Brain cancer cells dodge conventional Rx

Typically glioblastoma patients are dead within 15 months of diagnosis, no matter how complete and well-planned their therapy.

Cells sloughed from the brain tumor escape the surgery and somehow stand up to months of radiation and chemotherapy, leading to a recurrence of the tumor and the death of the patient.

Researchers at the University of Bonn in Germany are beginning to unwind how they do it. They have learned that these sleeper cells are fundamentally different from those in the tumor. They are more mobile, obviously, as they escaped the stationary existence that made the tumor vulnerable to conventional therapy.

But these migratory cells also have changed in other ways. They have other receptors than cells in the tumor itself. And they've changed their inner mechanism to resist radiation therapy and chemical attack.

How exactly they accomplish this feat is not known. Just recognizing that these cells are different, however, is a start, one that makes sense in the context of other discoveries about cancer cells. Already five years ago basic research into the mechanism of metastasis looked into the way cancer cells invade surrounding tissue.

Research at Albert Einstein College of Medicine in New York showed that cells responsible for metastasis alter their structure in response to the local microenvironment outside tumors (Curr Opin Cell Biol 17:559-564, 2005).

This early work was extended last year by studies done at the Max Planck Institute and University of Heidelberg, which showed that at least some types of migratory cancer cells change their structure in order to more effectively move into the surrounding tissue (PLoS One online, January 15, 2010).

“Glioblastoma cells change in ways that not only allow their seepage into healthy issue, but also protect them against conventional therapy.”

A biochemical quandry

The Bonn research takes this fundamental work a step further, applying it to one of the most confounding and lethal cancers. The work demonstrates that glioblastoma cells change in ways that not only allow their seepage into healthy tissue, but also protect them against conventional therapy (Annals of Neurology online, April 6, 2010).

In the research, glioblastoma cells were removed from patients through experimental biopsy of the margin around the excised tumor. They were compared with cells from the patients' resected tumors. In vitro analysis of proliferation, invasion, stem cell qualities, GBM-typical antigens, genotypes, and in vitro drug and irradiation challenge studies revealed these cells had unique attributes.

Just as the research raises a biochemical quandary-how can such a transformation occur?-so it also presents the tantalizing prospect that a better understanding of these cells might reveal weaknesses that can be exploited.

In the future, surgery might debulk the tumor, as it does now, and conventional radiation and chemotherapy might kill the remaining tumor cells. A third approach, tuned to the cells that have infiltrated healthy brain tissue, might also be launched, potentially staving off recurrence of the tumor.

Lead author Martin Glas, MD, and colleagues, who have begun this characterization of glioblastoma infiltrates, cautioned against exaggerated hopes. Before new approaches to therapy can be constructed, the biology of these cells must be thoroughly understood, and that work has just begun, they said.