The long-term goal of this project is to optimize adjuvant therapy for patients with malignant glioma. The short-term goal is to provide an optimal training environment for the applicant to pursue a research plan within the realm of translational neurooncology. The complement cascade is a well characterized effector arm of innate immunity, historically viewed as a mediator of cellular destruction. However, recent evidence has shown that activation of complement facilitates proliferation of endogenous stem cell populations. The paradigm of tissue injury followed by complement activation and subsequent proliferation of local stem cells may be a key component of normal physiology, and paradoxically cancer progression. Complement activation, secondary to tissue injury and necrosis, ultimately results in release of the anaphylotoxins C3a and C5a. These proteins in turn bind to specific receptors (C3aR and C5aR) on local stem cells, causing the activation of mitogenic signals (including MAP-kinase). From a physiological standpoint, the replenishment of injured tissue by stem cells in response to a mediator of necrosis is an elegant method to repair tissue in proportion to the extent of injury. Many cancers have components of this tissue repair pathway that suggest a possible role for complement in facilitating tumor progression. In particular, glioblastoma multiforme (GBM), which is the deadliest form of primary brain tumor, stands out as a tumor with large areas of necrosis and local stem cells that are capable of reconstituting the tumor. In this proposal, we hypothesize that complement activation and release of C3a from necrotic areas of tumor can increase proliferation of glioma cells. In support of this hypothesis, we provide preliminary results showing: 1) C3a localizes predominantly to areas of necrosis in GBM specimens, 2) that C3aR but not C5aR is expressed by glioma cell lines and primary cultures, 3) in primary GBM samples, cells expressing CD133+ (one of many markers for a brain tumor stem cell) co-express C3aR, and 4) in vitro depletion of complement from serum decreases proliferation of glioma cell lines in proportion to the level of C3aR expressed. Pursuing the aims outlined in this proposal will provide the applicant with an optimal training vehicle to facilitate a career in translational neurooncology.
