Lung adenocarcinoma, an aggressive form of cancer that makes up about 40 percent of U. S. lung malignancy cases, is believed to arise from benign tumors generally known as adenomas.

MIT biologists have identified a major switch that occurs as adenomas transition in order to adenocarcinomas in a mouse model of lung cancer. They’ve furthermore discovered that blocking this switch prevents the tumors through becoming more aggressive. Drugs that interfere with this switch might thus be useful in treating early-stage lung cancers, the particular researchers say.

“Understanding the molecular paths that get activated as a tumor transitions from a harmless state to a malignant one has important implications for therapy. These findings also suggests methods to prevent or hinder the onset of advanced disease, ” says Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and the study’s senior author.

The switch occurs when a small percentage of tissue in the tumor begin acting like stem cells, letting them give rise to unlimited populations of new cancer cells.

“It seems that the stem cells are the engine associated with tumor growth. They’re endowed with very robust proliferative potential, and they give rise to other cancer cells and also to a lot more stem-like cells, ” says Tuomas Tammela, a postdoc at the Koch Institute and lead author of the document, which appears in the May 10 online edition associated with Nature .

Growth stem cells

In this study, the particular researchers focused on the role of a cell signaling path known as Wnt. This pathway is usually turned on only throughout embryonic development, but it is also active in small populations of adult stem cells that can regenerate specific tissue such as the lining of the intestine.

One of the Wnt pathway’s major roles is maintaining cells in a stem-cell-like state, so the MIT team suspected that Wnt may be involved in the rapid proliferation that occurs when early-stage tumors turn out to be adenocarcinomas.

The researchers explored this query in mice that are genetically programmed to develop lung adenomas that usually progress to adenocarcinoma. In these mice, they discovered that Wnt signaling is not active in adenomas, yet during the transition, about 5 to 10 percent of the growth cells turn on the Wnt pathway. These cells after that act as an endless pool of new cancer cells.

In addition , about 30 to 40 percent of the growth cells begin to produce chemical signals that create a “niche, ” a local environment that is necessary to maintain cells in the stem-cell-like state.

“If you take an originate cell out of that microenvironment, it rapidly loses the properties of stem-ness, ” Tammela says. “You have one main cell type that forms the niche, and then you might have another cell type that’s receiving the niche tips and behaves like a stem cell. ”

While Wnt has been found to drive tumor formation in certain other cancers, including colon cancer, this study factors to a new kind of role for it in lung malignancy and possibly other cancers such as pancreatic cancer.

“What’s new about this finding is that the pathway is not the driver, but it modifies the characteristics of the cancer cells. This qualitatively changes the way cancer cells behave, ” Tammela says.

Targeting Wnt

When the researchers gave the mice a medication that interferes with Wnt proteins, they found that the cancers stopped growing, and the mice lived 50 percent longer. In addition, when these treated tumor cells were implanted straight into another animal, they failed to generate new tumors.

The researchers also analyzed human lung adenocarcinoma samples and found that 70 percent of the growths showed Wnt activation and 80 percent had specific niche market cells that stimulate Wnt activity. These findings recommend it could be worthwhile to test Wnt inhibitors in early-stage lung cancer patients, the researchers say.

Also, they are working on ways to deliver Wnt inhibitors in a more targeted style, to avoid some of the side effects caused by the drugs. Another feasible way to avoid side effects may be to develop more specific inhibitors that focus on only the Wnt proteins that are active in lung adenocarcinomas. The Wnt inhibitor that the researchers used in this research, which is now in clinical trials to treat other types associated with cancer, targets all 19 of the Wnt proteins.

The research was funded by the Janssen Pharmaceuticals Surpasse Program, the Lung Cancer Research Foundation, the Howard Hughes Medical Institute, and the Cancer Center Support give from the National Cancer Institute.