Removal of a tiny RNA molecule can inhibit cancer growth, researchers discover

ScienceDaily (June 7, 2011) — Research from the University of Louisville report in the Proceedings of the National Academy of Sciences indicates the removal of a tiny RNA molecule in mice suppresses carcinogenic tumor formation.

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Yong Li, Ph.D., associate professor of biochemistry and molecular biology, and his research team led by postdoctoral fellows Xiaodong Ma and Munish Kumar found that the removal of a non-coding RNA molecule known as MicroRNA 21 suppressed the formation of skin tumors in mice. This molecule -- abbreviated as miR-21 -- was targeted for study because of its presence in human cancer formation, Li said.

"In virtually all types of cancer, miR-21 is found to be present at elevated levels," Li said. "We believe it is essential to the growth of cancers."

Two groups of mice -- 18 with miR-21 removed and a control group of 23 with miR-21 intact -- were studied after skin tumors known as papillomas were induced with a heavy dose of a carcinogen. The group without miR-21 had just 1.5 tumors per mouse after 30 weeks as compared to 2.5 tumors per mouse in the control group. Moreover, one of the mice without miR-21 was tumor-free at the end of the study.

"Our work leads us to believe that miR-21 ablation (removal) increases the body's own tumor suppressing ability to hold back tumors," Li said. "The cancer research community is increasingly aware the importance of the surroundings around tumor cells. Our ongoing study of miR-21 involves looking at how this molecule contributes to tumor environment."

The study's funding indicates the serendipitous aspect of bench science, Li said, because it was not funded by a cancer research agency or organization but in part by the American Heart Association and the UofL Diabetes and Obesity Center.

"We began our work in 2008 with the hypothesis that miR-21 plays a role in cardiovascular disease and diabetes," he said. "However, our research and reports from other groups suggest it does not, although we are continuing our work in these areas.

"Funding basic research is important because you never know where science will take you. It is clear from our research that miR-21 is taking us a bit closer to understanding tumor formation."

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Plasticity of hormonal response permits rapid gene expression reprogramming: Gene expression reprogramming may allow cancer cell growth as well as normal differentiation

Rapid growth may be appropriate trigger for treatment in patients with renal masses

ScienceDaily (May 15, 2011) — With an increase in abdominal imaging over the past decade, there has been an increase in the detection of incidental kidney cancer, which has led to concerns that we may be over-treating indolent disease. As part of this effort, clinicians have started to investigate the effectiveness of active surveillance (AS), or close observation as opposed to immediate surgery, for select patients with small renal masses (SRMs).

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Fox Chase Cancer Center researchers have announced the results of its systematic review and pooled analysis, which for the first time combined several institutions' experience with active surveillance of small renal masses. Their goal was to identify trends in radiographic tumor growth rates and progression to either treatment or metastasis, and found that in select patients, active surveillance may be a viable option when surgery is risky due to poor health or advanced age.

Marc Smaldone, M.D., urologic oncology fellow at Fox Chase and lead author on the study, will present the results at the AUA 2011 Annual Meeting on Tuesday, May 17, 2011.

"Kidney cancer is most often a surgically treated disease, so studies such as this one, which help to confirm that active surveillance with curative intent can be an effective strategy for certain patients, are crucial," says Smaldone. "Surgery has substantial consequences for many patients with competing risks such as heart or lung disease. The ability to offer a management strategy that avoids the risks of potentially unnecessary surgery is an attractive concept in contemporary cancer treatment."

To further investigate the risks of cancer progression in patients undergoing active surveillance, Fox Chase researchers combined all the available individual data published by institutions examining the observation of small renal masses. The team identified and pooled a total of 18 institutional series, of which Fox Chase's experience represented the largest published series. The researchers then examined the pooled experience for trends in radiographic growth rates, tumor size at presentation, and progression to treatment or metastasis.

They found that, of the observed 936 SRMs in 880 patients, only a very small proportion -- 2.1% (18 patients) -- progressed to metastasis. Pooled analysis of progressors and non-progressors revealed significant trends including increased age, increased tumor size at presentation, and increased growth rates in the progression group. These metrics can be used to help determine if a patient should stop surveillance and undergo surgical intervention for his or her SRM. However, Fox Chase researchers learned that growth kinetics alone cannot predict a tumor's natural growth history. Therefore, active surveillance should not be considered an equivalent alternative to definitive surgical therapy, but it can be used as an initial short-term option for select patients who are poor surgical candidates.

"There is a perception that all cancers, once detected, should be treated immediately because they are all equally lethal, but what we've seen in this study is that small, asymptomatic kidney cancers can be managed through active surveillance," says Robert G. Uzzo, M.D., F.A.C.S., chairman of the department of surgery at Fox Chase and member of the AUA Guidelines Council. "As a medical community, we need to recognize this shift and begin to risk stratify patients and counsel them based on criteria other than the presence of small renal masses on scans."

While more research is necessary, this study suggests that growth kinetics may be the best measurement currently available for determining which patients should undergo immediate intervention and which should not. As a supplement to radiographic data, future biomarker discovery in conjunction with percutaneous -- or renal biopsy -- might ultimately influence management decisions on an individual patient basis. Based on these findings patients should seek out urologic oncology experts to help them understand the implications of small kidney cancers and avoid overtreatment.

Co-authors on the study include Fox Chase researchers Alexander Kutikov, Daniel J. Canter, Brian L. Egleston, Rosalia Viterbo, David Y.T. Chen, Richard E. Greenberg and Robert G. Uzzo.

Statistical analysis for this research was supported by Fox Chase Cancer Center's Keystone Program in Personalized Kidney Cancer Therapy. Established in 2008, this collaborative program brings researchers and clinicians from multiple disciplines together to investigate the biological mechanisms that lead to kidney cancer metastasis and to uncover the molecular signals that predict how an individual patient's kidney tumor will respond to therapies. Ultimately, the research supported by this privately-funded program will allow clinicians to optimize therapies for a given patient based on the unique molecular characteristics of his or her tumor.

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Obstructive sleep apnea linked to cancer growth in mice

ScienceDaily (May 17, 2011) — A new study links the intermittent interruption of breathing that occurs in patients with obstructive sleep apnea (OSA) to enhanced proliferation of melanoma cancer cells and increased tumor growth in mice, according to researchers in Spain. The study also found tumor cells of OSA mouse models tended to contain more dead cells, indicating a more aggressive type of cancer.

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The results of the study will be presented at the ATS 2011 International Conference in Denver.

"To our knowledge, this study is the first one providing experimental evidence that a high-rate intermittent lack of oxygen, or hypoxia, mimicking the one experienced by OSA patients enhances tumor growth," said Ramon Farre, PhD, professor of physiology at the University of Barcelona School of Medicine Biophysics and Bioengineering Lab.

Recurrent hypoxia is one of the hallmarks of OSA, which may affect around 5 percent of Americans. OSA has been associated with an increased risk of cardiovascular disease, including high blood pressure, as well as daytime sleepiness and a lower quality of life.

"Although earlier studies in animals have shown that lack of oxygen, or hypoxia, plays an important role in regulating the various stages of tumor formation and progression, the results obtained from human studies including large groups of OSA patients are not easy to interpret because there are other contributing conditions, most notably obesity," Dr. Farre added. "This well-controlled mouse model study allowed us to ensure that the only variable under study was intermittent hypoxia."

In this study, mice injected with melanoma tumor cells were divided among two groups. In the first group, mice were exposed to intermittent hypoxia, where oxygen was restricted for 20-second periods at a rate of 60 periods per hour for six hours per day, and normal oxygen levels for the remainder of the day. In the second group, mice received normal levels of oxygen (normoxia). Tumor volume was measured throughout the study and at the end of the study period. At the end of the 14-day study period, tumors from all mice were removed and weighed and tumor necrosis (indicated by the numbers of dead cells present) was measured to determine the aggressiveness of the tumors.

The authors found that while tumor volume progressively increased with time in both the intermittent hypoxia and control groups, the increase was higher in the mice subjected to intermittent hypoxia. Tumor weight and necrosis in the intermittent hypoxia group were almost two times that of the tumors in the control group.

"With the limitations of any animal model study, these results suggest that the intermittent hypoxia characterizing obstructive sleep apnea could enhance the growth of tumors," Dr. Farre said, adding that although the results were not entirely unexpected based on earlier studies connecting hypoxia with tumor growth, a link between breathing abnormalities specific to OSA and tumor progression had not previously been demonstrated.

"It was well known that continuous hypoxia promotes the growth of cancer cells and tumors," he said. "However, there were no data concerning the effects of the fast rate changes of oxygenation in sleep apnea on cancer."

Dr. Farre said the results of this study could have future clinical implications if the results are confirmed in large-scale human studies. "There are still several questions that need to be answered, both at the basic science and clinical levels," he said.

Future studies would need to evaluate whether intermittent hypoxia also triggers the initial formation of tumors and whether it promotes metastasis, or spread of tumors from one organ to another. Because this study focused on melanoma, Dr. Farre said additional studies should also explore whether intermittent hypoxia affects other types of cancer.

Extended population studies should also determine if there is a relationship between the incidence of cancer and the severity of OSA, as well as addressing the issue of obesity, which has been linked with OSA.

"Intermittent hypoxia is not the sole cancer-promoting challenge experienced by OSA patients," Dr. Farre said. "Obesity is also known to enhance cancer morbidity and mortality, and it is not clear to what extent intermittent hypoxia and obesity could interact to increase cancer growth in OSA patients.

Clarifying these questions certainly will require additional studies," he said. "If the current results in an animal model are confirmed by further clinical research, the public health impact of obstructive sleep apnea would be greater than currently known."

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Enzyme may drive breast cancer growth

ScienceDaily (May 20, 2011) — A recently discovered enzyme drives the production of a potent form of estrogen in human breast cancer tissue, researchers from the University of Illinois at Chicago College of Medicine have found.

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The extra-strength estrogen, called estradiol, then drives the production of even more enzyme, in what may be a lethal feed-forward mechanism. Estradiol has been implicated in exacerbating tumor growth in breast cancer.

The research is published in the May issue of the journal Molecular Endocrinology.

Scientists had observed the increased production of an unknown protein in ovarian tissue in response to estrogen. UIC researchers under the direction of Geula Gibori, UIC professor of physiology and biophysics, then purified the protein and cloned its gene. Several laboratories established that it is an enzyme that converts a weak estrogen, estrone, to the much more potent estradiol.

The UIC researchers then examined the production of the enzyme in a line of breast cancer cells known to respond to estrogen levels.

"Estradiol up-regulates the very enzyme that produces estradiol, creating a positive cycle where this potent form of estrogen is being produced over and over again, sustaining its own production," said Aurora Shehu, UIC postdoctoral research associate in physiology and biophysics and first author of the study.

In human breast tissue, the researchers found a "dramatic" up-regulation in the cancerous cells but not in the surrounding benign tissue, said Gibori, who is principal investigator on the study. The surrounding tissue, however, is a rich source of the estrone that the enzyme needs to produce more estradiol, she said.

The researchers were able to show how estradiol turns on the gene that produces the enzyme, and that this activation also required at least one other known regulatory factor.

They found that tamoxifen, a drug widely used to inhibit breast cancer growth, prevents estradiol's stimulation of the enzyme and thus may shut down local production of estradiol in breast cancer cells.

"Breast cancer tumors with this enzyme are likely to be a much more aggressive and potentially deadly type of cancer," Gibori said. "Identifying this enzyme and how its expression is turned on gives medical researchers potential targets for disrupting the lethal production of estradiol in breast cancers."

The enzyme is a promising therapeutic target because blocking it may halt production only of the dangerous estradiol, which would reduce the side effects seen with other drugs that inhibit production of many estrogen-related compounds, Gibori said.

This study was supported by grants from the National Institutes of Health. Y. Sangeeta Devi, Kristin Luther, Julia Halpern, Jamie Le, Jifang Mao, Rachel Duan and Jonna Frasor from UIC and Constance Albarracin of the University of Texas, Houston, also contributed to the study.

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