In Vivo Imaging Reveals Significant Tumor Vascular Dysfunction and Increased Tumor Hypoxia-Inducible Factor-1α Expression Induced by High Single-Dose Irradiation in a Pancreatic Tumor Model.
To investigate the effect of high-dose irradiation on pancreatic tumor vasculature and microenvironment using in vivo imaging techniques.



A BxPC3 pancreatic tumor xenograft was established in a dorsal skinfold window chamber model and a subcutaneous hind leg model. Tumors were irradiated with a single dose of 4, 12, or 24 Gy. The dorsal skinfold window chamber 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.



In vivo fluorescence imaging revealed temporary vascular dysfunction in tumors irradiated with a single dose of 4 to 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 nonirradiated controls 14 days after irradiation. This observation corresponded with increased expression of hypoxia-inducible factor-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.



Irradiation of the BxPC3 tumors with a single dose of 24 Gy caused transient vascular dysfunction and increased expression of hypoxia-inducible factor-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.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Azusa
A
Maeda
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Yonghong
Y
Chen
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Jiachuan
J
Bu
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Hilda
H
Mujcic
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
Bradly G
BG
Wouters
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Techna Institute, University Health Network, Toronto, Ontario, Canada. Electronic address: rdacosta@uhnres.utoronto.ca.
Ralph S
RS
DaCosta
D000818:Animals; D002199:Capillary Permeability / Q000528:radiation effects*; D002448:Cell Adhesion / Q000528:radiation effects; D015687:Cell Hypoxia; D004730:Endothelium, Vascular; D005260:Female; D064593:Heterografts; D006614:Hindlimb; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007962:Leukocytes / Q000528:radiation effects; D016688:Mice, Inbred NOD; D008856:Microscopy, Fluorescence; D009364:Neoplasm Recurrence, Local; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy*; D010973:Platelet Adhesiveness / Q000528:radiation effects; D011879:Radiotherapy Dosage; D013997:Time Factors; D047368:Tumor Burden; D059016:Tumor Microenvironment / Q000528:radiation effects*; D014463:Ultrasonography
D051795:Hypoxia-Inducible Factor 1, alpha Subunit