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Link Found Between Inflammation and Cancer

Link Found Between Inflammation and Cancer

A group of researchers at the Ohio State University Comprehensive Cancer Center (OSUCCC) has discovered that a certain type of RNA, microRNA-155, may provide the link between inflammation and cancer. The article describing the study was published online ahead of print in the Proceedings of the National Academy of Science in March (doi: 10.1073/pnas.1101795108).


Carlo M. Croce, MD
Ohio State University
Comprehensive Cancer Center

Many studies have linked chronic inflammation with cancer (ie, inflammatory bowel disease and colorectal cancer), and some estimate that as many as 25% of cancer cases are caused by chronic infection. This study, led by Carlo Croce, showed that inflammation stimulates a rise in levels of micro-RNA-155 (miR-155), and that this, in turn, causes a drop in levels of the proteins involved in DNA repair and results in a higher rate of the spontaneous gene mutations that can lead to cancer.

First author and post-doctoral researcher Esmerina Tili said, “Our study shows that miR-155 is upregulated by inflammatory stimuli and that overexpression of miR-155 increases the spontaneous mutation rate, which can contribute to tumorigenesis. People have suspected for some time that inflammation plays an important role in cancer, and our study presents a molecular mechanism that explains how it happens.”

MicroRNAs are involved in many important cell processes and act by suppressing the amounts of certain proteins; each type of microRNA can affect many different proteins. MiR-155 is known to influence blood-cell maturation, immune responses, and autoimmune disorders, and high levels of the molecule have been directly linked to the development of leukemias as well as breast, lung, and gastric cancers.

In the study, Tili and her colleagues examined the effects of inflammation-promoting substances such as tumor necrosis factor or lipopolysaccharide on miR-155 expression and on the frequency of spontaneous mutations in several breast-cancer cell lines. When the researchers exposed breast-cancer cells to the two inflammatory factors, the levels of miR-155 rose to abnormally high levels, and the mutation rate increased two- to three-fold. To understand why, the investigators focused on WEE1, a kinase that stops the process of cell division to allow damaged DNA to be repaired.

The investigators learned that miR-155 also targets WEE1 and showed that high levels of miR-155 lead to low levels of WEE1. They reasoned that low levels of WEE1 allowed cell division to continue even when DNA damage is present, and that this leads to an increased number of mutations.

“Our study suggests that miR-155, which is associated with inflammation, increases the mutation rate and might be a key player in inflammation-induced cancers generally,” said principal investigator Dr. Carlo M. Croce, professor and chair of molecular virology, immunology and medical genetics, and director of the Human Cancer Genetics program at the OSUCCC – James Cancer Hospital. “This could make miR-155 an important therapeutic target.”

Aggressive Prostate Cancer: High Blood Levels of Omega-3s Doubled the Risk, but High Levels of Trans–Fatty Acids Cut Risk in Half
An analysis of data from 3,400 men in the large nationwide Prostate Cancer Prevention Trial indicates that, contrary to what might be expected, men with the highest blood percentages of DHA (docosahexaenoic acid), an omega-3 fatty acid commonly found in fatty fish, had 2.5 times the risk of developing aggressive, high-grade prostate cancer, compared with men who had the lowest levels.

In another surprising finding, the investigators discovered that men with the highest blood ratios of trans–fatty acids, commonly found in processed foods containing partially hydrogenated vegetable oils, actually had a 50% reduction in the risk of aggressive prostate cancer.

Neither omega 3s nor trans–fatty acids were associated with a risk of low-grade prostate cancer, and omega-6 fatty acids, found in most vegetable oils and associated with inflammation and heart disease, were not associated with prostate cancer risk, the researchers reported.

The study authors are from Fred Hutchinson Cancer Research Center (FHCRC), The University of Texas Health Science Center at San Antonio, and the National Cancer Institute, which funded the research. The findings were published online on April 25 in the American Journal of Epidemiology.

Given the association between chronic inflammation and increased cancer risk, together with the cardiac benefits and anti-inflammatory effects of omega-3 fatty acids and the possible inflammation-promoting effects of omega-6 fats and trans-fats, the findings seem to be counterintuitive. “Specifically, we thought that omega-3 fatty acids would reduce and omega-6 and trans–fatty acids would increase prostate cancer risk,” commented lead author Theodore M. Brasky, PhD, a postdoctoral research fellow in the Cancer Prevention Program at FHCRC.


NovoTTF device

While the mechanisms by which omega-3s might increase the risk of high-grade prostate cancer are unknown, Dr. Brasky emphasized that omega-3 fats have effects on other biologic processes, some of which may have an impact on the development of certain prostate cancers, and much more research is needed before definitive conclusions can be drawn from the study findings. It is also premature to recommend that men (the majority of whom in the study got their omega 3s from eating fish, not from supplements) change their diets in any way. “Overall, the beneficial effects of eating fish to prevent heart disease outweigh any harm related to prostate cancer risk,” Dr. Brasky said. “What this study shows is the complexity of nutrition and its impact on disease risk, and that we should study such associations rigorously rather than make assumptions.”

First-in-Class Antimitotic Device Approved for Glioblastoma cancernetwork
The US Food and Drug Administration (FDA) has approved a portable noninvasive device, worn on the head, to treat adults whose glioblastoma multiforme (GBM) recurs or progresses following chemotherapy and radiation therapy.

A video from the manufacturer of the NovoTTF device demonstrating the treatment mechanism of action is available at CancerNetwork.com.

GBM, the most common primary brain cancer, is often resistant to surgery, radiation, and chemotherapy. In the United States, about 10,000 people are diagnosed with GBM annually. Median overall survival time from diagnosis is 15 months with optimal therapy, and median survival from the time of tumor recurrence is about 3 to 4 months without additional treatment.

The device, called the NovoTTF-100A System (Novocure, Portsmouth, NH, a subsidiary of Jersey Isle–based Standen Ltd.), weighs about 6 pounds and consists of an electric field generator, electrodes, and accessories. It can be powered with batteries for use outside the home, or plugged into an electrical outlet. Designed to be worn by the patient for at least 4 weeks continuously and until clinical disease progression, it is initially fitted by a healthcare professional. It is easily controlled by the patient and can be carried in an over-the-shoulder carrying case or backpack. The electrodes can be replaced with help from a caregiver.

Four electrically insulated disposable electrodes placed on the surface of the patient’s shaved scalp deliver low-intensity, intermediate-frequency alternating electric fields directly to the tumor site. These “tumor treatment fields,” or TTFs, exert physical forces on electrically charged cellular components of the GBM tumor, preventing the normal mitotic process and causing cancer cell apoptosis prior to division.

Specifically, the TTFs interfere with proper formation of the mitotic spindle during anaphase and cause intracellular dislocation of macromolecules and organelles during late telophase. The unique shape and electrical characteristics of dividing tumor cells make them susceptible to damage when exposed to TTFs. Most normal adult brain cells proliferate very slowly and are believed to be affected very little by TTFs. Also, the antimitotic effect of the 200 kHz TTF frequency has been shown to specifically inhibit replication of GBM tumor cells, while not affecting replication of other cell types, such as neurons.

FDA approval of the NovoTTF-100A System was based on the results of a single international clinical study in 237 patients whose GBM had recurred or progressed following traditional therapy. More than half of the patients were at their second or subsequent recurrence, and baseline tumors were large (> 5 cm in diameter).

Survival time in patients treated with the NovoTTF alone was comparable to that of patients treated with the physician’s choice of the best chemotherapy. Progression-free survival at 6 months was 21% in the NovoTTF group, compared with 15% in patients who received chemotherapy. Patients treated with the NovoTTF had a 14% tumor response rate, compared with a tumor response rate of 10% in the chemotherapy-treated patients. Three complete radiographic responses were observed in the NovoTTF group, but no responses were observed in the chemotherapy-treated group.

Patients in the NovoTTF group reported better quality of life scores and fewer side effects during the trial, compared with chemotherapy-treated patients, specifically in the domains of vomiting, nausea, pain, diarrhea, constipation, and cognitive and emotional functioning. The most commonly reported side effect from NovoTTF treatment was a mild-to-moderate rash beneath the electrodes.

Contraindications to use of the NovoTTF-100A System include an implanted medical device, a skull defect, or a known sensitivity to conductive hydrogels (eg, those used with electrocardiograms). The NovoTTF is not intended to be used in combination with other cancer treatment, and it should only be used in patients who do not respond to other treatments for GBM.

The NovoTTF-100A System is approved for marketing in both Europe and the United States, and there are plans to develop this therapy for use in “a range of other solid tumor cancers,” said Novocure’s Executive Chairman, William F. Doyle.

Novocure is sponsoring an ongoing pivotal trial of the NovoTTF device for patients with newly diagnosed GBM under an approved investigational device exemption application. Additional information is available at www.novocuretrial.com.

 
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