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Updated: Apr 2, 2026
In Vivo Model for Testing Effect of Hypoxia on Tumor Metastasis
Published on: December 9, 2016
Visualizing the antivascular effect of bortezomib on the hypoxic tumor microenvironment
Xiaorong Sun1,2, Ellen Ackerstaff3, Fuqiu He2
1Department of Radiology, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.
Abstract:
Bortezomib, a novel proteasome inhibitor, has been approved for treating multiple myeloma and mantle cell lymphoma and studied pre-clinically and clinically for solid tumors. Preferential cytotoxicity of bortezomib was found toward hypoxic tumor cells and endothelial cells in vitro. The purpose of this study is to investigate the role of a pretreatment hypoxic tumor microenvironment on the effects of bortezomib in vitro and ex vivo, and explore the feasibility of dynamic contrast enhanced magnetic resonance imaging (DCE MRI) to noninvasively evaluate the biological effects of bortezomib. It was shown in vitro by Western blot, flow cytometry, and ELISA that bortezomib accumulated HIF-1α in non-functional forms and blocks its hypoxia response in human colorectal cancer cell lines. Ex vivo experiments were performed with fluorescent immunohistochemical staining techniques using multiple endogenous and exogenous markers to identify hypoxia (pimonidazole, HRE-TKeGFP), blood flow/permeability (Hoechst 33342), micro-vessels (CD31 and SMA), apoptosis (cleaved caspase 3) and hypoxia response (CA9). After bortezomib administration, overall apoptosis index was significantly increased and blood perfusion was dramatically decreased in tumor xenografts. More importantly, apoptosis signals were found preferentially located in moderate and severe pretreatment hypoxic regions in both tumor and endothelial cells. Meanwhile, DCE MRI examinations showed that the tumor blood flow and permeability decreased significantly after bortezomib administration. The present study revealed that bortezomib reduces tumor hypoxia response and blood perfusion, thus, presenting antivascular properties. It will be important to determine the hypoxic/perfusion status pre- and during treatment at further translational studies.
Insights
Bortezomib preferentially kills hypoxic tumor cells by blocking hypoxia response and decreasing blood flow. This proteasome inhibitor shows antivascular properties, making it a potential treatment for solid tumors.
Area of Science:
- Oncology
- Cancer Biology
- Medical Imaging
Background:
- Bortezomib is a proteasome inhibitor used for multiple myeloma and mantle cell lymphoma.
- It exhibits preferential cytotoxicity towards hypoxic tumor and endothelial cells.
- Its effects on solid tumors, particularly in a hypoxic microenvironment, require further investigation.
Purpose of the Study:
- To investigate the impact of a pre-treatment hypoxic tumor microenvironment on bortezomib's effects.
- To explore the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) for evaluating bortezomib's biological impact.
- To understand bortezomib's mechanism in solid tumors, focusing on hypoxia and vascularization.
Main Methods:
- In vitro studies using Western blot, flow cytometry, and ELISA to assess HIF-1α accumulation and hypoxia response in colorectal cancer cell lines.
- Ex vivo experiments with fluorescent immunohistochemical staining to analyze hypoxia, blood flow, micro-vessels, apoptosis, and hypoxia response markers in tumor xenografts.
- In vivo assessment using DCE MRI to evaluate changes in tumor blood flow and permeability post-bortezomib administration.
Main Results:
- Bortezomib treatment led to increased apoptosis and decreased blood perfusion in tumor xenografts.
- Apoptosis was predominantly observed in pre-treatment hypoxic regions of both tumor and endothelial cells.
- DCE MRI demonstrated significant reductions in tumor blood flow and permeability after bortezomib administration.
- Bortezomib was shown to accumulate HIF-1α in non-functional forms, blocking the hypoxia response in cancer cells.
Conclusions:
- Bortezomib exhibits antivascular properties by reducing tumor hypoxia response and blood perfusion.
- The study highlights the importance of assessing hypoxic/perfusion status before and during bortezomib treatment in translational studies.
- DCE MRI is a feasible noninvasive method to evaluate the biological effects of bortezomib.
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