Benefits of a Good Neighborhood: Normal Cells Can Suppress Tumor Formation

Normal mammary epithelial cells were able to suppress the ability of the erbB2-overexpressing cells to grow into tumors; however, the effect was reversible. If the erbB2-overexpressing cells were separated from their normal counterparts in the mammary gland, and implanted into a fat pad by themselves, they were once again able to form tumors.

Normal mammary epithelial cells were able to suppress the ability of the erbB2-overexpressing cells to grow into tumors; however, the effect was reversible. If the erbB2-overexpressing cells were separated from their normal counterparts in the mammary gland, and implanted into a fat pad by themselves, they were once again able to form tumors.

For several years, researchers have been trying to unlock the mysteries of cancer by studying the genomic changes and signaling pathways within tumor cells. While these aberrations undeniably contribute to cancer development, it is becoming increasingly clear that factors external to the cell—including nearby cells, the immune system, blood vessels, and other factors—also play a role.

Brian Booth, Ph.D., working with Gil Smith, Ph.D., and other researchers in CCR’s Mammary Biology and Tumorigenesis Laboratory, conducted a series of experiments using transgenic mouse models to determine whether cells from a normal mammary gland could influence the behavior of mammary tumor cells. Like the human breast, mammary glands consist of a fat pad and epithelial cells. Epithelial cells make up the ducts and alveoli that are responsible for making and delivering milk and are also the cells that give rise to mammary cancer. To conduct their experiments, the research team used a technique called mammary gland transplantation in which epithelial cells from one mouse can be transferred the mammary fat pad of another mouse. The results of their research were published in a recent issue of Oncogene.

The researchers collected mammary tumor cells from a mouse model that overexpresses erbB2—a gene that is homologous to the HER2 gene that contributes to aggressive breast cancer in women. When transplanted into the fat pad of a wild-type mouse (that does not overexpress erbB2), the erbB2-overexpressing tumor cells quickly formed tumors in the mammary gland. However, the researchers discovered that if they combined the erbB2-overexpressing epithelial cells from tumors with wild-type mammary epithelial cells, tumors did not form. Closer examination revealed that the transplanted mixture of cells developed into a normal mammary gland comprised of both wild-type and erbB2-overexpressing cells. In fact, erbB2-overexpressing cells had developed into several of the different epithelial cells subtypes.

These data indicate that the wild-type cells were able to suppress the ability of the erbB2-overexpressing cells to grow into tumors, thus allowing their differentiation into different types of normal mammary epithelial cells. Additional experiments revealed that the erbB2 protein in the normal glands was not activated, suggesting that the normal cells somehow created an environment in which the erbB2 oncogene was not activated. Interestingly, participation of the erbB2-overexpressing cells in the normal mammary gland did not completely rescind their tumorigenic potential. If these cells were removed from the normal mammary gland, separated from their wild-type counterparts, and implanted into a fat pad by themselves, they were again able to form tumors. This shows that the wild-type cells do not irreversibly change the nature of the erbB2-overexpressing cells but rather are required to actively keep the tumorigenic behavior of these cells in check.

These experiments highlight the importance of the tissue environment in the initiation and progression of cancer. At least some aspects of tumorigenesis appear to be dictated by the interactions of potential tumor cells with other cells around them. These findings should spur additional research on how a cell’s surroundings influence its behavior, which may lead to identification of strategies for medical interventions to prevent potential tumor cells from growing out of control.

Summary Posted: 11/2010

Reference

Booth BW, Boulanger CA, Anderson LH, Smith GH. The normal mammary microenvironment suppresses the tumorigenic phenotype of mouse mammary tumor virus-neu-transformed mammary tumor cells. Oncogene. October 4, 2010 PubMed Link