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Co-chairs: James Goldman, M.D., Ph.D., and Rolando Del Maestro, M.D., Ph.D.

Participants: Candece Gladson Susan Hockfield Lois Lampson Marla B. Luskin Robert H. Miller Maiken Nedergaard Jasti S. Rao

Sandra Rempel Steve Rosenfeld John H. Sampson Harald Sontheimer Richard Vallee Jeanne Young

STATEMENT OF THE PROBLEM

A hallmark of primary neuroectodermal neoplasms is their infiltrative nature. By the time most such tumors are diagnosed, cells have spread beyond the neoplasm's identifiable mass and into surrounding tissues. These dispersed cells may contribute to tumor recurrence in situations in which the primary site can be controlled by surgery or other therapies. Rather little is known about the process of this spread.

The breakout group on Neurobiology: Cell Migration and Dispersal discussed the nomenclature used to describe cell movement from tumor masses into brain parenchyma. To avoid some implications of terms such as migration, invasion, and infiltration, it was agreed to use the word dispersal to describe the movement of tumor cells through the central nervous system (CNS).

CHALLENGES AND QUESTIONS

• The need to understand brain tumor dispersal through the CNS

• The need for more information on how tumor cells interact with normal cellular constituents of the brain. Emphasis should be placed on developing new models for studying tumor cell dispersal and tumor-CNS interactions.

• The need to consider how further knowledge of the first two phenomena could result in new therapies.

RESEARCH AND SCIENTIFIC PRIORITIES

Priority 1: Define the molecular constituents required for dispersal.

Although redundancy in motility-based genes may make it problematic to isolate specific targets, there is evidence that cell-specific isoforms exist for some of these proteins. It would be valuable, therefore, to identify and determine the function of gene products that regulate motility in neuroectodermal tumors. The molecules include possible tumor- or tumor-type specific motors and cytoskeletal proteins; small GTPases that regulate interactions between external signals and internal cytoskeletal organization; cell surface receptors involved in cell migration, including those that may mediate start or stop signals or maintain cell polarity; components of extracellular matrix, including proteases involved in remodeling extracellular matrix molecules as cells migrate; ion channels that may allow changes in cell shape or cell volume during migration; G protein-coupled receptors; and the extracellular matrix molecules produced by both tumor and CNS.

Resources needed:

• Use DNA chip technology to examine appropriate tumor cell types, preferably freshly isolated tumor cells rather than tumor cell lines. It may be worthwhile to search for differences among tumor types that display characteristic and different migratory patterns (e.g., juvenile pilocytic astrocytomas through white matter, oligodendrogliomas through white matter and into cortex, and medulloblastomas).

• This kind of search should also be carried out for normal glial and neuronal progenitors, because little is known about the specific molecular mechanisms underlying migration and because normal and tumor cells probably share many common regulatory mechanisms.

Priority 2: Examine how tumor cells interact with the brain's normal cellular constituents.

Little is known about how tumor cells interact with normal neurons and glia. Several kinds of interactions are worthy of investigation, including gap-junction formation between tumors and normal astrocytes, altered potassium or neurotransmitter (glutamate) buffering produced by tumor cells in proximity to neurons, synaptic disruption, interactions between migrating tumor cells and the CNS extracellular matrix, and interactions with the immune system (Do tumors activate resting microglia? If so, how? Do tumors, which express a variety of cytokines, attract lymphocytes into the CNS?)

Emphasis should be placed on examining tumor-CNS interactions in appropriate in vivo and in vitro tumor models. It is important to design assays that determine the functional consequences of these interactions and whether the perturbations are reversible. Studies that integrate the anatomy and physiology of tumor-CNS interactions should receive highest priority.

Resources needed:

• New models are needed for studying tumor cell dispersal and tumor-CNS interactions The group discussed existing models, including two- and three-dimensional models in vitro and co-culture experiments with tumor and normal brain, but focused on using existing models and on developing new models in which tumor cells could be studied moving through the normal CNS. This could be accomplished in brain slices or in whole animal models, from which slices could be used to examine tumor cell movements. These would be particularly useful if the models resulted in tumors whose cells disperse through the brain and are tagged to be clearly distinguishable from normal cells. It is hoped that such animal models would be freely available to investigators interested in tumor cell dispersal.

Priority 3: Determine how we can best use the knowledge acquired through research described in the priorities above to define new therapeutic targets.

For example, can lymphocytes be directed toward dispersed tumor cells? Can other migratory cells (progenitors) expressing therapeutic genes be directed toward dispersed tumor cells? Can chemoattractants be used to bring tumor cells back to the main tumor mass? Is there a way to stop migration so tumor dispersal is controlled? This may have the consequence of halting tumor spread without killing the tumor, thus turning a brain tumor into a chronic disease. Studies that emphasize controlling tumor dispersal should receive high priority. Interactions between cell movement and cell division must be carefully ascertained in various model systems. That is, what are the consequences of inhibiting cell motility in other cell functions, particularly proliferation?

Resources needed:

• A National Institutes of Health focus group in which researchers who study normal neuronal- and glial-progenitor migration interact with tumor biologists who study neoplastic cell movement. The two groups have a great deal to learn from each other, and such a meeting may result in beneficial collaborations.

• A consortium whose members work in established laboratories with expertise in various cell migration models, to allow new molecules that may be useful in blocking elements of tumor dispersal to be efficiently screened.

Last updated February 09, 2005