Brain metastases hijack neuron-supporting cells to resist chemotherapy

Cancer that spreads to other organs finds a particularly inviting hideout in the brain, where these metastases are usually far harder to treat than they are in other locations. Two researchers from The University of Texas M. D. Anderson Cancer Center discussed ways to more successfully target these tumors in their "sanctuary" at the American Association for Cancer Research 100th Annual Meeting 2009 in Denver.

Professor of Cancer Biology Isaiah J. Fidler, D.V.M., Ph.D., presented a novel theory about why brain metastases are resistant to chemotherapy.

"Astrocytes are spider-like cells that normally play the important role of providing oxygen and nutrients to neurons, and protecting neurons from naturally occurring toxins," Fidler said. "We show that brain metastases subvert astrocytes, tricking them into protecting the tumors, and that this is the important factor in resistance to chemotherapy."

Professor and Chair of Neurosurgery Raymond Sawaya, M.D., reviewed when and how to conduct surgery to remove metastatic tumors, including evidence that removing a tumor piecemeal raises the risk of cancer irretrievably spreading to the spinal fluid.

Fidler and Sawaya were among five speakers at "Invading the Sanctuary: New approaches to Brain Metastasis." Metastatic cancer causes the vast majority of cancer deaths. There are more than 100,000 new cases of metastatic brain cancer each year. By comparison, primary malignant brain tumors account for about 17,000 new cases annually.

Not all cancers spread to the brain. Sawaya lists lung, breast, melanoma, kidney and colon cancer as the most common. "It's common for us to operate on patients who no longer have known disease except for the metastasis in the brain," Sawaya said. Such patients have a better prognosis than those with heavier tumor burden elsewhere.

Research Shows Astrocytes Negate Chemotherapy

"The only way metastases can grow in an organ is to exploit the host organ's microenvironment," said Fidler, who with a series of experiments revived the seed-and-soil theory of metastasis first suggested by British physician Steven Paget more than 100 years ago. Paget argued that metastasis was not a random process, but that specific cancers spread only to certain organs – those who served as welcoming "soil" for specific cancer "seeds."

Fidler and colleagues examined alternate hypotheses for chemotherapy resistance. The blood-brain barrier, a tightness to brain vasculature that blocks blood-born toxins from entering the brain, was a prime suspect. They found that the barrier remains intact outside a metastasis, but breaks down inside metastases, which generally have leaky vasculature.

Another theory is that the P glycoprotein (PGP), a membrane protein that expels drugs from a cell's cytoplasm, blocks chemotherapy. "Our work and others' showed that using drugs that are totally resistant to PGP, or blocking PGP itself, did not improve survival," Fidler said.