March/April 2008

Understanding Metastasis

Continued from page 2

By Katherine Bourzac, SM '04

Mesenchymal stem cells are adult stem cells that originate in the bone marrow. Although poorly understood, they are known to travel to infected and inflamed sites in the body, where they play an important role in healing. Once in a tumor, ­Weinberg says, mesenchymal stem cells "educate" cancer cells on how to become metastatic. In mouse models, breast cancer cells that have been exposed to mesenchymal stem cells can form new tumors in the lung five to six times as efficiently as cells that have not been exposed.

Karnoub performed a series of mouse experiments with mesenchymal stem cells and breast cancer cells. First, he found that when injected into the bloodstream of mice with breast cancer, stem cells labeled with imaging dyes ended up concentrated in the tumors. This suggested that the tumor cells were "talking" to the stem cells, sending signals to draw them in. When such stem cells and tumor cells were mixed together and then implanted into the mice, the tumors were more metastatic than cancer cells implanted alone. This suggested that the stem cells were "talking back" to the tumors, sending them some kind of message that made them behave more aggressively.

Further work revealed that the cancer cells induce the stem cells to produce a signaling protein called CCL5, though the precise mechanism is uncertain. Cancer cells exposed to CCL5 move more readily from the bloodstream into the lungs, Karnoub found. When they leave the tumor, they lose contact with the stem cells; after reaching the lungs, they forget their CCL5 education and revert to a less metastatic form.

Karnoub and Weinberg's work upends the conventional wisdom about metastasis. For 30 years, says Weinberg, the "prevailing paradigm in cancer research" has been that cancer cells' behavior is dictated primarily by their genes. But Karnoub's work shows that at least in some cases, highly aggressive behavior is transient, sustained not by the cancer cells themselves but by signals from normal cells nearby. "We now realize that an equally important determinant of the behavior of the cancer cell is its context, its environment within the tissue," says Weinberg.

This revelation adds a new dimension to the emerging understanding of metastasis as a process that only some cancer cells are capable of, involving reactivation of embryonic behaviors by master genetic regulators--an understanding that has taken shape only over the past five years. It's unclear what kind of therapies all this work might lead to as the new framework of knowledge is filled in over the next decade or so. Weinberg says that the full implications for cancer in general aren't yet apparent but that his findings probably apply broadly to carcinomas, the class to which breast cancer belongs. Carcinomas arise in the skin and in the tissues that line organs including the lungs, liver, prostate, and colon.

"It may ultimately become a small part of the picture," Weinberg says, "but it's a hint of things to come."