Some breast cancer cells primed to prosper after metastasis to bone

Some metastasizing breast cancer cells express genes that make them more likely to prosper in bone tissue, according to new research. Whether or not cancer cells turn on those genes depends on what their surroundings were like in the primary breast tumor. If the breast tumor had molecular patterns similar to those in bone, the tumor is more likely to spread to bone later.

"It's like in society--who you hang out with shapes who you are," said senior author Joan Massagué, PhD, of Howard Hughes Medical Institute and Memorial Sloan-Kettering Cancer Center in New York, New York. "And that might make you better or worse equipped to handle situations you'll encounter."

When a cancer cell sloughs off the edge of a tumor in the breast, it must remain physically intact as it rushes through blood vessels. Also, it must find a new organ to lodge itself in, take in enough nutrients and oxygen to stay alive, and begin dividing, all while escaping notice by the body's immune system.

When cells from a primary tumor circulate through the body and begin growing in a new organ, a metastatic tumor is formed. Such metastases are often harder to treat than primary tumors; the vast majority of people who die of cancer have not only a primary tumor but also metastatic disease. So a major goal of cancer researchers is to stop cancer from metastasizing.

The new findings, published in Cell (2013; 154(5):1060-1073), could eventually lead to new drugs that block cancers from spreading to bone or other organs.

Massagué's lab group previously discovered that by looking at the genetics of breast cancer cells, they could predict which were most likely to spread to bone. A set of genes dubbed the Src response signature (SRS) was more often turned on in the cells that metastasized to the bone, but the reason was unknown.

Breast tumors with SRS turned on were further examined. The researchers tested for other genes, outside the known SRS pathway, that were always turned up or down in the same cells. Two were found, CXCL12 and IGF1, that were more highly expressed in tumors with SRS and also independently predictive of which tumors would migrate to the bone. Tumors with both genes turned up were more likely to lead to bone metastases.

But in the breast tumors with high levels of CXCL12 and IGF1, the researchers found, the genes weren't originating from cancer cells. Tumors consist of not only cancerous cells but also other supporting cells that are integrated into their structure. The gene signature, it turned out, was coming from noncancerous mesenchymal cells integrating into the breast tumor. Further, CXCL12 and IGF1 were also known to be expressed by bone cells. Both of the genes encode signaling molecules called cytokines.

"This was the eureka moment," said Massagué. "We realized there was mimicry between the environment of a primary tumor, and the environment of their preferred organ of metastasis."
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