Combination of vessel-targeting agents and fractionated radiation therapy: The role of the SDF-1/CXCR4 pathway
Journal
International Journal of Radiation Oncology Biology Physics
Journal Volume
86
Journal Issue
4
Pages
777-784
Date Issued
2013
Author(s)
Abstract
Purpose: To investigate vascular responses during fractionated radiation therapy (F-RT) and the effects of targeting pericytes or bone marrow-derived cells (BMDCs) on the efficacy of F-RT. Methods and Materials: Murine prostate TRAMP-C1 tumors were grown in control mice or mice transplanted with green fluorescent protein-tagged bone marrow (GFP-BM), and irradiated with 60 Gy in 15 fractions. Mice were also treated with gefitinib (an epidermal growth factor receptor inhibitor) or AMD3100 (a CXCR4 antagonist) to examine the effects of combination treatment. The responses of tumor vasculatures to these treatments and changes of tumor microenvironment were assessed. Results: After F-RT, the tumor microvascular density (MVD) was reduced; however, the surviving vessels were dilated, incorporated with GFP-positive cells, tightly adhered to pericytes, and well perfused with Hoechst 33342, suggesting a more mature structure formed primarily via vasculogenesis. Although the gefitinib+F-RT combination affected the vascular structure by dissociating pericytes from the vascular wall, it did not further delay tumor growth. These tumors had higher MVD and better vascular perfusion function, leading to less hypoxia and tumor necrosis. By contrast, the AMD3100+F-RT combination significantly enhanced tumor growth delay more than F-RT alone, and these tumors had lower MVD and poorer vascular perfusion function, resulting in increased hypoxia. These tumor vessels were rarely covered by pericytes and free of GFP-positive cells. Conclusions: Vasculogenesis is a major mechanism for tumor vessel survival during F-RT. Complex interactions occur between vessel-targeting agents and F-RT, and a synergistic effect may not always exist. To enhance F-RT, using CXCR4 inhibitor to block BM cell influx and the vasculogenesis process is a better strategy than targeting pericytes by epidermal growth factor receptor inhibitor. ? 2013 Elsevier Inc.
SDGs
Other Subjects
Combination treatments; Complex interaction; Epidermal growth factor receptors; Fractionated radiation; Methods and materials; Tumor microenvironment; Vascular perfusion; Vascular structures; Bone; Cells; Cytology; Mammals; Radiotherapy; Tumors; chemokine receptor CXCR4; gefitinib; green fluorescent protein; hoe 33342; plerixafor; stromal cell derived factor 1; angiogenesis; animal cell; animal experiment; animal model; animal tissue; article; blood vessel wall; bone marrow cell; cancer inhibition; cell adhesion; clinical effectiveness; controlled study; density; hypoxia; male; microvascular density; morphology; mouse; nonhuman; perfusion; pericyte; priority journal; prostate tumor; radiation dose; radiation dose fractionation; survival; treatment response; tumor microenvironment; tumor necrosis; tumor vascularization; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Benzimidazoles; Bone Marrow Cells; Chemokine CXCL12; Combined Modality Therapy; Dose Fractionation; Green Fluorescent Proteins; Heterocyclic Compounds; Luminescent Agents; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Pericytes; Prostatic Neoplasms; Quinazolines; Receptor, Epidermal Growth Factor; Receptors, CXCR4; Tumor Microenvironment
Type
journal article