Primary Appointment

Dual/Joint/Adjunct Appointment

Isaiah J. Fidler, D.V.M., Ph.D.

R. E. “Bob” Smith Distinguished Chair in Cell Biology

Professor of Cancer Biology and Urology

Director, Cancer Metastasis Research Center

Research in my laboratory continues to focus on the biology and therapy of cancer metastasis.  Most recently, we have focused on the development and progression of brain metastasis.  A large number of cancer patients develop metastasis to the brain.  For untreated patients, the median survival is 1-2 months, and conventional radio-chemotherapy can extend the median survival to 4-6 months.  The outcome of metastasis in general and brain metastasis in particular depends on the interaction of specific metastatic cells with host factors in the organ microenvironment (the “seed and soil” principle). 

Histological examination of clinical specimens of human breast, lung, melanoma, and colon brain metastases demonstrates that the lesions are surrounded and infiltrated by activated astrocytes expressing glial fibrillary acidic protein (GFAP).  GFAP-positive astrocytes are also associated with experimental brain metastases produced in mice by lung, brain, melanoma, and colon cancers.  We isolated astrocytes from the brain of the “ImmortoMouse” and established the cells in culture.  Multiple in vitro studies conclude that astrocytes cocultured with tumor cells protect the tumor cells from chemotherapeutic agents (Taxol, VCR, VBL, 5-FU).  Establishment of a gap junction between astrocytes and tumor cells is required for this chemoprotection.  Coculture of tumor cells with other tumor cells or fibroblasts does not protect the cells from chemotherapeutic drugs.  Microarray experiments for cross-species hybridization (human tumor cells cocultured with mouse astrocytes or mouse fibroblasts) identified upregulation of survival genes in tumor cells cocultured with astrocytes, but not with fibroblasts.  Significantly, these survival genes were uniformly upregulated in different tumor cells (breast, lung) cocultured with astrocytes.

The role of astrocytes in physiology is to supply glucose and oxygen to neurons to assure their survival.  Unfortunately, tumor cells that can proliferate in the brain parenchyma exploit astrocytes for these same functions.  Since the development of metastases depends on the interactions of tumor cells with host factors, treatment of brain metastasis must be directed against both the tumor cells and the organ microenvironment.

Military or Other Governmental Service

Last updated: 9/8/2009