Molecular Cause of Breast Cancer Metastasis Discovered
THURSDAY April 3, 2008 -- Certain cancers tend to spread to specific tissues, and now researchers have gained a molecular handle on how that happens.
Working with breast tumors, Joan Massague, chairman of the Cancer Biology and Genetics Program at Memorial Sloan-Kettering Cancer Center in New York City, and his colleagues discovered a signaling "relay" that enables the cancer to molecularly "soften" its target tissue -- the lung in this case -- allowing circulating breast cancer cells to pass through capillary walls and penetrate the lung.
"It provides a very nice mechanism for how breast cancer cells specifically get out of the circulation and into the lungs. Nobody knew how they did that before," said Karl Saxe, a scientific program director at the American Cancer Society.
The results were published in the April 4 issue of Cell.
Key to this study is a signaling molecule called TGF-beta. Early in cancer progression, TGF-beta acts as a tumor suppressor, inhibiting cancer growth. Later, it actually stimulates cancer progression and metastasis. Massague was interested in how tumors trigger this molecular dichotomy.
His team began by identifying a molecular signature, a pattern of gene expression of 153 genes that identifies tumors that are both expressing and responding to TGF-beta. They then applied that signature to hundreds of primary breast tumors.
While there was no apparent correlation between TGF-beta signaling and metastasis in breast cancers that also express the estrogen receptor, the team found that tumors that were estrogen receptor-negative and signature-positive were much more likely to metastasize to lung. No similar correlation was found for metastasis to the bone, liver or brain.
When the team then asked which of the genes in the signature was responsible for this selectivity, they identified a second element in the relay, a signaling molecule called angiopoietin-like 4 (ANGPTL4), whose expression is induced by TGF-beta. ANGPTL4 disrupts capillary walls, loosening the connections between adjacent cells and allowing the metastasizing cells to "seed" the tissue.
Disrupt TGF-beta signaling, or ANGPTL4 expression, and lung metastasis is disrupted, the researchers found. Enhance that signaling, and lung metastasis is increased.
"This is a molecular and biological explanation of why and how responding to TGF-beta contributes to lung metastasis," concluded Massague.
This study also suggests anticancer therapies based on both TGF-beta (which are currently in development) and ANGPTL4 could be useful against metastatic breast cancer, he added.
According to Saxe, the observation that cancers have a way to select targets to spread to is not surprising. "Something like this had to be going on," he said. "But what is very nice and satisfying is to find a very clear mechanism like this to explain why some kinds of breast cell tumors metastasize to the bone and some to lung."
Massague said the reason ANGPTL4 helps cells colonize the lungs but not the bone has to do with the different architecture of the two tissues. Lung tissue is highly vascularized, yet capillaries present a relatively impenetrable barrier to metastasizing cells. Bone, on the other hand, is different, Massague explained, because it has windows and "...every day in the bone marrow, the capillaries have to let cells in and out."
Similar molecular discriminators may turn out to play a role in a variety of tumors, Saxe said. TGF-beta signaling in general, and ANGPTL4 in particular, may control metastasis in a variety of tumor types. Other signaling pathways could also be involved, and Saxe said he expects this study will spark new research to investigate those possibilities.
As Dr. Kornelia Polyak, a researcher with the Breast Cancer Genetics Lab at the Dana-Farber Cancer Institute at Harvard Medical School, pointed out, metastasis likely involves "an orchestra of genes that together can contribute to different steps" of the process. "It's likely to be a combination of genes, and this particular one [ANGPTL4] is one of them."
For more on breast cancer, visit the National Cancer Institute.
Posted: April 2008