In Vivo Imaging Reveals Significant Tumor Vascular Dysfunction and Increased Tumor HIF-1α Expression Induced by High Single-Dose Irradiation in a Pancreatic Tumor Model

Publication date: Available online 14 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Azusa Maeda, Yonghong Chen, Jiachuan Bu, Hilda Mujcic, Bradly G. Wouters, Ralph S. DaCosta
PurposeTo investigate the effect of high-dose irradiation on pancreatic tumor vasculature and microenvironment using in vivo imaging techniques.Methods and MaterialsA BxPC3 pancreatic tumor xenograft was established in a dorsal skinfold window chamber (DSWC) model and a subcutaneous hind leg model. Tumors were irradiated with a single dose of 4, 12 or 24 Gy. The DSWC model was used to assess tumor response, vascular function and permeability, platelet and leukocyte adhesion to the vascular endothelium, and tumor hypoxia for up to 14 days after 24 Gy-irradiation. The hind leg model was used to monitor tumor size, hypoxia and vascularity for up to 65 days after 24 Gy-irradiation. Tumors were assessed histologically to validate in vivo observations.ResultsIn vivo fluorescence imaging revealed temporary vascular dysfunction in tumors irradiated with a single dose of 4-24 Gy, but most significantly with a single dose of 24 Gy. Vascular functional recovery was observed by 14 days after irradiation in a dose-dependent manner. Furthermore, irradiation with 24 Gy caused platelet and leukocyte adhesion to the vascular endothelium within hours to days after irradiation. Vascular permeability was significantly higher in irradiated tumors compared with non-irradiated controls 14 days after irradiation. This observation corresponded with increased expression of Hypoxia-Inducible Factor-1α (HIF-1α) in irradiated tumors. In the hind leg model, irradiation with a single dose of 24 Gy led to tumor growth delay, followed by tumor regrowth.ConclusionsIrradiation of the BxPC3 tumors with a single dose of 24 Gy caused transient vascular dysfunction and increased expression of HIF-1α. Such biological changes may impact tumor response to high single-dose and hypofractionated irradiation, and further investigations are needed to better understand the clinical outcomes of stereotactic body radiation therapy (SBRT).

Teaser

In vivo imaging methods were used to investigate the effects of high-dose irradiation on tumor vasculature and microenvironment using a BxPC3 pancreatic tumor model. A single dose of 24 Gy caused transient vascular dysfunction associated with adhesion of platelets and leukocytes to vascular endothelium, increased vascular permeability, and HIF-1 expression. Furthermore, tumor recurrence was evident by 65 days after irradiation. These data demonstrate the extent of radiation-induced vascular damage and its potential influence on tumor response.


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