Annals of Surgical Oncology

, Volume 16, Issue 5, pp 1403–1411

Combined IFN-γ–Endostatin Gene Therapy and Radiotherapy Attenuates Primary Breast Tumor Growth and Lung Metastases via Enhanced CTL and NK Cell Activation and Attenuated Tumor Angiogenesis in a Murine Model

Authors

  • Lin Lin Liu
    • Department of Academic SurgeryUniversity College Cork (UCC)/National University of Ireland (NUI), Cork University Hospital
    • Department of Radiation Oncology, The Second Affiliated HospitalJilin University
  • Myles J. Smith
    • Department of Academic SurgeryUniversity College Cork (UCC)/National University of Ireland (NUI), Cork University Hospital
  • Bao Sheng Sun
    • Department of Academic SurgeryUniversity College Cork (UCC)/National University of Ireland (NUI), Cork University Hospital
    • Department of Radiation Oncology, The Second Affiliated HospitalJilin University
  • Guan Jun Wang
    • Department of Radiation Oncology, The Second Affiliated HospitalJilin University
  • H. Paul Redmond
    • Department of Academic SurgeryUniversity College Cork (UCC)/National University of Ireland (NUI), Cork University Hospital
    • Department of Academic SurgeryUniversity College Cork (UCC)/National University of Ireland (NUI), Cork University Hospital
Breast Oncology

DOI: 10.1245/s10434-009-0343-6

Cite this article as:
Liu, L.L., Smith, M.J., Sun, B.S. et al. Ann Surg Oncol (2009) 16: 1403. doi:10.1245/s10434-009-0343-6

Abstract

Background

Gene–radiotherapy, a combination of gene therapy and radiotherapy, is a new paradigm for cancer treatment, with the potential to simultaneously improve local and systemic breast cancer control. The aim of this study was to evaluate antitumor effect of interferon (IFN)-γ-endostatin-based gene–radiotherapy in a murine metastatic breast tumor model, and to elucidate possible mechanisms involved.

Methods

Murine mammary adenocarcinoma 4T1 cells transfected with pEgr-IFN-γ and pEgr-endostatin plasmids were irradiated (2–20 Gy). IFN-γ and endostatin levels in the culture supernatants were measured. In vivo female BALB/c mice were inoculated with 1 × 105 4T1 cells by mammary fat pad injection and divided into control, empty vector, gene therapy (pEgr-IFN-γ and pEgr-endostatin), radiotherapy, and combined gene–radiotherapy groups. Tumor growth, tumor/body weight ratio, lung metastases, and survival of the tumor-bearing mice were observed. Splenic cytotoxic T-lymphocyte (CTL) and natural killer (NK) cell activity and intratumor microvessel density were also assessed.

Results

Irradiation significantly enhanced IFN-γ and endostatin secretion from the transfected 4T1 cells. In vivo mice that received combined gene–radiotherapy showed maximal attenuation in tumor growth rate and lung metastases with increased survival compared with mice that received gene therapy or radiotherapy alone. This was associated with significantly enhanced CTL and NK cell activity and reduced intratumor microvessel density.

Conclusion

These results demonstrate that IFN-γ-endostatin-based gene–radiotherapy provide a potent antitumor effect in a murine metastatic breast tumor model, which may relate to IFN-γ-stimulated CTL and NK cell activation, and endostatin-induced antiangiogenic activity. Thus, gene–radiotherapy may represent a useful addition to neoadjuvant management of locally advanced breast cancer.

Copyright information

© Society of Surgical Oncology 2009