Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra-arterial delivery of bevacizumab: From bedside to bench

Burkhardt, Jan Karl; Hofstetter, Christoph P.; Santillán, Alejandro; Shin, Benjamin J.; Foley, Conor P.; Ballon, Douglas; Gobin, Y. Pierre; Boockvar, John A.

doi:10.1016/j.jocn.2012.03.012

Cited by 30 publications

(15 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…So far, immunohistochemistry-based post-mortem analysis together with image quantification still provides information on cell engraftment or distribution after transplantation as accurate and quantitative as modern noninvasive techniques, helping at corroborating in vivo findings in the fields of stem cell therapy [32,35] or tumor xenograft [20]. …”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, most of these studies only focused on frozen sections [14–17], which is a shortcoming for applications on paraffin-embedded or long-stored/shipped specimens. In addition, human-specific Ab recognizing blood antigens such as TRA-1-85 [18,19] or minor/major histocompatibility antigens [20] have also been tested but have not yielded satisfactory results in terms of broad applicability, ubiquitous expression or lasting expression following differentiation.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Immunohistochemical Toolkit for Tracking and Quantifying Xenotransplanted Human Stem Cells

Allard

Lopez

et al. 2014

Regen. Med.

View full text Add to dashboard Cite

Aim Biomarker-based tracking of human stem cells xenotransplanted into animal models is crucial for studying their fate in the field of cell therapy or tumor xenografting. Materials & methods Using immunohistochemistry and in situ hybridization, we analyzed the expression of three human-specific biomarkers: Ku80, human mitochondria (hMito) and Alu. Results We showed that Ku80, hMito and Alu biomarkers are broadly expressed in human tissues with no or low cross-reactivity toward rat, mouse or pig tissues. In vitro, we demonstrated that their expression is stable over time and does not change along the differentiation of human-derived induced pluripotent stem cells or human glial-restricted precursors. We tracked in vivo these cell populations after transplantation in rodent spinal cords using aforementioned biomarkers and human-specific antibodies detecting apoptotic, proliferating or neural-committed cells. Conclusion This study assesses the human-species specificity of Ku80, hMito and Alu, and proposes useful biomarkers for characterizing human stem cells in xenotransplantation paradigms.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Immunohistochemical Toolkit for Tracking and Quantifying Xenotransplanted Human Stem Cells

Allard

Lopez

et al. 2014

Regen. Med.

View full text Add to dashboard Cite

show abstract

“…Although it is a reasonable assumption that bevacizumab gains access to the perivascular space in GBM, to our knowledge there are no published reports demonstrating this. One report indicated that human IgG (hIgG) was detectable in tumor lysates of orthotopic GBM xenograft tumors that had been propagated in nude mice administered bevacizumab (11). However, this was based on western blotting of whole tumor lysates and, thus, did not differentiate between the presence of the bevacizumab in the perivascular space and the tumor-associated vessels.…”

Section: Introductionmentioning

confidence: 99%

Macropinocytosis of Bevacizumab by Glioblastoma Cells in the Perivascular Niche Affects their Survival

Muller-Greven

Carlin

Burgett

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose Bevacizumab, a humanized monoclonal antibody to VEGF, is used routinely in the treatment of patients with recurrent glioblastoma (GBM). However, very little is known regarding the effects of bevacizumab on the cells in the perivascular space in tumors. Experimental Design Established orthotopic xenograft and syngeneic models of GBM were used to determine entry of monoclonal anti-VEGF-A into, and uptake by cells in, the perivascular space. Based on the results, we examined CD133+ cells derived from GBM tumors in vitro. Bevacizumab internalization, trafficking and effects on cell survival were analyzed using multi-label confocal microscopy, immunoblotting and cytotoxicity assays in the presence/absence of inhibitors. Results In the GBM mouse models, administered anti-mouse-VEGF-A entered the perivascular tumor niche and was internalized by Sox2+/CD44+-tumor cells. In the perivascular tumor cells, bevacizumab was detected in the recycling compartment or the lysosomes, and increased autophagy was found. Bevacizumab was internalized rapidly by CD133+/Sox2+-GBM cells in vitro through macropinocytosis with a fraction being trafficked to a recycling compartment, independent of FcRn, and a fraction to lysosomes. Bevacizumab treatment of CD133+ GBM cells depleted VEGF-A and induced autophagy thereby improving cell survival. An inhibitor of lysosomal acidification decreased bevacizumab-induced autophagy and increased cell death. Inhibition of macropinocytosis increased cell death, suggesting macropinocytosis of bevacizumab promotes CD133+ cell survival. Conclusions We demonstrate that bevacizumab is internalized by Sox2+/CD44+-GBM tumor cells residing in the perivascular tumor niche. Macropinocytosis of bevacizumab and trafficking to the lysosomes promotes CD133+ cell survival, as does the autophagy induced by bevacizumab depletion of VEGF-A.

show abstract

“…Based upon its drug kinetics, tumor uptake, and synergy with hyperthermia, the regional administration of melphalan may be effective for any tumor type and was therefore tested for ICA infusion in our proposed system. The model described here was developed independently based upon our experience with regional therapies at other tumor sites [16] and has potential advantages compared to the only other similar mouse models published to date [18, 19]. Firstly, our model of ICA infusion was designed to be delivered antegrade to ensure complete delivery of infusate unlike the retrograde approach via the external carotid artery [18].…”

Section: Introductionmentioning

confidence: 99%

A murine model of targeted infusion for intracranial tumors

et al. 2015

View full text Add to dashboard Cite

Historically, intra-arterial (IA) drug administration for malignant brain tumors including glioblastoma multiforme (GBM) was performed as an attempt to improve drug delivery. With the advent of percutaneous neuorovascular techniques and modern microcatheters, intracranial drug delivery is readily feasible; however, the question remains whether IA administration is safe and more effective compared to other delivery modalities such as intravenous (IV) or oral administrations. Preclinical large animal models allow for comparisons between treatment routes and to test novel agents, but can be expensive and difficult to generate large numbers and rapid results. Accordingly, we developed a murine model of IA drug delivery for GBM that is reproducible with clear readouts of tumor response and neurotoxicities. Herein, we describe a novel mouse model of IA drug delivery accessing the internal carotid artery (ICA) to treat ipsilateral implanted GBM tumors that is consistent and reproducible with minimal experience. The intent of establishing this unique platform is to efficiently interrogate targeted anti-tumor agents that may be designed to take advantage of a directed, regional therapy approach for brain tumors.

show abstract

Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra-arterial delivery of bevacizumab: From bedside to bench

Cited by 30 publications

References 30 publications

Immunohistochemical Toolkit for Tracking and Quantifying Xenotransplanted Human Stem Cells

Immunohistochemical Toolkit for Tracking and Quantifying Xenotransplanted Human Stem Cells

Macropinocytosis of Bevacizumab by Glioblastoma Cells in the Perivascular Niche Affects their Survival

A murine model of targeted infusion for intracranial tumors

Contact Info

Product

Resources

About