Arrangement of Connective Tissue Predicts Breast Cancer Prognosis
Madison, Wisconsin - Analyzing the spread of tumors in a way that's similar to looking at highways on a map may indicate how well a breast-cancer patient will do or not, researchers at the University of Wisconsin-Madison have found.
Straight "highways" of collagen fibers shooting through connective tissue perpendicularly from tumors are associated with poor patient outcomes. In analyzing 200 biopsy samples with a special microscope, the researchers found that patients with the straight, perpendicular alignment had a four-fold risk of relapsing or dying of breast cancer.
The study appears in the March American Journal of Pathology.
"We have identified a novel collagen-signature system that may become a very useful addition to the tools clinicians use to determine a breast cancer patient's prognosis," says senior author Dr. Patricia Keely, associate professor of cell and regenerative biology at the UW School of Medicine and Public Health (SMPH) and a member of the UW Carbone Cancer Center.
Collagen is the main component of connective tissue, which surrounds most organs in the body, including mammary ducts, essentially holding everything together. But it's not just a structural element. Collagen also instructs cells around it to behave in tissue-specific ways. Under a microscope, it normally looks like a jumble of softly curving footpaths or a plate of spaghetti noodles.
In previous studies, Keely and her team examined collagen in mouse breast tumors, where they could clearly see what changes occurred during early and late stages of cancer. The scientists were particularly interested in the stage when the tumor breaks through the basement membrane, a thin sheet surrounding connective tissue, as it tries to invade additional healthy breast tissue.
"We identified what we call tumor-associated collagen signatures, or TACS, which are arrangements of the collagen that change as cancer progresses to different stages," says Keely. TACS-1 is a very early stage of collagen accumulation, TACS-2 represents collagen fibers aligned more or less parallel to the tumor while TACS-3 represents a straight, perpendicular arrangement jutting out from a tumor.
In the current study, the UW-Madison researchers analyzed samples of tumor slices from 200 patients with invasive breast cancer that co-author Dr. Andreas Friedl, a professor of pathology and laboratory medicine at the School of Medicine and Public Health, had used in his connective-tissue studies of a protein called syndecan-1 (Sdc1).
Friedl's research, reported in last month's American Journal of Pathology, showed that Sdc1 alters collagen so that it aligns in TACS-3 fashion, and that the alterations cause breast cancer cells to move directionally and invade tissue.
Keely's team examined 16 collagen "areas of interest" in each sample, looking for TACS-3 in each area. A biostatistician then compared their findings to patient outcome information.
The analysis showed that in samples of early disease, the highway angle appeared parallel to the basement membrane. As tumors became invasive, the collagen realigned, and the angle became 90 degrees relative to the tumor boundary.
"We think the cancer cells start to pull on the collagen and straighten it out, forming a track or highway on which the cells can migrate," Keely says.
The scientists found that tumors readily used the highways. The more fully developed the highway was, the more the tumor was able to use it to spread.
Keely collaborated with Dr. Kevin Eliceri, director of the Laboratory for Optical and Computational Instrumentation at UW-Madison, to use a special microscope that can provide a three-dimensional look at breast tissue. In the future, portable versions of the microscope could be stationed outside surgery suites for quicker analysis, Keely says.
"Dr. Keely has provided clinicians taking care of breast cancer patients with another tool to help individualize breast cancer treatment," says Wilke. "The TACS signatures will need to be evaluated on a larger scale but the technology is simple and noninvasive and can be used on the core biopsy samples that are removed when a women is first diagnosed with breast cancer.
"Importantly, the work of Drs. Friedl and Keely offers a new set of targets for breast cancer therapy; namely, the environment around the breast ducts and lobules."
Keely expects that the TACS analysis of connective tissue may also be useful for other kinds of cancers, including colon, ovarian and some kinds of skin cancer.
Date Published: 03/01/2011