Cancer

Posted on Cancer, Diabetes

The paired perils of breast cancer and diabetes

Breast Cancer Cell


A breast cancer cell is captured in the process of division, with tubulin (a structural protein) in red; mitochondria in green; and chromosomes in blue. CREDIT Wei Qian\National Cancer Institute

Breast cancer and type 2 diabetes would seem to be distinctly different diseases, with commonality only in their commonality. Breast cancer is the second most diagnosed malignancy after some types of skin cancer; approximately 1 in eight U.S. women will develop invasive breast cancer over the course of their lifetime. More than 10 percent of the U.S. population has diabetes, with an estimated 2 in 5 Americans expected to develop the chronic disease during their lifetime. 

However, past research has uncovered associations between the two diseases. Women with diabetes, for example, have a 20 to 27 percent increased risk of developing breast cancer. Insulin resistance — a key characteristic of diabetes — has been associated with breast cancer incidence and poor survival. Population studies suggest diabetes risk begins to increase two years after a breast cancer diagnosis, and by 10 years post-diagnosis, the risk is 20 percent higher in breast cancer survivors than in age-matched women without breast cancer.  

But these epidemiological linkages are not clear-cut or definitive, and some studies have found no associations at all. In a new paper, publishing May 30, 2022 in Nature Cell Biology, a research team led by scientists at University of California San Diego School of Medicine describe a possible biological mechanism connecting the two diseases, in which breast cancer suppresses the production of insulin, resulting in diabetes, and the impairment of blood sugar control promotes tumor growth.

“No disease is an island because no cell lives alone,” said corresponding study author Shizhen Emily Wang, PhD, professor of pathology at UC San Diego School of Medicine. “In this study, we describe how breast cancer cells impair the function of pancreatic islets to make them produce less insulin than needed, leading to higher blood glucose levels in breast cancer patients compared to females without cancer.” 

Wang said the study was inspired by early work and guidance from Jerrold Olefsky, MD, professor of medicine and associate dean for scientific affairs in the Division of Endocrinology and Metabolism at UC San Diego School of Medicine. Olefsky is co-senior author of the study with Wang.  

The culprit, according to Wang and Olefsky, are extracellular vesicles (EV) — hollow spheres secreted or shed by cells that transport DNA, RNA, proteins, fats and other materials between cells, a sort of cargo communication system. 

In this case, the cancer cells were found to be secreting microRNA-122 into the vesicles. Wang said when vesicles reach the pancreas, they can enter the islet cells responsible for insulin production, dispense their miR-122 cargo and damage the islets’ critical function in maintaining a normal blood glucose level. 

“Cancer cells have a sweet tooth,” Wang said. “They use more glucose than healthy cells in order to fuel tumor growth, and this has been the basis for PET scans in cancer detection. By increasing blood glucose that can be easily used by cancer cells, breast tumors make their own favorite food and, meanwhile, deprive this essential nutrient from normal cells.”

The research was conducted using mouse models, which found that slow-releasing insulin pellets or a glucose-lowering drug known as an SGLT2 inhibitor restored normal control of glucose in the presence of a breast tumor, which in turn suppressed the tumor’s growth.

“These findings support a greater need for diabetes screening and prevention among breast cancer patients and survivors,” said Wang, noting that an inhibitor of miR-122, developed by Regulus Therapeutics Inc. in San Diego, is currently in clinical trial as a potential treatment for chronic hepatitis C. It has been found to be effective in restoring normal insulin production and suppressing tumor growth in mouse models of breast cancer.  

“These miR-122 inhibitors, which happen to be the first miRNA-based drugs to enter clinical trials, might have a new use in breast cancer therapy,” Wang said.

Posted on Cancer, Cardiovascular disease, Pain Management

New research may explain the unexpected effects of common painkillers like cancer or heart disease

Do You Know The Warning Signs of Heart Disease? - YouTube

 Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin are widely used to treat pain and inflammation. But even at similar doses, different NSAIDs can have unexpected and unexplained effects on many diseases, including heart disease and cancer.

Now, a new Yale-led study has uncovered a previously unknown process by which some NSAIDs affect the body. The finding may explain why similar NSAIDs produce a range of clinical outcomes and could inform how the drugs are used in the future.

The study was published May 23 in the journal Immunity.

Until now, the anti-inflammatory effects of NSAIDs were believed to arise solely through the inhibition of certain enzymes. But this mechanism does not account for many clinical outcomes that vary across the family of drugs. For example, some NSAIDs prevent heart disease while others cause it, some NSAIDs have been linked to decreased incidence of colorectal cancer, and various NSAIDs can have a wide range of effects on asthma.

Now, using cell cultures and mice, Yale researchers have uncovered a distinct mechanism by which a subset of NSAIDs reduce inflammation. And that mechanism may help explain some of these curious effects.

The research showed that only some NSAIDs — including indomethacin, which is used to treat arthritis and gout, and ibuprofen — also activate a protein called nuclear factor erythroid 2-related factor 2, or NRF2, which, among its many actions, triggers anti-inflammatory processes in the body.

“It’s interesting and exciting that NSAIDs have a different mode of action than what was known previously,” said Anna Eisenstein, an instructor at the Yale School of Medicine and lead author of the study. “And because people use NSAIDs so frequently, it’s important we know what they’re doing in the body.”

The research team can’t say for sure that NSAIDs’ unexpected effects are due to NRF2 — that will require more research. “But I think these findings are suggestive of that,” Eisenstein said.

Eisenstein is now looking into some of the drugs’ dermatological effects — causing rashes, exacerbating hives, and worsening allergies — and whether they are mediated by NRF2.

This discovery still needs to be confirmed in humans, the researchers note. But if it is, the findings could have impacts on how inflammation is treated and how NSAIDs are used.

For instance, several clinical trials are evaluating whether NRF2-activating drugs are effective in treating inflammatory diseases like Alzheimer’s disease, asthma, and various cancers; this research could inform the potential and limitations of those drugs. Additionally, NSAIDs might be more effectively prescribed going forward, with NRF2-activating NSAIDs and non-NRF2-activating NSAIDs applied to the diseases they’re most likely to treat.

The findings may also point to entirely new applications for NSAIDs, said Eisenstein.

NRF2 controls a large number of genes involved in a wide range of processes, including metabolism, immune response, and inflammation. And the protein has been implicated in aging, longevity, and cellular stress reduction.

Said Eisenstein, “That NRF2 does so much suggests that NSAIDs might have other effects, whether beneficial or adverse, that we haven’t yet looked for.”

Posted on Cancer, Diabetes

Computer drug simulations offer promising diabetes and cancer treatment

Metformin highly effective in targeting diabetes and some cancers but potentially dangerous with others
Metformin highly effective in targeting diabetes and some cancers but potentially dangerous with others


Using computer drug simulations, researchers have found that doctors need to be wary of prescribing a particular treatment for all types of cancer and patients.

The drug, called metformin, has traditionally been prescribed for diabetes but has been used in clinical settings as a cancer treatment in recent years.

The researchers say while metformin shows great promise, it also has negative consequences for some types of cancers.

“Metformin is a wonder drug, and we are just beginning to understand all its possible benefits,” said Mehrshad Sadria, a PhD candidate in applied mathematics at the University of Waterloo. “Doctors need to examine the value of the drug on a case-by-case basis, because for some cancers and some patient profiles, it may actually have the opposite of the intended effect by protecting tumour cells against stress.”

The computer-simulated treatments use models that replicate both the drug and the cancerous cells in a virtual environment. Such models can give clinical trials in humans a considerable head-start and can provide insights to medical practitioners that would take much longer to be discovered in the field.

“In clinical settings, drugs can sometimes be prescribed in a trial and error manner,” said Anita Layton, professor of applied mathematics and Canada 150 Research Chair in mathematical biology and medicine at Waterloo. “Our mathematical models help accelerate clinical trials and remove some of the guesswork. What we see with this drug is that it can do a lot of good but needs more study.”

The researchers say their work shows the importance of precision medicine when considering the use of metformin for cancer and other diseases. Precision medicine is an approach that assumes each patient requires individualized medical assessment and treatment. 

“Diseases and treatments are complicated,” Sadria said. “Everything about the patient matters, and even small differences can have a big impact on the effect of a drug, such as age, gender, genetic and epigenetic profiles. All these things are important and can affect a patient’s drug outcome. In addition, no one drug works for everyone, so doctors need to take a close look at each patient when considering treatments like metformin.” 

Posted on Cancer, Multiple Sclerosis

Does MS affect survival rate after colorectal cancer diagnosis?

Cancer and diet
Cancer and diet

People with multiple sclerosis (MS) who are diagnosed with colorectal cancer may be at a higher risk of dying from cancer or other causes over the next six months to one year than people with colorectal cancer who do not have MS, according to a study published in the September 15, 2021, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“These results warrant further investigation to determine what factors may lead to shorter survival times,” said study author Ruth Ann Marrie, MD, PhD, of the University of Manitoba in Winnipeg, Canada, and a member of the American Academy of Neurology. “Are people with MS less likely to receive cancer treatment? Or are they less able to tolerate the effects of chemotherapy? Are factors specific to MS involved? How accommodating is the cancer care system for people with disabilities? These are among the many questions that need to be investigated.”

For the study, researchers looked at health records for 338 people with MS and colorectal cancer who lived in Ontario and Manitoba, Canada. Each person was matched with four people who had colorectal cancer but did not have MS who were the same age and sex, and had the same year of cancer diagnosis, or 1,352 people. The participants were an average age of 65 when they were diagnosed with cancer.

The study found that people with MS were 45% more likely to die of any cause at six months after the cancer diagnosis than people without MS and 34% more likely to die of any cause at one year after diagnosis. After that point, the risk of death was the same for the two groups. People with MS were more likely to die of cancer than people without MS only at the six-month point after diagnosis, when their risk was 29% higher. The researchers adjusted for other factors that could affect risk of death, such as age, socioeconomic status and having other conditions like heart disease or diabetes.

Over five years, the fatality rate in Ontario was 16.4 deaths per 100 person-years for people with MS who died from any cause compared to 11.5 deaths for people without MS. Person-years take into account the number of people in a study as well as the amount of time spent in the study. In Manitoba, those numbers were 19.8 deaths per 100 person-years for people with MS and 15.4 deaths for people without MS.

Looking at deaths due to cancer, the fatality rate was 12.7 deaths per 100 person-years for people with MS in Ontario, compared to 9.9 deaths for people without MS. In Manitoba, those numbers were 13.6 for people with MS and 13.0 for people without MS.

“Understanding more about the factors involved in treating cancer in people with MS and their outcomes will be helpful for people with MS and their doctors as they balance the benefits of cancer treatment with the potential adverse effects and consider life expectancy and quality of life,” Marrie said.

A limitation of the study was that researchers may not have accounted for all other conditions people may have had in addition to MS and colorectal cancer.

Posted on Cancer, Diabetes, Parkinson's Disease

Parkinson’s, cancer, type 2 diabetes share a key element that drives disease

Parkin protein (green signal) is in a different part of the cell than the mitochondria (red signal) at time 0 (left image) but then co-localizes with the mitochondria after 60 minutes (right image). CREDIT Salk Institute

When cells are stressed, chemical alarms go off, setting in motion a flurry of activity that protects the cell’s most important players. During the rush, a protein called Parkin hurries to protect the mitochondria, the power stations that generate energy for the cell. Now Salk researchers have discovered a direct link between a master sensor of cell stress and Parkin itself. The same pathway is also tied to type 2 diabetes and cancer, which could open a new avenue for treating all three diseases.

“Our findings represent the earliest step in Parkin’s alarm response that anyone’s ever found by a long shot. All the other known biochemical events happen at one hour; we’ve now found something that happens within five minutes,” says Professor Reuben Shaw, director of the NCI-designated Salk Cancer Center and senior author of the new work, detailed in Science Advances on April 7, 2021. “Decoding this major step in the way cells dispose of defective mitochondria has implications for a number of diseases.”

Parkin’s job is to clear away mitochondria that have been damaged by cellular stress so that new ones can take their place, a process called mitophagy. However, Parkin is mutated in familial Parkinson’s disease, making the protein unable to clear away damaged mitochondria. While scientists have known for some time that Parkin somehow senses mitochondrial stress and initiates the process of mitophagy, no one understood exactly how Parkin was first sensing problems with the mitochondria–Parkin somehow knew to migrate to the mitochondria after mitochondrial damage, but there was no known signal to Parkin until after it arrived there.

Shaw’s lab, which is well known for their work in the fields of metabolism and cancer, spent years intensely researching how the cell regulates a more general process of cellular cleaning and recycling called autophagy. About ten years ago, they discovered that an enzyme called AMPK, which is highly sensitive to cellular stress of many kinds, including mitochondrial damage, controls autophagy by activating an enzyme called ULK1.

Following that discovery, Shaw and graduate student Portia Lombardo began searching for autophagy-related proteins directly activated by ULK1. They screened about 50 different proteins, expecting about 10 percent to fit. They were shocked when Parkin topped the list. Biochemical pathways are usually very convoluted, involving up to 50 participants, each activating the next. Finding that a process as important as mitophagy is initiated by only three participants–first AMPK, then ULK1, then Parkin–was so surprising that Shaw could scarcely believe it.

To confirm the findings were correct, the team used mass spectrometry to reveal precisely where ULK1 was attaching a phosphate group to Parkin. They found that it landed in a new region other researchers had recently found to be critical for Parkin activation but hadn’t known why. A postdoctoral fellow in Shaw’s lab, Chien-Min Hung, then did precise biochemical studies to prove each aspect of the timeline and delineated which proteins were doing what, and where. Shaw’s research now begins to explain this key first step in Parkin activation, which Shaw hypothesizes may serve as a “heads-up” signal from AMPK down the chain of command through ULK1 to Parkin to go check out the mitochondria after a first wave of incoming damage, and, if necessary, trigger destruction of those mitochondria that are too gravely damaged to regain function.

The findings have wide-ranging implications. AMPK, the central sensor of the cell’s metabolism, is itself activated by a tumor suppressor protein called LKB1 that is involved in a number of cancers, as established by Shaw in prior work, and it is activated by a type 2 diabetes drug called metformin. Meanwhile, numerous studies show that diabetes patients taking metformin exhibit lower risks of both cancer and aging comorbidities. Indeed, metformin is currently being pursued as one of the first ever “anti-aging” therapeutics in clinical trials.

“The big takeaway for me is that metabolism and changes in the health of your mitochondria are critical in cancer, they’re critical in diabetes, and they’re critical in neurodegenerative diseases,” says Shaw, who holds the William R. Brody Chair. “Our finding says that a diabetes drug that activates AMPK, which we previously showed can suppress cancer, may also help restore function in patients with neurodegenerative disease. That’s because the general mechanisms that underpin the health of the cells in our bodies are way more integrated than anyone could have ever imagined.”