We have previously described a panel of serially transplantable
glioblastoma multiforme xenograft lines established by direct
subcutaneous injection of patient
tumor tissue in the flanks of nude mice. Here we report the characterization of four of these lines with respect to their histopathologic, genetic, and growth properties following heterotopic-to-orthotopic (flank-to-intracranial) transfer. Cells from short-term cultures, established from excised flank xenografts, were harvested and injected into the brains of nude mice (10(6) cells per injection). The intracranial
tumors generated from these
injections were all highly mitotic as well as highly invasive, but they lacked necrotic features in most instances and failed to show endothelial cell proliferation in all instances. For mice receiving
injections from a common explant culture,
tumor intracranial growth rate was consistent, as indicated by relatively narrow ranges in survival time. In contrast to the loss of
epidermal growth factor receptor gene (EGFR) amplification in cell culture, high-level amplification and overexpression of EGFR were retained in intracranial
tumors established from two EGFR-amplified flank
tumors. A third intracranial
tumor retained patient
tumor amplification and high-level expression of
platelet-derived growth factor receptor alpha gene. Because the heterotopic-to-orthotopic transfer and propagation of
glioblastoma multiforme preserves the
receptor tyrosine kinase (RTK) gene amplification of patient
tumors, this approach should facilitate investigations for determining the extent to which RTK amplification status influences
tumor response to RTK-directed
therapies. The fact that such studies were carried out by using an invasive
tumor model in an anatomically appropriate context should ensure a rigorous preclinical assessment of agent efficacy.