Integrin α3ß1 promotes vessel formation of glioblastoma-associated endothelial cells through calcium-mediated macropinocytosis and lysosomal exocytosis.

Therapeutic targeting of angiogenesis in glioblastoma has yielded mixed outcomes. Investigation of tumor-associated angiogenesis has focused on the factors that stimulate the sprouting, migration, and hyperproliferation of the endothelial cells. However, little is known regarding the processes underlying the formation of the tumor-associated vessels. To address this issue, we investigated vessel formation in CD31+ cells isolated from human glioblastoma tumors. The results indicate that overexpression of integrin α3ß1 plays a central role in the promotion of tube formation in the tumor-associated endothelial cells in glioblastoma. Blocking α3ß1 function reduced sprout and tube formation in the tumor-associated endothelial cells and vessel density in organotypic cultures of glioblastoma. The data further suggest a mechanistic model in which integrin α3ß1-promoted calcium influx stimulates macropinocytosis and directed maturation of the macropinosomes in a manner that promotes lysosomal exocytosis during nascent lumen formation. Altogether, our data indicate that integrin α3ß1 may be a therapeutic target on the glioblastoma vasculature.

Limited brain metastases: a narrative review.

Limited brain metastases refer to an oligometastatic state in the brain for which focal therapy with stereotactic radiosurgery (SRS) is appropriate. The definition of what is considered "limited" for brain metastases, however, is not well defined. Multiple recent randomized trials show that metastasis-directed therapy with surgery or stereotactic radiation can prolong survival for patients with 1-5 metastases from various primary tumors, but patients with untreated brain metastases were largely excluded from these trials. Stereotactic radiosurgery allows for the treatment of multiple brain metastases while avoiding whole brain radiation (WBRT), which has a known negative impact on neurocognitive function. Randomized trials have shown that stereotactic radiation alone is effective for the treatment of up to 4 brain metastases with decreased neurocognitive side effects and no detriment to overall survival (OS). These data have led to our current definition of "limited" brain metastases. However, more recent data suggests that patients with up to 10 brain metastases can benefit from SRS. Ongoing trials are investigating if patients with up to 15-20 brain metastases may similarly benefit from SRS alone. Advances in systemic therapies which penetrate the blood-brain barrier and have greater activity in central nervous system (CNS) may also expand the population for whom radiosurgery is an appropriate treatment. Immunotherapy may also be synergistic with radiosurgery in some cases. This narrative review will discuss the evolving definition and management of limited brain metastases.

Dendritic cell immunotherapy for solid tumors: evaluation of the DCVax® platform in the treatment of glioblastoma multiforme.

DCVax(®) (Northwest Biotherapeutics, Inc., MD, USA) is a platform technology for delivering dendritic cell based therapeutic vaccines for a variety of cancers, including glioblastoma multiforme (GBM). DCVax(®)-L, one of the implementations of the DCVax platform, provides personalized active immunotherapy composed of autologous dendritic cells pulsed with autologous whole tumor lysate. Clinical trials with DCVax-L for GBM included previous Phase I/II clinical trials and an ongoing Phase III trial. Preliminary reports of patient outcomes after administration of the DCVax-L vaccine provide a promising therapeutic paradigm for patients with both initially diagnosed and recurrent GBM. Here we evaluate the current literature and clinical experience with the DCVax platform, with a particular focus on GBM treatment.