Mechanisms of neovascularization and resistance to anti-angiogenic therapies in glioblastoma multiforme

Abstract

Glioblastoma Multiforme (GBM) is the most malignant brain tumor and highly resistant to intensive combination therapies. GBM is one of the most vascularized tumors and vascular endothelial growth factor (VEGF) produced by tumor cells is a major factor regulating angiogenesis. Successful results of preclinical studies of anti-angiogenic therapies using xenograft mouse models of human GBM cell lines encouraged clinical studies of anti-angiogenic drugs such as bevacizumab (Avastin), an anti-VEGF antibody. However, these clinical studies have shown that most patients become resistant to anti-VEGF therapy after an initial response. Recent studies have revealed some resistance mechanisms against anti-VEGF therapies involved in several types of cancer. In this review, we address mechanisms of angiogenesis, including unique features in GBMs, and resistance to anti-VEGF therapies frequently observed in GBM. Enhanced invasiveness is one such resistance mechanism, and recent works report the contribution of activated MET signaling induced by inhibition of VEGF signaling. On the other hand, tumor cell-originated neovascularization including tumor-derived endothelial cell-induced angiogenesis and vasculogenic mimicry has been suggested to be involved in the resistance to anti-VEGF therapy. Therefore, these mechanisms should be targeted in addition to anti-angiogenic therapies to achieve better results for patients with GBM.

Improved Treatment Efficacy of Antiangiogenic Therapy when Combined with Picornavirus Vaccination in the GL261 Glioma Model

“…While tumor cells initially grow along pre-existing blood vessels, tumor progression is accompanied by an increase in angiogenesis, mediated primarily through the cytokine vascular endothelial growth factor (VEGF) [2,3]. As tumors grow and normal vasculature is disrupted, hypoxic conditions induce endothelial cells and tumor cells to express VEGF and proangiogenic transcription factors, promoting vascular remodeling and sprouting [2,[4][5][6]. Importantly, increased VEGF expression has been shown to correlate with higher tumor grade and decreased patient survival [7,8].…”

“…Bevacizumab is a humanized monoclonal antibody that neutralizes circulating VEGF, preventing its interaction with VEGF receptors and subsequent angiogenesis through tumor vessel formation [2,9]. While bevacizumab is the first antiangiogenic therapy approved for the treatment of recurrent GBM, results in clinical trials have been mixed [10].…”

Mechanistic patient-specific predictive correlation of tumor drug response with microenvironment and perfusion measurements

“…GBM is the most malignant primary brain tumor and secretes high levels of vascular endothelial growth factor, inducing vascular proliferation. Despite its vascular density, GBM is highly resistant to chemotherapy and antiangiogenic therapies (11). Comparison of postchemotherapy biopsies of GBM with our model addresses questions of how tissue architecture and vascular distribution influence chemotherapeutic delivery in addition to validating the generality of our modeling approach.…”

Expression of CXC-motif-chemokine 12 and the receptor C‑X‑C receptor 4 in glioma and theeffect on peritumoral brain edema

“…Glioma, which is the most common intracranial tumor in adults, is characterized by high vascularization and invasive capacity, as well as peritumoral brain edema (PTBE) (1)(2)(3)(4). In preoperative magnetic resonance imaging (MRI), the degree and morphological characteristics of PTBE vary between different types of glioma (5).…”

“…In preoperative magnetic resonance imaging (MRI), the degree and morphological characteristics of PTBE vary between different types of glioma (5). PTBE, which facilitates glioma cell invasion and significantly affects patient prognosis, is a major cause of the high disability and mortality rate of glioma (4,6). A previous study has demonstrated that glioma recurrence patterns are affected by the degree and morphological characteristics of PTBE (7).…”