Surveying genes in stromal and cancer cells
Cancer is a disease of genes. Whatever its cause—toxic exposures, radiation, inherited predisposition, viruses, or simply bad biological luck—cancer is the result of changes, or mutations, in genes that disable the "brakes" keeping cell growth under control.
Breast cancer progression
Normal: In cross-section of normal milk ducts, the inner red and blue layers are cells of the duct lining, the green layer is basement membrane, and scattered multicolored cells make up the stroma. Signals from stromal cells (yellow arrows) can cause cancer cells within the ducts to become more aggressive.
DCIS: Abnormal growth of cells lining the duct (red) fills it with cancer, but it is not dangerous when confined within the duct.
Invasive: Cancer cells, spurred by signals from the stroma, break through the duct lining and basement membrane into breast tissue.
Metastatic: Invasive cancer cells spread through the bloodstream to other organs, including bone, in advanced stage breast cancer
Illustration by John DiGianni, based on artwork by Kornelia Polyak, MD.
In a project that culminated in a paper published in Cancer Cell in July 2004, Dr. Polyak and colleagues purified samples of the many types of cells within and outside the breast ducts and then carried out an extensive survey of their genes. The researchers compared gene activity in normal and cancerous breast cells supplied by the Tissue Bank at Dana-Farber/Brigham and Women's Cancer Center. Because they studied genes from normal breast tissue, DCIS lesions, and invasive tumors, the researchers captured snapshots of the genes' behavior changes as the cells went from normal to cancerous (but confined to the ducts) to fully invasive tumors to those that had metastasized (spread) to other organs.
"We wanted to see how much of a role these stromal changes play in the progression of breast tumors," says Dr. Polyak. Collaborators on the project included Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) colleagues Andrea Richardson, MD, a breast cancer pathologist, and William Sellers, MD, an expert in genomics.
The scientists found, as expected, that the cancerous epithelial cells were rife with genetic changes—mutations, damaged chromosomes, and other alterations— that drive cancer cells into a life of biological crime. By contrast, there were few if any outright gene alterations in the surrounding stromal cells, which include fibroblasts, myofibroblasts, and leukocytes.
Just because the bystander cells' genes were structurally normal, however, doesn't mean their behavior was. Dr. Polyak found that many genes in the stromal cells were "upregulated"—making proteins at a faster-than-normal rate. Some of these revvedup signaling proteins caused the neighboring cancerous epithelial cells to become more mobile and able to dissolve and cross the basement membrane.
In surveying gene activity in all the cell types of the breast ducts and their microenvironment, and observing how it changed as the cells went from normal to metastatic, Dr. Polyak accomplished a feat that was hailed as an important step toward a more comprehensive understanding of breast cancer development.
"The work done by Kornelia Polyak is a step forward in cancer research," says J. Dirk Iglehart, MD, director of the Women's Cancers Program at Dana-Farber and chief of Surgical Oncology at Brigham and Women's Hospital (both part of the DF/BWCC). "It also represents how the Women's Cancers Program works. Cancer research is a team effort, and teamwork is an essential part of success."
There's more than academic interest afoot here. If these not-so-innocent neighbors are contributing to cancer, why not broaden the attack on breast cancer to include them? Already, Dr. Polyak and some pharmaceutical companies are exploring this new line of approach with optimism.
"You have to treat the whole tumor as an organ, with its own blood vessels and connective tissue," she explains. "Finding the genes in the stromal cells that support the growth of the tumor and targeting them with chemotherapy might be more effective than aiming at the tumor cells alone."
Some breast cancer patients are already receiving antiangiogenic drugs designed to destroy blood vessels that nourish breast cancers. Generally, though, strategies to target cells in the stroma are in very early stages of testing.
In her recent work, Dr. Polyak found that substances known as chemokines, which activate the immune system, are secreted in high amounts by stromal cells surrounding breast cancers. If they are culprits in prodding cancerous epithelial cells to become more aggressive, blocking that signal could be a new way to restrain breast cancer. Some such compounds are in preliminary testing.
The researchers found that two chemokines, known as CXCL12 and CXCL14, were more active in invasive breast cancers than in DCIS or epithelial cells. Signals turning up the production of these two cancer-driving molecules are generated by stromal cells and also by myoepithelial cells, which are part of the milk duct itself. One of the chemokine-inhibiting drugs in testing blocks the receptor molecule for CXCL12; the receptor for CXCL14 hasn't yet been found.
- Next: Where will her journey of discovery lead now?
- Page: 1 | 2 | 3 | 4
