6)beta(4).

Chemotherapy Makes Cancer Far Worse

Woops! Study Accidentally Finds Chemotherapy Makes Cancer Far Worse

Anthony Gucciardi

August 7th, 2012

A team of researchers looking into why cancer cells are so resilient accidentally stumbled upon a far more important discovery. While conducting their research, the team discovered that chemotherapy actually heavily damages healthy cells and subsequently triggers them to release a protein that sustains and fuels tumor growth. Beyond that, it even makes the tumor highly resistant to future treatment.

Reporting their findings in the journal Nature Medicine, the scientists report that the findings were ‘completely unexpected’. Finding evidence of significant DNA damage when examining the effects of chemotherapy on tissue derived from men with prostate cancer, the writings are a big slap in the face to mainstream medical organizations who have been pushing chemotherapy as the only option to cancer patients for years.

The news comes after it was previously ousted by similarly-breaking research that expensive cancer drugs not only fail to treat tumors, but actually make them far worse. The cancer drugs were found to make tumors ‘metasize’ and grow massively in size after consumption. As a result, the drugs killed the patients more quickly.

Known as WNT16B, scientists who performed the research say that this protein created from chemo treatment boosts cancer cell survival and is the reason that chemotherapy actually ends lives more quickly. Co-author Peter Nelson of the Fred Hutchinson Cancer Research Center in Seattle explains:

“WNT16B, when secreted, would interact with nearby tumour cells and cause them to grow, invade, and importantly, resist subsequent therapy.”

The team then complimented the statement with a word of their own:

“Our results indicate that damage responses in benign cells… may directly contribute to enhanced tumour growth kinetics.”

Meanwhile, dirt cheap substances like turmeric and ginger have consistently been found to effectively shrink tumors and combat the spread of cancer. In a review of 11 studies, it was found that turmeric use reduced brain tumor size by a shocking 81%. Further research has also shown that turmeric is capable of halting cancer cell growth altogether. One woman recently hit the mainstream headlines by revealing her victory against cancer with the principal spice used being turmeric.

This accidental finding reached by scientists further shows the lack of real science behind many ‘old paradigm’ treatments, despite what many health officials would like you to believe. The truth of the matter is that natural alternatives do not even receive nearly as much funding as pharmaceutical drugs and medical interventions because there’s simply no room for profit. If everyone was using turmeric and vitamin D for cancer (better yet cancer prevention), major drug companies would lose out.

Additional sources:

Pubmed/21775121

Pubmed/19138983

Shock study: Chemotherapy can backfire, make cancer worse by triggering tumor growth

Shock study: Chemotherapy can backfire, make cancer worse by triggering tumor growth

Scientists found that healthy cells damaged by chemotherapy secreted more of a protein called WNT16B, which boosts cancer cell survival. 'The increase in WNT16B was completely unexpected," said Peter Nelson, of the Fred Hutchinson Cancer Research Center.

AFP RELAX NEWS

Monday, August 6, 2012, 12:59 PM

SVEN HOPPE /SHUTTERSTOCK.COMHealthy cells damaged by chemotherapy secrete more of a protein called WNT16B, which boosts cancer cell survival

Long considered the most effective cancer-fighting treatment, chemotherapy may actually make cancer worse, according to a shocking new study.

The extremely aggressive therapy, which kills both cancerous and healthy cells indiscriminately, can cause healthy cells to secrete a protein that sustains tumor growth and resistance to further treatment.

Researchers in the United States made the "completely unexpected" finding while seeking to explain why cancer cells are so resilient inside the human body when they are easy to kill in the lab.

They tested the effects of a type of chemotherapy on tissue collected from men with prostate cancer, and found "evidence of DNA damage" in healthy cells after treatment, the scientists wrote in Nature Medicine.

Chemotherapy works by inhibiting reproduction of fast-dividing cells such as those found in tumors.

The scientists found that healthy cells damaged by chemotherapy secreted more of a protein called WNT16B which boosts cancer cell survival.

"The increase in WNT16B was completely unexpected," study co-author Peter Nelson of the Fred Hutchinson Cancer Research Center in Seattle told AFP.

The protein was taken up by tumor cells neighboring the damaged cells.

"WNT16B, when secreted, would interact with nearby tumor cells and cause them to grow, invade, and importantly, resist subsequent therapy," said Nelson.

In cancer treatment, tumors often respond well initially, followed by rapid re-growth and then resistance to further chemotherapy.

Rates of tumor cell reproduction have been shown to accelerate between treatments.

"Our results indicate that damage responses in benign cells... may directly contribute to enhanced tumor growth kinetics," wrote the team.

The researchers said they confirmed their findings with breast and ovarian cancer tumors.

CANCER TREATMENT OVERVIEW

The result paves the way for research into new, improved treatment, said Nelson.

"For example, an antibody to WNT16B, given with chemotherapy, may improve responses (kill more tumor cells)," he said in an email exchange. Curcumin extracts demonstrates ability for stopping cancer growth and tumor spreading.

"Alternatively, it may be possible to use smaller, less toxic doses of therapy."

Cholesterol Myth by Dr. George V. Mann

The Cholesterol Myth

“Saturated fat and cholesterol in the diet are not the cause of coronary

heart disease. That myth is the greatest ‘scientific’ deception of the century,

and perhaps any century.”

- George V. Mann, M.D.

Professor of Biochemistry and Medicine

There is simply no one better in the 21st century at developing practical health-related solutions based on the world’s leading medical and nutritional science. “Science – Not opinion” is Brian’s trademark. When
Brian is through explaining a topic it is “case closed!” When he says it, you “can take the information to the bank!”

Unlike most of his peers’ recommendations, Brian’s health and nutritional recommendations have stood the test of time. Brian has never had to reverse or significantly alter any of his medical reports—reports
that have tackled everything from the dangers of soy, to the wrongly popularized need for fiber in the diet, to his warning about the potential harm of supplementing with copious amounts of omega-3. In 1995 he
published the report “Fiber Fiction” and finally, eleven years later, others in research are acknowledging the silliness of recommending fiber in the diet of a human being. Brian’s latest crusade is to warn of the dangers of excess omega-3 (in particular, fish oil) and how it will lead to increased cases of skin cancer. The list goes on and on… Brian received an appointment as an Adjunct Professor at Texas Southern University in the Department of Pharmacy and Health Sciences (1998-1999). The former president of the University said of his discoveries: “...His nutritional discoveries and practical applications through Life-Systems Engineering are unprecedented.” Brian earned his Bachelor of Science degree in Electrical Engineering from Massachusetts Institute of Technology (MIT) in 1979. Brian founded the field of Life-Systems Engineering Science in
1995. This field is defined as The New Science of Maximizing Desired Results by Working Cooperatively with the Natural Processes of Living Systems. To many, Brian is THE MOST TRUSTED AUTHORITY ON HEALTH AND NUTRITION IN THE WORLD.

Brian continues to be a featured guest on hundreds of radio and television shows both nationally and internationally. His sheer number of accomplishments during the last decade of the 20th century and into
the 21st century are unprecedented and uniquely designate him as the #1 authority in the world of what really works and why. Forget listening to the popular press or most popular so-called health magazines. Their
editors simply don’t understand the complicated science that they write about – they merely “parrot” what everyone else says without independent scientific verification. Their recommendations often have no basis in reality of how the body works, based on its physiology.

Brian has dedicated his life to provide the truth – which is almost always opposite to what everyone says. Here’s why Brian is the #1 man in America to listen to when it comes to your health.

Breast Cancer HER2, Metastasis and Natural Compounds

Natural Compound Attacks HER2 Positive Breast Cancer Cells

By Duke Medicine News and Communications

DURHAM, N.C. – A common compound known to fight lymphoma and skin conditions actually has a second method of action that makes it particularly deadly against certain aggressive breast tumors, researchers at Duke Medicine report. Natural supplements keep rising to the surface as the method for treating cancer. “Natural” confounds the whole system of research, grants, funding and marketing.

The compound is called psoralen, a natural component found in foods such as figs and celery, and researchers have long understood that it that works by disrupting DNA replication and causing cell death when activated by an energy source such as UV light. UV light from the sun combined with natural supplementation has much promise. Whethere is it HER2 cells or STEM cells, cancer proliferation, spreading factor and metastasis is the most important goal for any cancer therapy. Unfortunately, chemotherapy and radiation will cause cancer to proliferate and get worse according to Stanford Univeristy researchers and University of Michigan. This is particularly important because these universiteis are the two most proliferative researchers on metastasis and that as a cause of fatality in cancer patients.

Duke researchers have now identified another way the compound works to kill tumor cells, raising the potential for psoralen to be developed as an effective therapy for cancers that are particularly vulnerable to this second mode of action.

Reporting in the Feb. 14, 2014 issue of the journal PLOS ONE, the researchers detail how psoralen blocks the signaling pathway of the HER2 receptor, which is overproduced in 25 percent of breast cancers, plus ovarian, gastric and other solid tumors. When HER2 is overproduced, it fuels uncontrolled cell growth, leading to an aggressive form of cancer. Psoralen shut down this process in experiments using HER2 overexpressing breast cancer cell lines.

“This was very unexpected,” said senior author Neil L. Spector, M.D., the Sandra Coates Associate Professor of Medicine at Duke. “The therapy has been known to kill cancer cells by causing DNA damage, but it is also having a direct anti-tumor effect on HER2 overexpressing breast cancer cells by blocking HER2 signaling.”

Psoralen also attacks another form of HER2 that is present in the nucleus of tumor cells. This form of the protein is resistant to cancer therapies such as lapatinib and trastuzumab that are otherwise effective in targeting HER2-positive cancers.

“Cancer drugs can recognize HER2 receptors when they are outside of the cell, but they don’t recognize the truncated version inside the cell nucleus,” Spector said. “We have shown that psoralen is effective in targeting this other form of HER2 that is resistant to current HER2-targeted therapies.” Other natural substances have shown promise in all types of cancer cells and cancer STEM cells. Only 1% of the tumor is a metastasizing element.

Spector said the benefits of psoralen remain dependent on its activation by an energy source, which has been an impediment to its use in solid tumors. Currently, psoralen is primarily used as a topical treatment in conjunction with UV light exposure in a process called PUVA. The treatment is used for skin conditions such as psoriasis and as a therapy for lymphoma by exposing treated blood to UV radiation during a dialysis-type procedure.

“The challenge all along has been to figure out a way of generating UV light deeper in the body,” Spector said. That challenge is close to being resolved. In a previous publication, Duke investigators from the Pratt School of Engineering, working in collaboration with Spector and scientists from Immunolight, the company that has funded the research, reported the development of micron-sized particles that absorb energy from X-rays to emit UV light in and around cells, much like the cathode ray tube technology used in televisions. Sunlight, unfiltered, also provides this UV light.

The tiny particles are injected into tumors along with the psoralen, then targeted by low-dose X-ray that cause the micron particles to create the UV light necessary to trigger psorlen’s anti-tumor properties. Spector said the technology is being tested in animals, and may be approved for human trials as early as this year.

“A good part of four years has been trying to figure out how to overcome the biophysics challenge of generating enough energy inside the body to activate the particles and the drug,” Spector said. “We’ve come a long way.”

In addition to Spector, study authors include Wenle Xia, David Gooden, Leihua Liu, Sumin Zhao, Erik J. Soderblom, Eric J. Toone, Wayne F. Beyer Jr., and Harold Walder.

Immunolight funded the study. Duke and Immunolight have filed several joint patent applications on the technology.

 While universities wait for elements to patent, clinics around the world use natural elements that accomplish the same goal. 

Cholesterol and Heart Disease - Myth of epic proportions

According to Dr. George Mann, one of the original authors of the study on cholesterol and heart disease: “Saturated fat and cholesterol in the diet are not the cause of coronary heart disease. That myth is the greatest ‘scientific’ deception of the century, and perhaps any century.”

- George V. Mann, M.D.,  Professor of Biochemistry and Medicine

The cholesterol “problem” has not been due to eating (natural) fat in general, but due to the kinds of fats, period. Bad fats - hydrogenated oils, often found in margarine and most supermarket items, which we’ve been led to believe are better for us, have replaced the good healthy ones like butter, the natural fat from meat, and unprocessed, full-fat dairy products.

Let’s take a look at the structure of our cells. The critical bi-lipid membrane cell walls are composed of half fat and half protein. There is no structural carbohydrate in your 100 trillion cells. Of the half fat about 25%-33% is suppose to be from natural polyunsaturated fats (EFAs) and from saturated fat. Saturated fat has been incorrectly termed “bad” over the past 5 decades! The saturated fat supports cellular structure, keeps out impurities, protects the delicate polyunsaturated fat (EFAs), and gives cellular support.

The polyunsaturated fat allows essential nutrients, hormones, numerous biochemical processes, and vital oxygen into the cell. Fats have a particular molecular structure. But when good, natural dietary fats are altered into trans-fats and other man-made unnatural, biochemically altered structures (the kinds found in popular low-fat, highly processed foods), the molecular biochemistry and structure is changed. This is what makes them so dangerous. Our bodies use them in place of the good natural fats it needs, but the
structure is all wrong; very dangerous, and malfunctioning!

Imagine what these bad transfats do to your cell structure. Damaged fats create damaged cells. Transfats don’t work because they don’t have the required structure our bodies are designed to use. What makes them so bad is that they “fit” into the cell even though they are defective. These hydrogenated oils and other man-made modified oils are known to stop the oxygen transfer of EFAs and cause cancer. Even when margarine and other hydrogenated products contain relatively few transfats—as little as just 1%-2%—this translates to an enormous number of transfat molecules. Obesity is more related to bad fats, carbohydrates, sugar and processed foods. Process milk is not the same as raw milk.

In absolute numbers there will be some 1x1021 molecules (one followed by 21 zeros, or 100 million-trillion) in each tablespoon of oil. Therefore, the potential for them to cause damage, either integrally in the cellular structure, or in biochemical reactions, is highly significant, because only a tablespoon of defective oil provides some 100,000 defective oil molecules for each cell in our body—a tremendous overload potential. Add to this defective number the huge number of defective fat molecules from other processing sources and you will be terrified at what you and your family have been consuming for decades!

In absolute numbers there will be (an order of magnitude of) some 1x1021 molecules (1 followed by 21 zeros!) per tablespoon of oil - an overload potential of 104 (10,000 to 1) defective EFAs/cell).

Damaged fats and oils ruin our bodies in a number of ways. Rather than “high” or “low” cholesterol being a problem, the real issue is not the amount of cholesterol or the HDL or LDL number, but rather whether your cholesterol structure has been damaged.

Meat, butter and cheese, per se, do not relate to bad health, and heart disease in particular. There is nothing in the literature to indicate any poor health relating to meat, eggs, cheese, etc. and high cholesterol levels. There is a great deal of poor health related to process foods, chronic high glucose levels, and high intake of a diet saturated with carbohydrate food choices.

Glycemic Index, Insulin Resitance, High Sugar Diets show close correlation to High Incidence of Cancer

Dietary Glycemic Load and Risk of Colorectal Cancer in the Women's Health Study

1. Susan Higginbotham, 
2. Zuo-Feng Zhang, 
3. I-Min Lee, 
4. Nancy R. Cook,
5. Edward Giovannucci, 
6. Julie E. Buring and 
7. Simin Liu

+Author Affiliations

1. Affiliations of authors: Department of Epidemiology, University of California at Los Angeles, Los Angeles (SH, ZFZ); Division of Preventive Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA (IML, NRC, JEB, SL); Departments of Epidemiology (IML, EG, JEB, SL) and Nutrition (EG), Harvard School of Public Health, Boston.

1. Correspondence to: Simin Liu, MD, ScD, Division of Preventive Medicine, Harvard Medical School and Brigham and Women's Hospital, 900 Commonwealth Ave., Boston, MA 02215 (e-mail:simin.liu@channing.harvard.edu)

• Received July 22, 2003.
• Revision received November 12, 2003.
• Accepted November 22, 2003.

Next Section

Abstract

Although diet is believed to influence colorectal cancer risk, the long-term effects of a diet with a high glycemic load are unclear. The growing recognition that colorectal cancer may be promoted by hyperinsulinemia and insulin resistance suggests that a diet inducing high blood glucose levels and an elevated insulin response may contribute to a metabolic environment conducive to tumor growth. We prospectively followed a cohort of 38 451 women for an average of 7.9 years and identified 174 with incident colorectal cancer. We used baseline dietary intake measurements, assessed with a semiquantitative food-frequency questionnaire, to examine the associations of dietary glycemic load, overall dietary glycemic index, carbohydrate, fiber, nonfiber carbohydrate, sucrose, and fructose with the subsequent development of colorectal cancer. Cox proportional hazards models were used to estimate relative risks (RRs). Dietary glycemic load was statistically significantly associated with an increased risk of colorectal cancer (adjusted RR = 2.85, 95% confidence interval [CI] = 1.40 to 5.80, comparing extreme quintiles of dietary glycemic load; P_trend = .004) and was associated, although not statistically significantly, with overall glycemic index (corresponding RR = 1.71, 95% CI = 0.98 to 2.98; P_trend = .04). Total carbohydrate (adjusted RR = 2.41, 95% CI = 1.10 to 5.27, comparing extreme quintiles of carbohydrate; P_trend = .02), nonfiber carbohydrate (corresponding RR = 2.60, 95% CI = 1.22 to 5.54; P_trend = .02), and fructose (corresponding RR = 2.09, 95% CI = 1.13 to 3.87; P_trend = .08) were also statistically significantly associated with increased risk. Thus, our data indicate that a diet with a high dietary glycemic load may increase the risk of colorectal cancer in women.

The growing recognition that colorectal cancer may be promoted by hyperinsulinemia and insulin resistance suggests that a diet inducing high blood glucose levels and an elevated insulin response may contribute to a metabolic environment conducive to tumor growth. Dietary and lifestyle risk factors for developing insulin resistance, such as physical inactivity, obesity, and positive energy balance, also increase the risk of developing colorectal cancer and other cancers (1,2). Insulin stimulates pathways that increase levels of insulin-like growth factor, and both insulin and insulin-like growth factor promote mitosis and cell proliferation but inhibit apoptosis in normal and cancer cells of the colonic epithelium (3,4). Foods rapidly digested and absorbed can cause sudden increases in blood glucose and corresponding increases in insulin response (5). The glycemic index is used to rank foods containing a fixed amount of carbohydrate (generally, 50 g) by their effects on blood glucose (6). A food's glycemic load is determined from its glycemic index and the carbohydrate content of a standard serving (7). Although diet is believed to influence colorectal cancer risk, the long-term effects of a diet with a high glycemic load are unclear. We investigated whether dietary glycemic load was associated with the risk of colorectal cancer by using data from the Women's Health Study.

The Women's Health Study is composed of 39 876 health professionals who were 45 years old or older at baseline from April 1993 to January 1996. It was originally designed as a randomized trial of aspirin, vitamin E, and β-carotene for prevention of cardiovascular disease and cancer, although the β-carotene treatment was terminated in January 1996. This study has been conducted according to the ethical guidelines of Brigham and Women's Hospital. Written informed consent was obtained from all participants.

A 131-item semiquantitative food-frequency questionnaire was administered at baseline to assess averagedietary intake during the previous year (8). Women with more than 70 blanks in the dietary questionnaire or with a daily total energy intake of less than 2514 kJ or more than 14 665 kJ were excluded from these analyses, leaving a cohort of 38 451. Participants completed risk factor questionnaires at baseline and annually thereafter. Glycemic index values were obtained from published tables (9) and from The Nutrition Center of the University of Toronto. We used the mean when multiple glycemic index test values were reported. For mixed dishes, we used a weighted average of the glycemic index of each component food. The glycemic load for each food item was calculated by multiplying the food's glycemic index by the number of carbohydrate grams in a serving. Dietary glycemic load for each participant was estimated by multiplying the glycemic load for each food by the participant's frequency of consumption and then summing over all foods (8). The overall glycemic index for each participant represents the average glycemic index of carbohydrate in the diet and was obtained by dividing the participant's dietary glycemic load by total carbohydrate intake. Glucose was used as the standard in calculating glycemic index and glycemic load values.

The physiologic relevance and validity of dietary glycemic load, as assessed by food-frequency questionnaires, are supported by several studies. In a cross-sectional study of healthy postmenopausal women (8), dietary glycemic load was positively associated with plasma triacylglycerol concentrations and negatively associated with plasma high-density lipoprotein cholesterol concentrations. In another study (10), it was positively associated with high-sensitivity C-reactive protein, a marker of systemic inflammation and a risk factor for ischemic heart disease. In prospective cohort studies (7,11,12), dietary glycemic load has been positively associated with increased risk of coronary heart disease and diabetes mellitus.

We categorized dietary exposures into quintiles of intake and, after determining that the data met the assumptions for using Cox proportional hazards modeling, we used this method to estimate hazard ratios. We used baseline dietary intake measurements, assessed with a semiquantitative food-frequency questionnaire, to examine the associations of dietary glycemic load, overall glycemic index, carbohydrate, fiber, nonfiber carbohydrate, sucrose, and fructose with colorectal cancer risk. To test for trend, we assigned the quintile median value to each subject in that quintile. We report 95% confidence intervals (CIs) and P values from two-sided statistical tests. All dietary variables were adjusted for total energy intake with the residual method (13). Follow-up time was calculated from baseline through the date of diagnosis of colorectal cancer, death, drop-out, loss to follow-up, or the end of the follow-up period.

Average follow-up was 7.9 years, during which we identified 174 patients with incident colorectal cancer (148 of the colon and 26 of the rectum). The mean dietary glycemic load for the cohort was 117, and the mean overall glycemic index was 53 (Table 1). In age-adjusted models, we observed statistically significant positive associations of both dietary glycemic load and overall glycemic index with colorectal cancer (Table 2). In multivariable analyses that included total energy intake and nutrient risk factors (fat, fiber, folate, calcium, and vitamin D) in the models, colorectal cancer risk estimates for dietary glycemic load increased (adjusted relative risk [RR] = 2.85, 95% CI = 1.40 to 5.80, comparing extreme quintiles of dietary glycemic load; P_trend = .004), but overall glycemic index risk estimates were essentially unchanged (adjusted RR = 1.71, 95% CI = 0.98 to 2.98; P_trend = .04, comparing extreme quintiles of overall glycemic index). Including fruit and vegetable, red meat, and whole grain intake in place of the nutrient risk factors resulted in risk estimates similar to those in the age-adjusted models, although confidence intervals were wider and crossed the null (data not shown). Risk estimates for total carbohydrate (adjusted RR = 2.41, 95% CI = 1.10 to 5.27, comparing extreme quintiles of carbohydrate; P_trend = .02), nonfiber carbohydrate (corresponding RR = 2.60, 95% CI = 1.22 to 5.54; P_trend = .02), sucrose (corresponding RR = 1.51, 95% CI = 0.90 to 2.54; P_trend = .06), and fructose (corresponding RR = 2.09, 95% CI = 1.13 to 3.87; P_trend = .08) were consistent with but lower than the dietary glycemic load findings. Fiber intake was inversely associated with risk, although estimates crossed the null, and there was no evidence of a linear trend (adjusted RR = 0.79, 95% CI = 0.45 to 1.38, comparing extreme quintiles of fiber; P_trend = .50).

Dietary glycemic load and overall glycemic index risk estimates did not change appreciably in separate analyses when we excluded the first year of follow-up or when we restricted the outcome to colorectal cancer to women who did not report a colon polyp at baseline or to women with no history of diabetes mellitus (data not shown). Although the randomized treatments in this study should not be associated with the exposure measures and, hence, should not be a source of confounding, we checked this possibility by including these variables in a set of models and found that estimates were unchanged. We used restricted cubic spline regression(14) to test dietary glycemic load (Fig. 1), overall glycemic index, and carbohydrate intake for nonlinearity of the dose-response curves; none of the results was statistically significant. Risk was greater for distal colorectal cancer (adjusted RR = 2.87, 95% CI = 0.98 to 8.46, comparing extreme quintiles of dietary glycemic load; P_trend = .08) than for proximal colorectal cancer (corresponding RR = 1.75, 95% CI = 0.53 to 5.77; P_trend= .18), although these estimates are based on few cases. We examined the combined effects of dietary glycemic load and body mass index on colorectal cancer risk (adjusted RR = 2.91, 95% CI = 1.26 to 6.75, comparing body mass index ≥25 kg/m² and highest quintile of glycemic load to body mass index <25 kg/m² and lowest quintile of glycemic load;P_interaction = .77) and the combined effects of dietary glycemic load and physical inactivity (adjusted RR = 2.31, 95% CI = 0.85 to 6.23, comparing highest quintile of glycemic load and lowest tertile of physical activity to lowest quintile of glycemic load and highest tertile of physical activity;P_interaction = .28), but we did not have sufficient statistical power to fully examine this question.

Previous studies examining dietary glycemic load and colorectal cancer have yielded mixed results. Three case-control studies (15–17) have reported positive associations, but a large prospective cohort study of Canadian women (18) found no increase in risk (adjusted RR = 1.05, 95% CI = 0.73 to 1.53, comparing extreme quintiles of dietary glycemic load;P_trend = .94). As in our study, however, an increase in risk was reported for cancer of the distal colon.

The dietary and lifestyle factors that we examined are interrelated and difficult to measure. Our findings may be biased by unmeasured confounders or by residual confounding. In this cohort, women with a high dietary glycemic load intake, compared with women with a low intake, had an otherwise beneficial risk profile. Residual confounding by risk factors such as body mass index, physical inactivity, smoking, alcohol use, and nutrient intake would most likely bias risk estimates toward the null, implying that true risk may be greater than our estimates. When the glycemic index value of a particular food was unavailable, we used the reported value for a similar food. This procedure is a source of possible measurement error because glycemic index values can vary greatly, depending largely on how a food is processed and cooked. A dietary questionnaire designed primarily to measure glycemic load could include different or additional food items and groupings that would allow better discrimination between participants and possibly facilitate comparison between studies. A diet with a high glycemic load may increase the risk of colorectal cancer by affecting insulin and insulin-like growth factors or, as suggested by the cross-sectional association between dietary glycemic load and C-reactive protein (10), by exacerbating proinflammatory responses, either locally or systemically. Further work is needed to elucidate these mechanisms. In conclusion, findings from this prospective cohort study suggest that a diet with a high glycemic load may increase the risk of colorectal cancer in women.

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Fig. 1.

Multivariable-adjusted relative risk of colorectal cancer as a function of glycemic load. Data were fit by using a restricted cubic spline Cox proportional hazards model, adjusted for the same covariates as in Table 2. Glycemic load values above the 95^thpercentile were deleted to make the graph more stable; knots were placed at the 5^th, 25^th, 75^th, and 95^th percentiles of the remaining observations. Dotted lines = 95% confidence intervals; solid line = adjusted relative risk of colorectal cancer as a function of glycemic load.

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Table 1.

Baseline distributions of nutrients and colorectal cancer risk factors by quintile of energy-adjusted dietary glycemic load

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Table 2.

Relative risk of colorectal cancer by quintiles of energy-adjusted dietary glycemic load, overall glycemic index, carbohydrate, fiber, nonfiber carbohydrate, sucrose, and fructose

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Footnotes

• Supported by Public Health Service grants CA47988 and T32 CA09142 (National Cancer Institute), HL43851, HL58755 (National Heart, Lung, and Blood Institute), DK02767 (National Institute of Diabetes and Digestive and Kidney Diseases), from the National Institutes of Health, Department of Health and Human Services.
• We acknowledge the crucial contributions of the entire staff of the Women's Health Study (WHS), under the leadership of David Gordon, as well as Susan Burt, Mary Breen, Marilyn Chown, Lisa Fields-Johnson, Georgina Friedenberg, Inge Judge, Jean MacFadyen, Geneva McNair, David Potter, Claire Ridge, and Harriet Samuelson. We are also indebted to the 39,876 dedicated and committed participants of the WHS.

• © Oxford University Press

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