Photo compliments of Christian Frantz
Biophysical and molecular dialogue of glioma cells and the brain microenvironment
Gliomas account for more than 50% of all primary brain tumors and are by far the most common primary brain tumor in adults. Patients with high-grade GBM tumors (the most common form of glioma) have a median survival expectancy of approximately one year,even with the current standard-of-care, surgical resection followed by adjuvant radiotherapy plus temozolomide chemotherapy, given concomitantly with and after radiotherapy. Temazolamide is one of the only chemotherapeutic agents with a proven survival benefit (extending life by approximately three months5). However, only a subset of patients will respond to temozolomide, as anti-tumor activity is limited to gliomas that methylate and silence the MGMT promoter. Nevertheless, temozolomide is offered to all patients, due to a lack of few, if any, effective alternative agents. Newer therapies include the anti-angiogenic agent bevacizumab and the small molecule EGFR inhibitor erlotinib. While both agents are used commonly in glioma, with bevacizumab now the standard of care in relapsed high-grade tumors, it is not clear that either agent leads to improved overall survival.
Malignant gliomas are associated with such dismal prognoses in part because glioma cells can actively migrate relatively long distances through the narrow extracellular spaces in the brain, making them elusive targets for effective surgical management. Additionally, after surgical resection and adjuvant treatment of malignant gliomas, the residual cancer cells peripheral to the excised lesion give rise to a recurrent tumor that in more than 90% of cases develops immediately adjacent to the resection margin. Moreover, invasive malignant glioma cells show a decrease in proliferation rate and a relative resistance to apoptosis compared to the highly dense cellular center of the tumor, and this may contribute to their resistance to conventional pro-apoptotic chemotherapy and radiotherapy. They are also one of the most vascularized human cancers, with the formation of tumor-specific vessels occurring early at the onset of tumor growth. Furthermore, these highly aggressive tumors contain large regions of hypoxia, which contributes to their aggression and compromises treatment efficacy.
Evidence suggests that the physical, cellular, and non-cellular microenvironment of defined anatomical regions within the brain and the suggested neural stem cell (NSC) origin of GBMs contribute to their aggressiveness and resistance to treatment. We at the UCSF Tumor Microenvironment Network Brain Cancer Center (TMEN-BCC) pose the hypothesis that the vascular niche represents a micro-anatomical unit with distinct host cell constituents and unique mechano-properties that, in concert with elevated intracranial pressure and ECM stiffness, and the unique mechano-phenotype of high-grade gliomablastomas (GBMs) with tumor initiating potential (TICs), fosters the pathogenesis, recurrence, and treatment resistance of these aggressive cancers. Because GBMs are frequentlyassociated with the subventricular zone (SVZ), which is also a source of NSCs, we focus our efforts on understanding the pathology of GBMs derived from this region.
Our program, which is funded by a five-year National Institutes of Health U54 grant, encompasses three independent but interwoven projects that are supported by two scientific cores and one Administrative Core. The main scientific objectives of the Center are to first, delineate the distinct perivascular innate immune cells within the vascular niche and to implicate these infiltrating cells as constituents critical in promoting neovascularization and GBM survival, specifically in the face of irradiation, temozolomide chemotherapy, and anti-vascular therapies; second, to test the idea that the SVZ region of GBM is mechanically-challenged and aggressive GBMs with high TIC potential have a unique mechano-phenotype that fosters the vascular niche by promoting inflammation, neovascularization, and GBM differentiation; and third, to test the hypothesis that the intrinsic mechano-phenotype of high-grade GBMs, together with therapy-induced changes in the mechanical features (compression, stiffness) of SVZ-localized GBMs, enhance/induce resistance and tumor recurrence by driving GBM differentiation to re-establish the vascular niche and promote an aggressive, invasive mesenchymal-like phenotype. These goals will be achieved through a multidisciplinary approach that melds concepts and techniques from the physical sciences with classic cell and molecular biology strategies with clinical input.