Nicotine Does Not Promote Lung Cancer Growth in Mouse Models, Study Finds

ScienceDaily (Apr. 4, 2011) — Nicotine at doses similar to those found in most nicotine replacements therapies did not increase lung cancer tumor incidence, frequency or size, according to results of a mouse study presented at the AACR 102nd Annual Meeting 2011, held in Orlando, Florida April 2-6.

"If you take our data and combine it with epidemiological data from Europe, even in people who quit smoking and maintain the use of nicotine replacement therapy for months or years, there does not appear to be increased lung cancer incidence," said Phillip A. Dennis, M.D., Ph.D., senior investigator at the medical oncology branch of the National Cancer Institute. "This suggests that nicotine replacement therapy is probably safe and is certainly safer than smoking."

According to Dennis, about 20 percent of all smokers are truly addicted to tobacco. In these people, the use of nicotine replacement therapy has markedly helped them to quit smoking. The current Food and Drug Administration indication for most nicotine replacement therapies, such as a nicotine patch, is limited to 10 to12 weeks.

There is a subset of smokers who will need to stay on nicotine replacement therapy longer in order to appease addiction, according to Dennis. However, expanding the use of this therapy is controversial. Research to date has linked nicotine to cancer in various ways, including laboratory studies that indicate nicotine promotes the growth or spread of tumor cells or that it helps transform normal lung airway cells into cancerous cells, according to Dennis.

Therefore, the researchers conducted a study in mice to determine if nicotine had any tumor-promoting effects. Three groups of mice were administered nicotine in drinking water for up to 12 weeks.

In the first group, the mice were administered three weekly injections of NNK, a known tobacco carcinogen, prior to receiving nicotine. The second group of mice was genetically engineered to have activation of the KRAS oncogene, which is frequently mutated in lung cancers derived from smokers. The third group was made up of mice that were given cell lines derived from mouse lung cancers.

The researchers found that all the mice had normal water consumption. Cotinine, a metabolite of nicotine, was found to be at a level that is comparable to levels found in nicotine replacement users.

"We observed that there was no effect of nicotine on the mice in all three groups," said Dennis. "Nicotine did not increase tumor incidence, multiplicity or size."

At the levels measured in mice, nicotine did not activate signaling pathways associated with lung cancer that had been shown to be activated by high concentrations of nicotine.

"Based on our study and human epidemiological studies to date, nicotine replacement therapy is probably a safe option," he suggested.

Carbon Dioxide Capture: Health Effects of Amines and Their Derivatives

ScienceDaily (Apr. 4, 2011) — Carbon dioxide capture by means of amines is considered to be the most appropriate method to quickly begin with CO2removal. During this capture process, some of the amines escaping the recycling process will be emitted into the air and will also form other compounds such as nitrosamines and nitramines. The Norwegian Institute of Public Health (NIPH) was commissioned by the Climate and Pollution Agency (Klif) to assess whether these new emissions are harmful to health -- particularly in terms of the cancer risk to the general population. The results of the risk assessments have now been submitted.

These amines by themselves are not very harmful at typical concentrations that might occur, for example, near power plants. However, the amines could take part in complex chemical reactions and form new compounds such as nitrosamines and nitramines, which can affect health and the environment.

There is relatively little knowledge about the various health effects for many of these compounds, but it is known that several of them can be highly carcinogenic. The cancer risk ultimately depends on how much is formed, how much is released, how much is decomposed in the atmosphere by light and how strong the cancer-causing substances are.

The NIPH has assessed the cancer-causing ability of compounds that can be formed in connection with CO2capture. Nitrosodimethylamine (NDMA) was found to be one of those that may be the most carcinogenic. Therefore, this compound is used to calculate the risk from the total amount of various nitrosamines in the air.

Uncertainty about nitramines

There is a lack of knowledge about nitramines but the compounds in this group are generally believed to be less carcinogenic than nitrosamines. However, studies show that the nitramine we know most about, (N-nitrodimethylamine) is a highly carcinogenic substance, although it is not as potent as NDMA.

The NIPH recommends that the risk estimate for NDMA is also used for nitramines. This must be regarded as a risk estimate that will provide good protection of the population. If nitramines are detected in significant quantities in emissions, there will be a need for more knowledge for the NIPH to be able to perform a full risk evaluation.

Recommendation

When released from the CO2 capture plant, the NIPH recommends that the risk estimate for NDMA should be used for the total concentration of both nitrosamines and nitramines in air and water. We recommend maximum levels that provide minimal or negligible risk of cancer from exposure to these substances. The NIPH therefore concludes that the total amount of nitrosamines and nitramines should not exceed 0.3 ng/m3 (nanogram/m3) air.

Serum Test Could Identify Lung Cancer in People Who Never Smoked

ScienceDaily (Apr. 4, 2011) — A panel of biomarkers appears to be able to identify the presence of lung cancer in the blood samples of people who have never smoked, according to data presented at the AACR 102nd Annual Meeting 2011, held here April 2-6.

While lung cancer has long been linked to smoking, approximately one-fourth of patients with lung cancer have never smoked. Researchers are working on ways to identify the presence of lung cancer in these patients.

Charlie Birse, Ph.D., associate director of product development at Celera Corporation, and colleagues are investigating the potential for a serum test that would examine the reliability of a proprietary panel of biomarkers for lung cancer. The goal is to administer this test in patients with suspect chest scans using computed axial tomography (CT) technology.

"In addition to intentional CT scans for lung cancer, many people undergo chest scans for heart disease prevention or other conditions and incidental nodules appear in the lungs that may or may not be benign," said Birse. "This panel of biomarkers would allow these imaging tests to be further evaluated and provide a degree of certainty in diagnosis."

Birse and colleagues examined more than 600 specimens. Samples were randomly divided into a training set comprising patients with non-small cell lung cancer (NSCLC) who were smokers and matched controls followed by a testing set of additional NSCLC cases and matched controls. Once the researchers established the biomarkers, they conducted additional studies in 80 people who have never smoked, 40 of whom had varied stages of cancer and histological cell types and 40 control subjects matched by age and gender.

Researchers found strong performance with a sensitivity and a specificity of 83 percent in identifying lung cancer. All stages of lung cancer and histological cell types were distinguished.

"While promising, these findings still need to be confirmed in larger sets," Birse said.

Social Isolation, Stress-Induced Obesity Increases Breast Cancer Risk in Mice

ScienceDaily (Apr. 4, 2011) — Stress from social isolation, combined with a high-fat diet, increases levels of a brain neurotransmitter -- neuropeptide Y, or NPY -- in mice that then promotes obesity, insulin resistance, and breast cancer risk, say researchers at Georgetown Lombardi Comprehensive Cancer Center, a part of Georgetown University Medical Center (GUMC).

Major increases in NPY levels are seen when isolation and the high fat diet are combined. Still, the mice that were isolated for two weeks and fed a control diet had elevated NPY levels and increased terminal end buds, a structure in the mammary gland where mammary cancers form.

The researchers say their findings, reported at the American Association for Cancer Research (AACR) 102nd Annual Meeting 2011 in Orlando, Florida, appear to link a number of findings in humans, such as the fact that social isolation is associated with an increased risk of cancer development and mortality, and that obesity is a risk factor for breast cancer."

"We suspect that NPY may play a role in development of human breast cancer, but we have no evidence for such a connection because no human studies have yet been done," says the study's lead investigator, Allison Sumis, a Ph.D. student in the Tumor Biology program.

"We do know that NPY has been shown to increase growth of human breast cancer cells in the laboratory," she says. Sumis works with Leena Hilakivi-Clarke, Ph.D., Co-Director of the Division of Molecular Endocrinology, Nutrition and Obesity at GUMC, who is the study's senior investigator.

To conduct the study, the researchers used female mice that develop breast cancer when given progesterone and a carcinogen. They established four groups of these mice: one group that lived together (not socially isolated) and ate a normal diet; a group that was isolated (each alone in a cage) and ate normally; an isolated group that ate a high-fat diet, and a group that lived together and ate a high-fat diet.

Ten weeks after treatment and living in these environments (for a total of 17 weeks), 92 percent of the socially-isolated mice fed a high-fat diet had developed tumors, compared to 36 percent of socially-isolated mice fed a normal diet and 36 percent of grouped mice that were also fed normally. But 67 percent of mice who were happy in group homes, but were fed a high fat diet, developed breast cancer.

Sumis adds that the tumors that developed in the high-fat, socially isolated mice appeared earlier and were larger than in the other groups.

"We have yet to translate these findings to humans, but it does suggest that social isolation is a potent stressor and initiates a robust central nervous system response," she says. "Others have found that a majority of women gain weight after a diagnosis of breast cancer, and it seems likely that stress, even if it is not from social isolation, may play a role."

The study was funded by the National Cancer Institute. The authors report having no personal financial interests related to the study.

Tumors Resistant to Radiation Therapy May Be Controlled by the MET Oncogene

ScienceDaily (Apr. 4, 2011) — Ionizing radiation treats many cancers effectively, but in some patients a few tumor cells become resistant to radiation and go on to cause relapse and metastasis. A growth factor-receptor protein called MET may be a key player in these cells' resistance to radiation, and drugs targeting MET may help to prevent radiation-induced metastasis, according to a study published online April 4th in the Journal of the National Cancer Institute.

The gene that encodes MET is known as a cancer-promoting gene, or oncogene. It is expressed at high levels in many cancers and is associated with metastasis. But the exact role it plays and how it may induce radiation-resistant tumor cells is unclear.

To explore the molecular mechanisms behind radioresistance, the group led by Carla Boccaccio, M.D. and Paolo M. Comoglio, M.D., of the Institute for Cancer Research at Candiolo, University of Turin Medical School, examined the expression of the MET gene and the activity of the MET protein in human cancer cell lines before and after exposure to ionizing radiation. They also observed the effect of radiation on two proteins that regulate MET--ataxia telangiectasia mutated (ATM) and nuclear factor kappa B or NF-κB.

They found that after radiation treatment, MET expression increased up to fivefold due to activation of ATM and NF-κB. The tumor cells that survived irradiation became more invasive than previously. Moreover, inhibiting MET counteracted this increased invasiveness and promoted death of the tumor cells (apoptosis). In mice, treatment with MET inhibitors, such as specific small-molecule kinase inhibitors, enhanced the effect of radiation, stopping growth or inducing shrinkage of tumors.

The authors conclude that ionizing radiation drives overexpression and activity of MET through the ATM and NF-κB signaling pathways, making some tumor cells resistant to radiation and more invasive. They also conclude that drugs that inhibit MET might counter radiation resistance.

"This has important therapeutic implications," they write, "as it suggests that the combination of radiotherapy with MET inhibition can radiosensitize cancer cells."

In an accompanying editorial, Olga Guryanova M.D., Ph.D. and Shideng Bao, Ph.D., of the Lerner Research Institute at the Cleveland Clinic, Cleveland, Ohio, note that the study adds new details to emerging knowledge of the roles of MET and NF-κB in therapeutic resistance. "The finding that NF-κB activation is ATM dependent adds yet another vignette to the picture," they write.

The editorialists point out that the study also raises questions for future investigation. One step, they suggest, would be to test human tumor cells isolated from surgical specimens to confirm the results. Another would be to determine whether MET expression is elevated in cancer stem cells, which have shown resistance to radiation and chemotherapy in some studies.

"Augmenting the sensitivity of resistant cancer cells to conventional treatments has been the subject of great effort," they write. "Improved radiotherapy with radiosensitizers is expected to increase the efficacy of cancer treatment."