Introduction by Ginny Mason, Executive Director
The buzz word in the medical field these days is “outcomes.” For a treatment to be considered useful, there must be measurable improvement (outcomes). Sometimes outcomes are very difficult to quantify, especially if you’re talking about early bench research. How do we measure the anticipated “bang for the buck” when the Inflammatory Breast Cancer Research Foundation gives a research grant? Grantees are required to provide quarterly progress reports during the active grant period. Once a relationship has been established we follow the research, hopefully to publication. But those aren’t often read by the public, so we’ve asked Patricia Steeg, PhD, to present progress on work funded by a grant to Diane Palmieri, PhD in 2009. While Dr. Palmieri is no longer in the lab, Dr. Steeg has continued the work. Our thanks to Dr. Steeg for her dedication and this exciting update! Read more about research grants awarded 2009-2013.
Establishment and Characterization of an IBC Model of Brain Metastasis.
Patricia S. Steeg, Ph.D., National Cancer Institute
Brain metastases of breast cancer appear to be increasing as our systemic therapies improve. This may result from patients living longer, or it may be particular to the brain. The normal brain is surrounded by a blood-brain barrier (BBB), which protects it from harmful substances. When a metastasis forms, the degree to which the BBB is broken down, is poorly understood. Some say that it is gone, as we image by Gadolinium uptake to diagnose brain mets; others say that, while it may be open to some degree, it is not opened enough, since chemotherapy does not work at all in the brain. While most research has focused on HER2+ and triple-negative breast cancers for brain mets, IBC spawns brain mets as well. The purpose of our work was therefore to establish a working brain metastasis model from an IBC cell line, so that this disease type could be included in our studies.
We used the SUM190 IBC cell line, passing it through mice three times to obtain a subline that reliably metastasizes to the brain (Figure 1A). The line makes large “bowling ball” looking lesions throughout the brain, distinct from the other models that we have produced.
These lesions have a prominent neuro-inflammatory response- they are surrounded by activated microglia and astrocytes.
When we asked how much of the BBB was intact, we found that most IBC brain mets in this model were relatively impermeable (Figure 1 B-D). Our studies are now using this model system, together with several others, to identify exactly what has changed in the BBB when a met forms. In particular we want to know what changes between the impermeable and highly permeable mets, so that hopefully we can drug this pathway and increase drug uptake to therapeutic levels. We are drafting our first paper on the subject, which will examine the traditional components of the BBB and narrow in on the pericytes that line the blood vessels of the BBB. In the Sum190-BR3 cells, and in the other models, the subtypes of pericytes appear to change when lesions are poorly versus highly permeable. Figure 2 shows staining for a subtype of pericytes (Desmin+) in a highly permeable IBC met. The pericytes line the blood capillaries to a higher degree than in impermeable brain metastases by about 60%. In future experiments we will determine if these Desmin+ pericytes actually cause an increase in drug permeability. If so, we will then work on increasing their abundance.
We would like to thank the donors and volunteers of the Inflammatory Breast Cancer Research Foundation for funding this work. We hope that, by including this novel model system, any answer that we come up with will be preclinically validated to be tested on IBC patients.