The interaction of human benign neoplasms with the growth regulating protein, interleukin-6 (IL-6) and its surface receptor IL-6R

Brain tumors, including benign and malignant, have as their most common and severe presentation the relentless and progressive deterioration of the patient's neurological functions. Abnormal regulation of cell growth is the fundamental characteristic that defines a malignant tumor or cancer. Phenotypically normal tissue, on the other hand, can present uncontrolled autocrine and paracrine factors that may trigger the multistep process of benign tumorigenesis. These steps include tumor mass formation, expansion, vascularization and inflammation. Studies have shown evidence of a pleiotropic influence of cytokines like IL-6 in this multistep transformation in a variety of tissues. Our studies with meningiomas confirm these findings, but in the case of meningiomas, neuroimmunological studies on IL-6 and IL-6R are limited. Proliferation analyses of these tumors in vitro are generally complicated by senescence and culture contamination. Our initial efforts focused on the successful establishment of long-term meningioma cell cultures to facilitate the study of these tumors. We started cultures derived from 14 human tumor explants diagnosed as benign meningiomas by frozen section. We characterized the cultures using immunohistochemistry, conventional and electron microscopy. Initial experiments with these cells demonstrated evidence of a relationship between IL-6R and proliferating cell nuclear antigen (PCNA), the cell cycle regulated protein.; This thesis investigates the proliferative properties of reliable longterm meningioma cell cultures generated in our own laboratory. Using advanced PCR techniques we investigated the role of IL-6 in the biology of meningioma cell growth via its gp130 dependent receptor. Using the advantages of highly sensitive immunofluorescence, we obtained insight into the mechanism of autocrine/paracrine regulation that meningiomas exert on themselves and the tissue surrounding the tumor. Finally, we targeted the whole complex and specific IL-6 binding sites in the gp80 subunit of the IL-6R in an attempt to interrupt the factors that trigger the multistep process of benign tumorigenesis. Results from these perturbative studies describe the initial steps of tumorigenesis and suggest promising immunotherapy models for treatment of human meningiomas.