University of Virginia Health System

The prognosis for patients with malignant astroglial tumors is poor. The capacity of astrocytomas both to invade adjacent brain sites and to migrate into distant ones precludes curative surgical resection; and little progress has been made in designing adjuvant therapies that significantly affect long-term survival. In order to formulate more novel therapeutic strategies, it is essential to have a better understanding of how the invasive growth of these tumors is controlled.

The primary interest of the laboratory is the regulation of LRP (low density lipoprotein receptor-related protein) expression and function in astrocytic tumor cells. LRP is an endocytic receptor involved in the trafficking of a variety of protein/protein complexes that have pathophysiologic relevance in the central nervous system, including urokinase (uPA) and its receptor (uPAR), lipoprotein metabolites, and activated alpha2-macroglobulin. Changes in LRP expression may regulate the levels of modulators (uPA, uPAR and PAI-1) of migration/invasion around the microenvironment of astrocytic tumors.

The second project in my laboratory focuses on understanding differences in PKC-eta activation and expression between malignant vs. non-neoplastic astrocytes and on the role of PKC-eta in the control of cell proliferation and apoptosis. The regulation of cell proliferation and apoptosis in malignant astrocytic tumors is undoubtedly complex; however, we are investigating how PKC-eta regulation of these processes may be exploited to provide an experimental system in which proliferative or apoptotic phenotype may be selectively induced and studied. We are also extrapolating some of our results in cultured cells to glioblastoma animal models. We hypothesize that pharmacological regulation of PKC-eta, in combination with drugs targeting cellular migration, may present a new therapeutic paradigm for these aggressive brain tumors.

REFERENCES:

• Sando JJ, Beals JK and Hussaini IM (2003). Subcellular Translocation of PKC:  Methods in Molecular Biology edited by Alexandra Newton; 233: 77-86.
• Elias WJ, Lopes MBS, Hussaini IM, Chadduck JB, Laws ER Jr. and Jane JA Sr. (2002). Hemangiopericytoma in the Setting of Acromegaly: Case Report.   Endocrine Pathol.13(3): 251-261.
• Hussaini IM, Sando JJ, Shaffrey ME, VandenBerg SR. Protein kinase C-n regulates resistance to UVA- and y-irradiation-induced apoptosis by preventing caspase-9 cleavage in astrocytomas. Neuro-Oncology 2002; 4(1):9-13.
• Goldfarb AN, Delehanty LL, Wang D, Facke FKE, Hussaini IM. Stromal inhibition of megakaryocytic differentiation correlates with blockade of signaling b protein kinase C-epsilon and ERK/MAPK. J Biol Chem 2001; 276(31):29526-29530.
• Hussaini IM, Zhang YH, Lysiak JJ, Shen TY. Dithiolane analogs of lignans inhibit interferon-gamma and lipopolysaccharide-induced nitro-oxide production in macrophages. Acta Phamacol Sin. 2000;21(10):897-904.
• Hussaini IM, Karns LR, Griffith V, Carpenter JE, Redpath GT, Sando JJ, VandenBerg SR. Phorbol 12-Myristate-13-Acetate induces protein kinase C-n-specific proliferative response in astrocytic tumor cells. J Biol Chem 2000; 275(29):22348-22354.
• Hussaini IM, Brown MD, Weaver AM, Carpenter J, Karns LR, Vandenberg SR, Gonias SL: Stable antisense RNA expression neutralizes the activity of low-density lipoprotein receptor-related protein and promotes urokinas accumulation in the medium of an astrocytic tumor cell line. Antisense Nucleic Acid Drug Dev 1999; 9: 183-190.
• Hussaini IM, Karns LR, Redpath GT, Carpenter J, Gonias SL, Vandenberg SR: Epidermal growth factor receptor ligands induce transcriptional down-regulation of low density lipoprotein receptor-related protein (LRP) gene expression in human glioblastoma cells. Glia 1999; 25: 71-84.
• Mandell JW, Hussaini IM, Zecevic M, Weber MJ, Vandenberg SR: In situ visualization of intratumor growth factor signaling: immunohistochemical localization of activated ERK/MAP kinase in glial neoplasms. Am J Pathol 1998; 153: 1411-1423.
• Nguyen DH, Hussaini IM, Gonias SL: Binding of urokinase-type plasminogen activator to its receptor in MCF-7 cells activates extracellular signal-regulated kinase 1 and 2 which is required for increased cellular motility. J Biol Chem 1998; 273: 8502-8507.