A wide range of cancers can be removed with surgery or eliminated with chemotherapy, but in some patients, tumor cells metastasize. Breaking off, they cause widespread damage in other areas of the body and make treatment much more difficult. Ninety percent of cancer deaths are caused by metastasis, and the risk is greater in some individuals, including those who are obese.
At Tufts School of Engineering, Assistant Professor of Biomedical Engineering Madeleine Oudin and her team have made some fascinating discoveries about metastasis and how obesity may promote it.
The researchers found that specific proteins in the scaffolding on which the cells grow, known as the extracellular matrix (ECM), may play an important role in triggering the invasion of cancer cells in the breast fat tissue of obese individuals. Differences in their ECM may explain why obese women have higher rates of metastasis.
ECM is a complex mix of collagen, elastins, fibronectin, enzymes, laminins, and other glycoproteins, but in obesity, the amount and composition of those components change, leading to fibrosis. The molecular scaffolding for tumors in obese patients is very different from that in lean patients.
The Oudin lab developed a novel method to study the effects of the ECM on cancer cells. Specifically, they took mammary tissue from obese and lean mouse models, as well as tumor-bearing mice, and stripped them of cells to obtain a complete but “empty” ECM, called a sponge.
They then added tumor cells of triple negative breast cancer—a particularly difficult cancer to treat—back into the ECM sponge to see its effects on the tumor cells.
They found that both ECM from the obese and tumor-bearing mice are equally effective at making tumor cells more metastatic. The ECM from lean mice, though, were less so. In other words, the ECM from obese mice acts as if it has already been primed with a tumor, and is ready to promote metastasis at a much earlier stage.
By looking at the changes in the ECM linked to invasive tumor behavior, Oudin and her colleagues zeroed in on the protein Collagen VI. Added to the ECM by fat cells present in the breast tissue, Collagen VI had been promoting the migration and invasion of the breast cancer cells to surrounding areas. The researchers also showed that applying certain drugs that inhibit the production of Collagen VI can rein in tumor growth and invasion.
The discovery might help point to new drug targets for cancer, and it is, according to Oudin, just the beginning of a more complete inventory of the biological mechanisms contributing to metastasis.
Pictured above: Madeleine Oudin (center) with a student from the Graduate School of Biomedical Sciences