Current Research in Neurosurgery: Ian E. McCutcheon, M.D.

Pituitary neoplasms, neurofibromatosis, IGF-1 and other growth factors in meningiomas, iNOS in gliomas

The research effort of my laboratory remains focused on several areas. The biology of the meningioma, one of the most common primary brain tumors, continues as a particular emphasis. Meningiomas can be benign, atypical, or malignant. They may be inherited and are commonly seen in patients carrying mutation of the neurofibromatosis (NF)-2 gene. Using meningioma specimens held in tissue banks and tumors grown in primary culture, we have studied the involvement of growth factors in cell culture, and in animal models which we have developed to better study the biology of meningiomas in living creatures.

We have researched the proteases relevant to tumor invasiveness, including serine proteases and metalloproteases and their inhibitors. We have also studied the invasiveness of meningiomas in cell culture and we have characterized the behavior of different grades of meningioma in culture with respect to recent advances in immunohistochemistry and changes in the neuropathologic grading scheme of these tumors. Most importantly, we have created an orthotopic animal model of meningiomas using athymic mice injected intracranially with meningioma cell suspensions. The tumors thus created replicate well the favored anatomic sites and histologic appearance of meningiomas in humans. Current work is focused on autocrine growth factor loops in meningiomas and their control mechanisms as well as the signal-sorting pathways connecting cell-surface events with gene activation in the cell nucleus. In this regard, in collaboration with Dr. Keith Friend (Section of Endocrinology) and Dr. Robert Radinsky (Department of Cancer Biology), we have recently demonstrated the presence of functional growth hormone (GH) receptors in meningiomas and have established an important role for both platelet-derived growth factor and insulin-like growth factor 1 (IGF-1) in stimulating meningioma growth. We have also shown that a specific GH receptor antagonist reduces GH-induced mitogenesis in these tumors, and we are trying to determine how somatostatin receptors (profusely abundant in meningiomas) tie in to the GH/IGF-1 system. We are also collaborating with Dr. Reuben Lotan (Department of Thoracic/Head and Neck Medical Oncology) to formulate chemoprevention strategies for meningiomas using retinoids and other modulators of differentiation, an approach we hope to apply toward the future treatment of neurofibromatosis. Finally, in collaboration with Dr. Timothy Schaefer, we have established that interleukin-6, a likely constituent of autocrine loops in meningiomas and other tumors, activates the Stat 3 protein. This work is being extended to demonstrate the intracellular effects of interferon (which we have shown interferes with growth factor-induced cell proliferation), prolactin and other molecules on meningiomas. We also hope to assess the efficacy of gene therapy in our animal model.

My second area of research is the mapping of glial tumor margins, a topic of direct relevance to clinical neurosurgery. In this effort, we have collaborated with Dr. Sharon Thomsen (Department of Pathology) and Dr. Anita Mahadevan (Vanderbilt University, Nashville, TN) in the use of laser-induced autofluorescence spectra for differentiating among tumor, infiltrated brain adjacent to tumor, and normal gray and white matter, both in rats and in patients with gliomas who undergo craniotomy or stereotactic biopsy. We have also collaborated with Dr. Edward Jackson (Department of Diagnostic Radiology) to validate predictions made in such patients on the basis of dynamic MRI findings regarding tumor heterogeneity and identity. I plan to extend this work by comparing intracerebral microdialysis and laser-induced autofluorescence with intraoperative techniques that assess other physiologic parameters (including cerebral blood flow, tissue partial pressure of oxygen and pH). Such an examination of the pathophysiology of the brain-tumor interface should permit better intraoperative tumor margin detection, thereby maximizing tumor resection and optimizing patient outcome.