New research in an animal model suggests that a diet high in inorganic phosphates, which are found in a variety of processed foods including meats, cheeses, beverages, and bakery products, might speed growth of lung cancer tumors and may even contribute to the development of those tumors in individuals predisposed to the disease.

The study also suggests that dietary regulation of inorganic phosphates may play an important role in lung cancer treatment.  The research, using a mouse model, was conducted by Myung-Haing Cho, D.V.M., Ph.D., and his colleagues at Seoul National University, appears in the first issue for January of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

“Our study indicates that increased intake of inorganic phosphates strongly stimulates lung cancer development in mice, and suggests that dietary regulation of inorganic phosphates may be critical for lung cancer treatment as well as prevention,” said Dr. Cho.

Lung cancer is the number one cause of cancer deaths in the world and is also the most frequently diagnosed solid tumor.  Non–small cell lung cancer (NSCLC) constitutes over 75 percent of lung cancers and has an average overall 35-year survival rate of 14 percent.  Earlier studies have indicated that approximately 90 percent of NSCLC cases were associated with activation of certain signaling pathways in lung tissue.  This study revealed that high levels of inorganic phosphates can stimulate those same pathways.

“Lung cancer is a disease of uncontrolled cell proliferation in lung tissue, and disruption of signaling pathways in those tissues can confer a normal cell with malignant properties,” Dr. Cho explained.  “Deregulation of only a small set of pathways can confer a normal cell with malignant properties, and these pathways are regulated in response to nutrient availability and, consequently, cell proliferation and growth.

“Phosphate is an essential nutrient to living organisms, and can activate some signals,” he added.  “This study demonstrates that high intake of inorganic phosphates may strongly stimulate lung cancer development by altering those (signaling) pathways.”

In the study, lung cancer-model mice were studied for four weeks and were randomly assigned to receive a diet of either 0.5 or 1.0 percent phosphate, a range roughly equivalent to modern human diets.  At the end of the four-week period, the lung tissue was analyzed to determine the effects of the inorganic phosphates on tumors.

“Our results clearly demonstrated that the diet higher in inorganic phosphates caused an increase in the size of the tumors and stimulated growth of the tumors,” Dr. Cho said.

Dr. Cho noted that while a moderate level of phosphate plays an essential role in living organisms, the rapidly increasing use of phosphates as a food additive has resulted in significantly higher levels in average daily diets.  Phosphates are added to many food products to increase water retention and improve food texture.

“In the 1990s, phosphorous-containing food additives contributed an estimated 470 mg per day to the average daily adult diet,” he said.  “However, phosphates are currently being added much more frequently to a large number of processed foods, including meats, cheeses, beverages, and bakery products.  As a result, depending on individual food choices, phosphorous intake could be increased by as much as 1000 mg per day.”

“Although the 0.5 percent was defined as close to ‘normal,’ the average diet today is actually closer to the one percent diet and may actually exceed it,” Dr. Cho noted.  “Therefore, the 0.5 percent intake level is actually a reduced phosphate diet by today’s scale.”

Dr. Cho said future studies will help refine what constitutes a “safe” level of dietary inorganic phosphate, with recommendations that will be easily achievable in the average population.

“The results of this study suggest that dietary regulation of inorganic phosphates has a place in lung cancer treatment, and our eventual goal is to collect sufficient information to accurately assess the risk of these phosphates,” he said.

John Heffner, M.D., past president of the ATS, stated that this line of investigation in animals addresses the complex interactions between host factors and the environment that underlie cancer in man.  “We know that only some patients who smoke develop lung cancer but the reasons for this varying risk are unknown.  This study now provides a rationale for funding case-control studies in humans to determine the potential role of dietary phosphates in promoting cancer.”

Working as part of a multi-institutional collaboration, scientists at Washington University School of Medicine in St. Louis have assembled the most complete catalog to date of the genetic changes underlying the most common form of lung cancer.  The research, published Oct. 23 in Nature, helps lay the foundation for more personalized diagnosis and treatment of a disease that is the leading cause of U.S. cancer deaths.

The research team identified 26 genes that are frequently mutated in a type of cancer called lung adenocarcinoma, a finding that more than doubles the number of genes already known to be linked to the deadly disease.  What’s more, by casting a wide net in their search for genetic alterations, the scientists are now beginning to see intriguing relationships.  They found that some of the same genes associated with lung tumors are also defective in other cancers, that smokers and non-smokers with lung cancer have distinct genetic defects and that several molecular pathways underlie most of the mutations.

“This genomic approach has given us a completely different view of lung cancer,” says Richard K. Wilson, Ph.D., director of Washington University’s Genome Sequencing Center and one of the study’s lead authors.  “This broad view will allow scientists to more accurately categorize tumors, which should speed efforts to develop more targeted therapies to fight the disease.”

More than 1 million people worldwide die of lung cancer each year, including more than 160,000 in the United States.  About 40 percent of them are adenocarcinoma, a type of non-small cell lung cancer and one that is exceedingly difficult to treat.  Only about 15 percent of patients are still alive five years after diagnosis.

“By harnessing the power of genomic research, this pioneering work has painted the clearest and most complete portrait yet of lung cancer’s molecular complexities,” says Alan E. Guttmacher, M.D., acting director of the National Human Genome Research Institute, the agency that funded the research.

The Nature study was conducted as part of the Tumor Sequencing Project, a collaborative effort to assemble a genome-wide catalog of the genetic mutations in lung adenocarcinoma.  Like most cancers, lung adenocarcinoma arises from changes that accumulate in people’s DNA over the course of their lives.  However, little is known about the precise nature of these genetic alterations, how they occur and how they disrupt biological pathways to cause cancer’s unfettered cell growth.

Working with lung cancer samples donated by 188 patients from across the United States, the group sequenced 623 suspect genes and compared them to the same genes in healthy tissues from the same patients.  Initially, they found more than 1,000 mutations across the samples.  Looking more closely, the researchers identified 26 genes mutated in a significant number of samples.  Most of the genes had not previously been associated with lung cancer but are found in other tumors.

The new genes fingered in lung adenocarcinoma include:

* Neurofibromastosis 1: Mutations in this gene cause a rare inherited neurological disorder that increases the risk of tumors that form on nerve tissues, including the brain, spinal cord and individual nerves;

* Ataxia telangiectasia mutated (ATM): Mutations of this gene have been found in a rare inherited neurological disorder and in various types of leukemia and lymphoma;

* Retinoblastoma 1: Mutations in this gene have linked to a rare childhood cancer that begins in the retina;

* Adenomatosis polyposis coli (APC): Mutations of this gene are common in colon cancer.

The team also examined the effects of the genetic mutations on biological pathways and determined which of the pathways is most crucial to lung adenocarcinoma.  This line of discovery is essential to efforts to develop new and better treatments for cancer.

For example, the researchers discovered that more than 70 percent of the 188 tumors had at least one mutation affecting the mitogen-activated protein kinase (MAPK) pathway, indicating it plays a pivotal role in lung cancer.  Based on those findings, the researchers suggested new treatment strategies for some subtypes of lung adenocarcinoma might include compounds that affect this pathway.  One such group of compounds, the MEK inhibitors, has produced promising results in mouse models of lung cancer.

“Looking at the pathways helps simplify the picture,” Wilson explains.  “Generally, we found that each mutation only occurs in a small percentage of the tumor samples, but when we looked at all the mutations that intersect a particular signaling pathway, we were surprised to find a lot of overlap in only a handful of pathways.  This gives us a much better idea of what goes wrong in cells when they become cancerous.”

Additionally, the finding that more than 30 percent of tumors had mutations affecting the rapamycin (mTOR) pathway raises the possibility that the drug rapamycin might be tested in lung adenocarcinoma.  The drug, which inhibits mTOR, is approved for use in organ transplants and renal cancer.

The researchers also analyzed the patterns of genetic changes in both smokers and non-smokers with lung cancer.  About 90 percent of lung cancer is linked to smoking, but 10 percent of patients diagnosed with the disease have never smoked.  They found that the number of mutations detected in tumor samples from smokers was significantly higher than in tumors from never-smokers.  Smokers’ tumors contained as many as 49 mutations, while none of the never-smokers’ tumors had more than five.

More work is needed to determine the clinical significance of these differences.  However, doctors do know that in some other types of cancer, high mutation levels may cause a tumor to spread rapidly or be resistant to treatment.

The study also confirmed previous observations that indicated lung cancer in never-smokers may be triggered by different genetic mutations than those in smokers.  For example, mutations in the epidermal growth factor (EGFR) gene were prevalent in tumors from non-smokers, while mutations in the KRAS and Src tyrosine kinase 11 genes were common in tumors from smokers.

“Our findings underscore the value of systematic, large-scale genome studies for exploring cancer.  We now must move forward to apply this approach to even larger groups of samples and a wider range of cancers,” Wilson says.

Moderate consumption of red wine may decrease the risk of lung cancer in men, according to a report in the October issue of Cancer Epidemiology, Biomarkers & Prevention¸ a journal of the American Association for Cancer Research.

“An antioxidant component in red wine may be protective of lung cancer, particularly among smokers,” said Chun Chao, Ph.D., a research scientist at Kaiser Permanente Department of Research and Evaluation in Pasadena, California.

Chao analyzed data collected through the California Men’s Health Study, which linked clinical data from California’s health system with self-reported data from 84,170 men aged 45 to 69 years. Researchers obtained demographics and lifestyle data from surveys computed between 2000 and 2003, and identified 210 cases of lung cancer.

Researchers measured the effect of beer, red wine, white wine and liquor consumption on the risk of lung cancer. Adjustments were made for age, race/ethnicity, education, income, body mass index, history of chronic obstructive pulmonary disease or emphysema, and smoking history.

Among the study participants, there was on average a two percent lower lung cancer risk associated with each glass of red wine consumed per month. The most substantial risk reduction was among smokers who drank one to two glasses of red wine per day. The researchers reported a 60 percent reduced lung cancer risk in these men. Researchers warned men to stop smoking as the best way to reduce lung cancer risk; noting that even men who drank one to two glasses of red wine per day still face higher lung cancer risk than do non-smokers.

No clear associations with lung cancer were noted for consumption of white wine, beer, or liquor. “Red wine is known to contain high levels of antioxidants. There is a compound called resveratrol that is very rich in red wine because it is derived from the grape skin. This compound has shown significant health benefits in preclinical studies,” Chao said.

Chao said their findings should not be construed to recommend heavy alcohol consumption.

The identification of five genes involve in the metastasis of breast tumours to the lung is the principal finding of a scientific team made up of two bodies from the University of Navarra, the Applied Medical Research Centre (CIMA) and the University Hospital of the University of Navarra.

Doctor Alfonso Calvo, researcher in the area of Oncology at the CIMA, led the work with the special collaboration of Doctor Ignacio Gil Bazo, cancer specialist from the University Hospital.  The study made up a significant part of Mr Raúl Catena’s PhD thesis.

For this research, recently published in the scientific journal Oncogene, a transgenic mouse model which presented a greater tendency for developing metastasis was employed.  The increase in what is known as the Vascular Endothelial Growth Factor (VEGF) in its mammary glands triggered profound changes in the tumoural structure, which enabled the malignant cells to leave the tumour and invade the lungs.

Finally, the pattern of genes responsible for this tumoural migration to the lungs was analysed and this was compared to that shown by women with breast tumours with pulmonary metastatic affectation.  It was shown that five of these genes were common to the animal model and patients with breast cancer.  Most effective ways of treatment

According to the results of this study, of the five genes identified, the Tenascina-C gene seems to be a good therapeutic target for the treatment of metastatic breast cancer.  In fact, the blocking of the expression of this gene in the animal model enabled a significant reduction, both in tumour growth and in the incidence of pulmonary metastasis.

This new discovery in the complex network that is the metastasis process of tumours provides key data on the knowledge of cancer and its spreading, at the same time identifying new targets for which new pharmaceutical medicines that contribute to more efficacious treatment of this disease can be designed.

New data, generated by Hongbing Shen and colleagues, at the Cancer Center of Nanjing Medical University, People’s Republic of China, has identified a genetic variation that seems to help predict survival in individuals with non–small cell lung cancer (NSCLC).

A systematic screen of the DNA carrying the information for generating regulatory RNA molecules known as a microRNAs identified a specific genetic variant that was associated with decreased survival in individuals with NSCLC.  The specific genetic variation resulted in increased levels of expression of the functional miRNA molecule.  This was not because more of the miRNA was made but because more of the precursor form of the functional molecule was processed to become functional.  The functional miRNA molecule generated by the genetic variation also had different functional properties.  The authors hope that further characterization of genetic variations that modify miRNA expression and/or function will uncover other indicators of survival and opportunities for developing new therapeutics.