Uncovering the Mechanisms Linking Obesity and Cancer Risk

By Sharon Reynolds
NCI Cancer Bulletin Staff Writer 

Being overweight or obese is associated with an increased risk for many types of cancer, including postmenopausal breast cancer; endometrial cancer; and colorectal, esophageal, gallbladder, kidney, pancreatic, and thyroid cancer.

These risks are not minor. In 2002, the International Agency for Research on Cancer, using European data, estimated that obesity contributed to more than one-third of endometrial and esophageal cancer cases and a quarter of kidney cancer cases. (See the table below.)

Being overweight or obese also raises the risk of dying of cancer. In an often-cited paper published in 2003 in the New England Journal of Medicine, researchers from the American Cancer Society estimated that 14 percent of all cancer deaths in men and 20 percent in women could be blamed on excess weight.

The obvious question is: Why? What biological processes mediate the relationship between excess body fat and increased cancer risk? Researchers are only beginning to tease out the answers, but almost all the factors under study are rooted in the fact that adipose (fat storage) tissue is highly metabolically active.

Once thought to be just a passive storage depot for fuel, adipose tissue is now known to pump out an astounding array of hormones, growth factors, and signaling molecules, all of which can influence the behavior of other cells in the body.

Excess Hormones, Extra Risk

Most, if not all, of the molecules being studied as potential mediators between obesity and cancer are not cancer-causing but cancer-promoting. That is, they do not cause the mutations that turn a normal cell into a cancerous cell, but instead feed the growth and proliferation of malignant cells.

One of the best understood of the pathways that may lead from obesity to cancer involves the hormone estrogen, which fuels a large number of breast and endometrial cancers. In postmenopausal women, the levels of estrogen circulating in the bloodstream normally drop drastically, as the ovaries stop producing the hormone.

But fat tissue also produces estrogen, through a cellular pathway involving the enzyme aromatase, the target of several breast cancer therapies called aromatase inhibitors.

In obese women, “the body fat just becomes an estrogen-producing machine,” explained Dr. Leslie Bernstein, director of the Division of Cancer Etiology at City of Hope Comprehensive Cancer Center, who has studied the relationship between estrogen and cancer risk for years through the California Teachers Study.

This excess estrogen produced by fat can feed cancer cells that express the estrogen receptor. But estrogen alone does not account for all of the extra risk for these cancers in obese postmenopausal women.

Another likely player in many types of cancer, including breast, colorectal, and pancreatic cancer, is insulin, the hormone that triggers cells in the body to take up glucose (sugar) from the bloodstream.

Adipose Tissue

Obesity often goes hand in hand with metabolic syndrome and type II diabetes. In type II diabetes, the body’s cells stop responding to insulin, causing a buildup of glucose in the blood, which in turn stimulates the body to produce even more insulin.

And in some cancers, “insulin acts as a mitogen—it makes cancers grow faster,” said Dr. Michael Pollak, director of the Division of Cancer Prevention at McGill University in Montreal.

Interestingly, a diabetes drug called metformin, which lowers the levels of blood glucose, has shown some anticancer activity. Several studies have suggested that people with diabetes who took metformin had a lower risk of developing cancer ordying from the disease compared with diabetics who did not take metformin.

Currently, several clinical trials, including one in breast cancer, are testing the addition of metformin to standard treatment.

It will be important, stressed Dr. Pollak, to continue basic science research on metformin, given the many unanswered questions about who should take the drug.

“I think this is an extremely promising area of cancer research, but we need to do more basic science research before we’ll be able to design the best clinical trials” to figure out which patients are most likely to benefit from the drug, he said.

For example, other diabetes drugs lower insulin levels but don’t show a similar anticancer effect, suggesting that metformin may affect more than just the insulin pathway.

Also, some patients’ tumors have mutations in the insulin signaling pathway that make the cells act as if extra insulin is always present, even when it’s not. In these cases, reducing insulin would be futile in terms of cancer control. “So maybe those patients shouldn’t be on clinical trials of metformin,” said Dr. Pollak.

Digging Deeper

A myriad of other molecules are being studied to see if they contribute to the relationship between obesity and cancer. Some of these molecules, such as certain interleukins, are part of the body’s natural inflammatory response, which is often chronically overstimulated in people who are obese.

Others are signaling molecules called adipokines (cytokines produced by fat tissue), levels of which can be affected by weight gain.

Within NCI, researchers in the Division of Cancer Epidemiology and Genetics (DCEG) are using several multimarker panels to study molecular pathways that may link obesity to cancer risk in humans. Two panels—one that assesses 15 different estrogens and estrogen metabolites, and one that assesses 79 molecular markers of inflammation—are already being used to examine these mechanisms.

A third, more experimental panel simultaneously tests 400 to 600 small molecules to give a snapshot of metabolism at the time of sample collection, said Dr. Steve Moore, a research fellow in DCEG’s Nutrition Epidemiology Branch.

With these panels, “you can look at how the markers are related to cancer risk, you can look at how obesity is related to cancer risk, and you can look at how obesity is related to cancer risk after adjusting for the marker levels,” explained Dr. Moore. “So by triangulating these three things, you can estimate which molecular mechanisms obesity is most likely to act through.”

Other researchers are examining genetic variants that might also influence how obesity and cancer risk intersect. “A lot of people have looked at biomarkers like insulin, but what are the [full] genetic and molecular pathways being affected by obesity?” asked Dr. Li Li, associate director for Prevention Research at Case Comprehensive Cancer Center, Case Western Reserve University.

His project, supported by the first tranche ofTransdisciplinary Research on Energetics and Cancer (TREC) funding, is looking at how genetic variants found naturally in the population influence whether obesity can promote colon polyp formation.

All of this research may eventually help create targeted cancer prevention measures and treatments for overweight and obese patients, based on a better understanding of the molecular events driving progression.

For now, “I would say what we know now supports the adoption of a healthier lifestyle that promotes weight control,” concluded Dr. Moore.

The NCI Cancer Bulletin is an award-winning biweekly online newsletter designed to provide useful, timely information about cancer research to the cancer community. The newsletter is published approximately 24 times per year by the National Cancer Institute (NCI), with day-to-day operational oversight conducted by federal and contract staff in the NCI Office of Communications and Education. The material is entirely in the public domain and can be repurposed or reproduced without permission. Citation of the source is appreciated.

Do the radio waves that cell phones emit pose a threat to health?

Although research is ongoing, the Food and Drug Administration (FDA) says that available scientific evidence—including World Health Organization (WHO) findings released May 17, 2010—shows no increased health risk due to radiofrequency (RF) energy, a form of electromagnetic radiation that is emitted by cell phones.

FDA also cites a separate National Cancer Institute program finding that, despite the dramatic increase in cell phone use, occurrences of brain cancer did not increase between 1987 and 2005.

FDA shares regulatory responsibilities for cell phones with the Federal Communications Commission.

Although cell phones can be sold without FDA clearance or approval, the agency monitors the effects the phones have on health. FDA has the authority to take action if cell phones are shown to emit RF energy at a level that is hazardous to the user.

Largest Study of Its Kind

The findings released in May 2010 are from Interphone, a series of studies initiated in 2000 and conducted in 13 countries (the United States was not one of them). Interphone was coordinated by WHO’s International Agency for Research on Cancer.

The study reported little or no risk of brain tumors for most long-term users of cell phones.

“There are still questions on the effect of long-term exposure to radio frequency energy that are not fully answered by Interphone,” says Abiy Desta, network leader for science at FDA’s Center for Devices and Radiological Health. “However, this study provides information that will be of great value in assessing the safety of cell phone use.”

WHO reports that Interphone is the largest case-control study of cell phone use and brain tumors to date, and includes the largest numbers of users with at least 10 years of RF energy exposure.

The study focuses on four types of tumors found in the tissues that most absorb RF energy emitted by cell phones: tumors of the brain known as glioma and meningioma, of the acoustic nerve, and of the parotid gland (the largest of the salivary glands). The goal was to determine whether cell phone use increased the risk of developing these tumors.

Recent Findings

The recent Interphone findings, which are being posted online in the June 2010 International Journal of Epidemiology, did not show an increased risk of brain cancer from using cell phones.

Although some of the data suggested an increased risk for people with the heaviest use of cell phones, the study’s authors determined that biases and errors limit the strength of conclusions that can be drawn from it.

According to WHO, cell phone use has become much more prevalent and it is not unusual for young people to use cell phones for an hour or more a day. This increasing use is tempered, however, by the lower emissions, on average, from newer technology phones, and the increasing use of texting and hands-free operations that keep the phone away from the head.

Minimizing RF Exposure

Although evidence shows little or no risk of brain tumors for most long-term users of cell phones, FDA says people who want to reduce their RF exposure can:

• reduce the amount of time spent on the cell phone
• use speaker mode or a headset to place more distance between the head and the cell phone

PHOTO CREDIT: Kprateek88 under a GNU Free Documentation License.

This article appears on FDA’s Consumer Updates page, which features the latest on all FDA-regulated products.

For more information:

• International Agency for Research on Cancer Press Release

• National Cancer Institute Statement on Cell Phone Study

• Health Issues

• Children and Cell Phones

Date Posted: May 17, 2010

Research for a Cure: Local doctors and scientists collaborate to develop new treatments for brain cancer patients

While there has been great progress in the fight against many common cancers, progress againstbrain cancers, some of the deadliest cancers known, has been agonizingly slow.

Over the past 25 years, for example, only three new drug have been approved for the treatment of brain cancers, and survival rates remain essentially the same as they were a century ago.

In this column, Dr. Greg Foltz, a neurosurgeon at the Swedish Neuroscience Institute, writes about the challenges brain cancers pose, about efforts by Seattle researchers to find new treatments, and about this weekend’s Annual Seattle Brain Cancer Walk.

Dr. Greg Foltz

Dr. Foltz writes:

While a small group of scientists and doctors are working hard toward a cure, the lack of funding and awareness for the disease, coupled with the limited survival of patients, has left brain cancer as an “orphaned” disease.

Research for a Cure: Local doctors and scientists collaborate to develop new treatments for brain cancer patients

By Dr. Greg Foltz

Brain cancer is the most malignant form of cancer known to humankind. Despite significant advances in the research and treatment of more common cancers, brain cancer survival rates, measured in terms of median survival, have essentially remained unchanged over the past 100 years.

Patients with Glioblastoma Multiforme (GBM), the most common and aggressive type of primary brain cancer, face a particularly bleak future.

With survival measured in just one to two years, the majority of these patients will tell you that their lives become focused on a simple equation of time and hope.

With each month they continue to live, there is renewed hope for a medical breakthrough, an effective treatment or perhaps even a potential cure.

Unfortunately, the odds are against them as funding for brain cancer research is extremely limited. Only three new treatments have been approved for brain cancer in the past 25 years – one of which is the recently FDA approved Avastin.

None of these treatments extend median survival by more than a few months.

While a small group of scientists and doctors are working hard toward a cure, the lack of funding and awareness for the disease, coupled with the limited survival of patients, has left brain cancer as an “orphaned” disease.

For the 1200 patients in the Pacific Northwest newly diagnosed each year with brain cancer, this reality is especially devastating.

They have grown accustomed to reading about the latest medical and scientific breakthroughs from our world-class research institutions.

Seattle is now established as a global leader in healthcare. Yet, until recently, few clinical trials or advanced treatment options have been available for brain cancer. These patients expect more. They deserve more.

Recent developments and partnerships that have sprouted in the Pacific Northwest’s biotechnology community are providing some hope for new advancements.

Last year, the Swedish Neuroscience Institute opened the Center for Advanced Brain Tumor Treatment (CABTT) as a regional hub for community-based brain tumor clinics.

The opening of CABTT put in motion a network of doctors, researchers and scientists working toward a common goal – to discover more effective treatments for brain cancer.

Other local institutions and research groups such as the Allen Institute for Brain Science, the Institute of Systems Biology, Accium Biosciences and Providence Regional Medical Center Everett are working closely with CABTT in innovative ways such as sharing tissue samples, research findings and methods.

This collaborative approach is leading to new scientific advances with potential impact on patient care in the near term.

Doctors can now use genomic profiling (the individualized study of a patient’s tumor to determine which genes are being expressed) to predict why some patients respond to standard treatments while others do not.

This could potentially allow physicians to “customize” their patients’ treatments, bringing more advanced treatments or clinical trials into play sooner.

With continued research and increased clinical trials, transforming brain cancer from a rapidly fatal disease to one with a meaningful possibility for long term survival is within our grasp.

The effort to raise awareness and support for brain cancer research has continued to gain momentum locally as the community gears up for the 2^nd Annual Seattle Brain Cancer Walk on May 30th.

Initially started by a volunteer who lost a close friend to brain cancer, the Seattle Brain Cancer Walk is an annual event that provides an opportunity for our community to take a stand against this deadly disease.

Last year 550 participants raised $120,000 for brain cancer research and the hope is that this year, the Walk will double in size and fundraising. To register or donate to this years event, please visit www.braincancerwalk.org.

While a good start, these efforts represent only an initial step toward our common goal. For our patients, hope can be something that is sometimes difficult to grasp.

But when they see increased community activism and awareness lead to funding for new research, hope does not seem quite so far out of reach.

Medical research and clinical trials are essential in the fight against brain cancer and it is only through increased awareness and doctor/scientist collaboration that treatment advances, and someday a cure, is possible.

About the Author

Greg Foltz, M.D., is a neurosurgeon at the Swedish Neuroscience Institute in Seattle, Wash., surgical director of the Center for Advanced Brain Tumor Treatment and founder of the Pacific Northwest Brain Tumor Alliance.

PHOTO CREDIT:

Photograph of Dr. Foltz courtesy of Swedish Medical Center

PET scans courtesy of the National Cancer Institute.

To learn more:

• Read our article on the new Swedish Neuroscience Institute.
• Visit the Swedish Neuroscience Institute.
• Visit the Center for Advanced Brain Tumor Treatment.
• Visit the Pacific Northwest Brain Tumor Alliance.
• Visit the Brain Cancer Walk Web site.
• Visit the National Library of Medicine’s MedlinePlus page on brain cancer.

Over the past 25 years, for example, only three new drug have been approved for the treatment of brain cancers, and survival rates remain essentially the same as they were a century ago.

In this column, Dr. Greg Foltz, a neurosurgeon at the Swedish Neuroscience Institute, writes about the challenges brain cancers pose, about efforts by Seattle researchers to find new treatments, and about this weekend’s Annual Seattle Brain Cancer Walk.

Dr. Greg Foltz

Dr. Foltz writes:

While a small group of scientists and doctors are working hard toward a cure, the lack of funding and awareness for the disease, coupled with the limited survival of patients, has left brain cancer as an “orphaned” disease.

Research for a Cure: Local doctors and scientists collaborate to develop new treatments for brain cancer patients

By Dr. Greg Foltz

Brain cancer is the most malignant form of cancer known to humankind. Despite significant advances in the research and treatment of more common cancers, brain cancer survival rates, measured in terms of median survival, have essentially remained unchanged over the past 100 years.

Patients with Glioblastoma Multiforme (GBM), the most common and aggressive type of primary brain cancer, face a particularly bleak future.

With survival measured in just one to two years, the majority of these patients will tell you that their lives become focused on a simple equation of time and hope.

With each month they continue to live, there is renewed hope for a medical breakthrough, an effective treatment or perhaps even a potential cure.

Unfortunately, the odds are against them as funding for brain cancer research is extremely limited. Only three new treatments have been approved for brain cancer in the past 25 years – one of which is the recently FDA approved Avastin.

None of these treatments extend median survival by more than a few months.

While a small group of scientists and doctors are working hard toward a cure, the lack of funding and awareness for the disease, coupled with the limited survival of patients, has left brain cancer as an “orphaned” disease.

For the 1200 patients in the Pacific Northwest newly diagnosed each year with brain cancer, this reality is especially devastating.

They have grown accustomed to reading about the latest medical and scientific breakthroughs from our world-class research institutions.

Seattle is now established as a global leader in healthcare. Yet, until recently, few clinical trials or advanced treatment options have been available for brain cancer. These patients expect more. They deserve more.

Recent developments and partnerships that have sprouted in the Pacific Northwest’s biotechnology community are providing some hope for new advancements.

Last year, the Swedish Neuroscience Institute opened the Center for Advanced Brain Tumor Treatment (CABTT) as a regional hub for community-based brain tumor clinics.

The opening of CABTT put in motion a network of doctors, researchers and scientists working toward a common goal – to discover more effective treatments for brain cancer.

Other local institutions and research groups such as the Allen Institute for Brain Science, the Institute of Systems Biology, Accium Biosciences and Providence Regional Medical Center Everett are working closely with CABTT in innovative ways such as sharing tissue samples, research findings and methods.

This collaborative approach is leading to new scientific advances with potential impact on patient care in the near term.

Doctors can now use genomic profiling (the individualized study of a patient’s tumor to determine which genes are being expressed) to predict why some patients respond to standard treatments while others do not.

This could potentially allow physicians to “customize” their patients’ treatments, bringing more advanced treatments or clinical trials into play sooner.

With continued research and increased clinical trials, transforming brain cancer from a rapidly fatal disease to one with a meaningful possibility for long term survival is within our grasp.

The effort to raise awareness and support for brain cancer research has continued to gain momentum locally as the community gears up for the 2^nd Annual Seattle Brain Cancer Walk on May 30th.

Initially started by a volunteer who lost a close friend to brain cancer, the Seattle Brain Cancer Walk is an annual event that provides an opportunity for our community to take a stand against this deadly disease.

Last year 550 participants raised $120,000 for brain cancer research and the hope is that this year, the Walk will double in size and fundraising. To register or donate to this years event, please visit www.braincancerwalk.org.

While a good start, these efforts represent only an initial step toward our common goal. For our patients, hope can be something that is sometimes difficult to grasp. 

But when they see increased community activism and awareness lead to funding for new research, hope does not seem quite so far out of reach.

Medical research and clinical trials are essential in the fight against brain cancer and it is only through increased awareness and doctor/scientist collaboration that treatment advances, and someday a cure, is possible.

About the Author

Greg Foltz, M.D., is a neurosurgeon at the Swedish Neuroscience Institute in Seattle, Wash., surgical director of the Center for Advanced Brain Tumor Treatment and founder of the Pacific Northwest Brain Tumor Alliance.

PHOTO CREDIT:

Photograph of Dr. Foltz courtesy of Swedish Medical Center

PET scans courtesy of the National Cancer Institute.

To learn more:

• Read our article on the new Swedish Neuroscience Institute.
• Visit the Swedish Neuroscience Institute.
• Visit the Center for Advanced Brain Tumor Treatment.
• Visit the Pacific Northwest Brain Tumor Alliance.
• Visit the Brain Cancer Walk Web site.
• Visit the National Library of Medicine’s MedlinePlus page on brain cancer.