Modeling Human Brain Tumors in Mice

While brain tumors are fortunately uncommon (2% of all cancers), they are unfortunately among of the most debilitating and deadly disorders, with mean survival times typically less than 1 year for adults with malignant brain tumors (5). In this respect, brain tumors are the most common cause of cancer-related death in children and the fourth leading cause in adults. In an effort to develop improved strategies for treating these tumors in both children and adults, numerous laboratories worldwide have investigated the seminal genetic changes important for human brain tumor development and growth, examined the various different cell types that comprise human tumors and searched for surrogate markers that might predict or reflect human tumor growth. The lessons learned from these studies have been instrumental in the design of new approaches to brain tumor therapeutics; however, they have provided only limited insights into the cellular and molecular changes essential for tumor formation and continued growth, and do not distinguish between causative changes and alterations resulting from progressive genomic instability. Moreover, research using human tumor specimens does not provide a tractable platform to adequately define the individual factors that limit the successful treatment of these complex tumors. Improved outcomes following human brain tumor therapy will depend on surmounting several important barriers (Figure 1). First, we must target the correct cell type(s) within the tumor. Work from many laboratories has shown that brain tumors are composed of numerous different cell types, including stem/progenitor cells, immunologic elements (microglia), reactive astrocytes, angiogenic constituents and neoplastic cells (10, 14, 19, 27, 31). Each of these cell types has a critical role in tumorigenesis and growth, and may need to be individually targeted in order to achieve optimal tumor growth arrest. Similarly, it is important to inhibit the dominant growth regulatory pathways important for cancer cell proliferation, survival and invasion. While several signaling pathways contribute to inappropriate cell proliferation or survival, it is necessary to develop therapeutic strategies that block the activity of those molecules most responsible for conferring these cancer phenotypes. Along these lines, therapies that inhibit key signaling pathways may also allow the cancer cells to acquire secondary genetic or molecular changes that facilitate their resistance to treatment. Excellent examples abound in the literature, including secondary mutations that facilitate tumor recurrence following Imatinib treatment (9, 24). In addition to secondary changes that culminate in treatment resistance, other molecular or genetic factors may enhance treatment, including individual differences in the ability to metabolize antineoplastic agents (pharmacogenetics and pharmacokinetics) and the presence of “modifier” genes that influence tumor development, growth and response to therapy. Another consideration germane to the treatment of brain tumors is the effect of chemotherapy or radiation therapy on the normal brain. This is especially important when treating children whose brains are still maturing and are exquisitely sensitive to agents that impair normal cell growth or differentiation. Lastly, since it is often difficult to accurately assess tumor response to treatment by conventional imaging, the identification of serum or radiologic biomarkers of disease activity would greatly augment our therapeutic armamentarium. Brain Pathology ISSN 1015-6305