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Suppression of Lung Tumor Growth and Metastasis in Mice by Adeno-Associated Virus-Mediated Expression of Vasostatin

Authors' Affiliations: Departments of ¹ Biochemistry and ² Surgery, Li Ka Shing Faculty of Medicine and ³ Institute of Molecular Biology, The University of Hong Kong, Pokfulam, Hong Kong, China and ⁴ Institute of Molecular Medicine, Huaqiao University, Fujian, China

Requests for reprints: Mai Har Sham, Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 3rd Floor Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong, China. Phone: 852-28199195; Fax: 852-28551254; E-mail: mhsham{at}hkucc.hku.hk.

Purpose: Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. Vasostatin, the N-terminal domain of calreticulin, is a potent angiogenesis inhibitor. In this study, we determined the effectiveness of vasostatin delivered by recombinant pseudotype adeno-associated virus 2/5 (rAAV2/5-VAS) as a gene therapy approach for lung cancer treatment.

Experimental Design: We used rAAV2/5 to deliver vasostatin intratumorally or systemically in different mouse lung tumor models — subcutaneous, orthotopic xenograft, and spontaneous metastasis lung tumor models. The therapeutic efficacy of rAAV2/5-VAS was determined by monitoring tumor volume, survival rate, and degree of neovascularization after treatment in these models.

Results: Mice bearing subcutaneous tumor of rAAV2/5-VAS pretreated Lewis lung carcinoma cells showed >50% reduction in primary tumor volume and reduced spontaneous pulmonary metastases. The tumor-suppressive action of rAAV2/5-VAS in subcutaneous human lung tumor A549 xenograft correlated with a reduced number of capillary vessels in tumors. In the orthotopic xenograft model, rAAV2/5-VAS suppressed metastasis of A549 tumors to mediastinal lymph nodes and contralateral lung. Furthermore, treatment of immunocompetent mice in the spontaneous lung metastases model with rAAV2/5-VAS after primary tumor excision prolonged their median survival from 21 to 51.5 days.

Conclusion: Our results show the effectiveness of rAAV2/5-VAS as an angiogenesis inhibitor in suppressing tumor growth during different stages of tumor progression, validating the application of rAAV2/5-VAS gene therapy in treatment against lung cancer.