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Anti-Angiogenic Effects of Cd73-Specific Sirna-Loaded Nanoparticles in Breast Cancer-Bearing Mice Publisher Pubmed



Ghalamfarsa G1 ; Rastegari A2, 3 ; Atyabi F3 ; Hassannia H4, 5 ; Hojjatfarsangi M6, 7 ; Ghanbari A1 ; Anvari E8 ; Mohammadi J9 ; Azizi G10 ; Masjedi A11, 12 ; Yousefi M2 ; Yousefi B11 ; Hadjati J13 ; Jadidiniaragh F11, 12, 13
Authors
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Authors Affiliations
  1. 1. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
  2. 2. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  3. 3. Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Immunogenetic Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
  5. 5. Amol Faculty of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
  6. 6. Department of Oncology-Pathology, Immune and Gene therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden
  7. 7. Department of Immunology, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
  8. 8. Department of Physiology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
  9. 9. Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
  10. 10. Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
  11. 11. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  12. 12. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
  13. 13. Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Source: Journal of Cellular Physiology Published:2018


Abstract

CD73 facilitates tumor growth by upregulation of the adenosine (immunosuppressive factor) in the tumor microenvironment, however, its precise molecular mechanisms is not precisely understood. Regarding the importance of angiogenesis in tumor development and spreading, we decided to assign the anti-angiogenic effects of CD73 suppression. We used chitosan lactate (ChLa) nanoparticles (NPs) to deliver CD73-specific small interfering RNA (siRNA) into cancer cells. Our results showed that treatment of the 4T1 cells with CD73-specific siRNA-loaded NPs led to potent inhibition of cancer cell proliferation and cell cycle arrest, in vitro. This growth arrest was correlated with downregulation of angiogenesis-related molecules including vascular endothelial growth factor (VEGF)-A, VEGF-R2, interleukin (IL)-6, and transforming growth factor (TGF)-β. Moreover, administration of NPs loaded with CD73-siRNA into 4T1 breast cancer-bearing mice led to tumor regression and increased mice survival time accompanied with downregulation of angiogenesis (VEGF-A, VEGF-R2, VE-Cadherin, and CD31) and lymphangiogenesis (VEGF-C and LYVE-1)-related genes in the tumor site. Furthermore, the expression of angiogenesis promoting factors including IL-6, TGF-β, signal transducer, and activator of transcription (STAT)3, hypoxia inducible factor (HIF)-1α, and cyclooxygenase (COX)2 was decreased after the CD73 suppression in mice. Moreover, analysis of leukocytes derived from the tumor samples, spleen, and regional lymph nodes showed that they had lower capability for secretion of angiogenesis promoting factors after CD73-silencing. These results indicate that suppression of tumor development by downregulation of CD73 is in part related to angiogenesis arrest. These findings imply a promising strategy for inhibiting tumor growth accompanied with suppressing the angiogenesis process. © 2018 Wiley Periodicals, Inc.
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