Journal of Neuro-Oncology 18: 89-103, 1994. 9 1994 Kluwer Academic Publishers.Printedin the Netherlands'. Tumor invasion, proteolysis, and angiogenesis Unnur R Thorgeirsson, Carol K. Lindsay, David W. Cottam and Daniel E. Gomez Office of the Director, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA Key words: tumor invasion, proteinases, proteinase inhibitors, cytokines, growth factors, angiogenesis Summary In this review, some of the current literature on the regulation of proteolysis and angiogenesis during tumor invasion is discussed. Due to the critical location of brain tumors, an understanding of tumor cell interactions with the local environment is particularly relevant. Tissue breakdown during tumor invasion is associated with proteolytic activity, mediated by tumor cells, and surrounding host cells. This review covers two classes of proteinases and inhibitors that have commonly been associated with tumor invasion i.e., plasminogen activa- tor (PA)/plasmin and matrix metalloproteinases (MMP) with special emphasis on the MMP inhibitors, TIMP-1 and TIMP-2. At different steps of the metastatic process, tumor cells interact with endothelial cells. Tumor cells also stimulate the formation of new vessels through the expression of specific angiogenic mole- cules. At least eight angiogenic molecules have been purified, sequenced and cloned, four of which are dis- cussed here. Regulation of angiogenic activity has been the focus of intense studies recently, and a wide range of synthetic and natural angiogenesis inhibitors have been discovered. Targeting of angiogenic molecules and tumor vasculature may prove useful in future cancer therapeutic strategies. Introduction Invasive behavior of tumors is influenced by nu- merous tumor and host cell factors, as well as by ex- tracellular matrix molecules in the surrounding stroma. Malignant tumors, in particular high grade gliomas, contain heterogeneous and often geneti- cally unstable cell populations which are contin- uously changing [1, 2]. Tumor cell invasion requires highly coordinated expression of a multitude of reg- ulatory factors, such as adhesion molecules, protei- nases, proteinase inhibitors, and motility factors. When dealing with malignant tumors within the central nervous system (CNS), expansive growth becomes a critical consideration, since the cranium provides limited space in which the tumor can ex- pand before becoming fatal. Unlike most other ma- lignancies where metastases are responsible for death, patients with primary intracranial malignan- Addressfor offprints': U.R Thorgeirsson,Officeof the Director, Room2D02,Bethesda,Maryland 20892, USA cies generally succumb to the primary tumor. The majority of malignant primary brain tumors, i.e. gliomas, arise from the stromal tissue of the CNS. They are notorious for their invasive and migratory capacity from the primary focus, and also spread through the cerebrospinal fluid. Intravasation and distant hematogenous metastasis of malignant brain tumors however, are extremely rare [3]. The reason for this is unknown, but possible explana- tions include: high immunogenicity of gliomas; spe- cific properties of the brain vasculature which pre- vents extravasation of tumor cells; suboptimal gen- eration of metastatic cells; and short survival of pa- tients [4]. The progressive growth of the primary tumor and metastases is dependent on continuous stimulation of new blood vessel formation. During the past decade remarkable progress has been made in identifying new angiogenic factors and in- hibitors [5]. These may be of special importance in National CancerInstitute,NationalInstitutesof Health,Building 37, [1]