Suppression of lung tumor growth and metastasis in mice by adeno-associated virus-mediated expression of vasostatin.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Cai
Ke Xia
KX
Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
Tse
Lai Ying
LY
Leung
Carly
C
Tam
Paul K H
PK
Xu
Ruian
R
Sham
Mai Har
MH
D000230:Adenocarcinoma / Q000473:pathology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D037282:Calreticulin / Q000235:genetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D003001:Cloning, Molecular; D000229:Dependovirus / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D037282:Calreticulin; D010446:Peptide Fragments; D011994:Recombinant Proteins; C121986:vasostatin