A signaling molecule commonly found in cancerous tissue primes some breast tumor cells to metastasize to lung but not bone tissue, according to a study to be published in Cell tomorrow (Apr. 4).

"This work basically provides a deeper understanding of how breast cancer spreads throughout the body," said David Padua, the lead author of the study and a Weill Cornell Medical College graduate student who works in the Sloan-Kettering Cancer Center lab of the team's leader, oncologist Joan Massague. "This is one of the first examples of this priming phenomenon," Padua said.

The researchers, including scientists in New York City and Spain, showed that a cytokine, transforming growth factor beta (TGFβ), can instruct some tumor cells to invade lungs by sparking signaling pathways and inducing gene expression that can make metastasis more efficient in lung tissue.

"It gives us a little bit more focused view of what TGFβ may do in breast cancer," said Boris Pasche, director of the Cancer Genetics Program at Northwestern University's Feinberg School of Medicine, who was not involved with the study.

The study focused on one particular gene, angiopoietin-like 4 (ANGPTL4), which is induced by TGFβ in some primary tumor cells about to enter the circulatory system to hunt for metastasis sites. ANGPTL4 induction makes lung tissue more permeable to tumor cells by disrupting cell-cell junctions in pulmonary blood vessels, thus upping the chances for tumor cell retention by the lungs. These cells are not similarly suited to invade bone tissue. "We suspect that these signaling molecules in the tumor are empowering the cells with specific metastatic abilities," Padua said.

TGFβ is known to influence tumor progression in a variety of model systems. But Padua and his collaborators developed a bioinformatics tool that showed that the cytokine was regulating a core group of about 150 genes in human breast tumor cell lines and then applied this tool to clinical data from hundreds of breast cancer patients. The researchers found that TGFβ activity in some of these patients was linked to lung metastases. "This patient tissue-specific progression is something that is poorly understood in oncology," said Pasche.

Though Padua cautioned that his study was mostly a conceptual work, he said that TGFβ was probably going to become "a molecule that's interesting to target" after continued research. He added that the ANGPTL4 gene and its products could become targets for antibody therapy at some point in the future.

"It gives us a focus group of patients who may benefit from therapies that target TGFβ," agreed Pasche.

Padua also said that the team is using the bioinformatics tool they developed for determining TGFβ's activity to look for similar priming in other tumor types, such as colon and bladder. "There's definitely a possibility of other priming signals that can enhance [metastasis]," he said.