Abstract
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. 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. 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. 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.
Highlights
Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression
In an ex vivo setting, we showed that rAAV2/5-mediated expression of human vasostatin from highly metastatic Lewis lung carcinoma could reduce neovascularization during tumor initiation, resulting in suppression of primary tumor growth and subsequent pulmonary metastasis
For the first time, that rAAV2/5-mediated delivery of the angiogenesis inhibitor vasostatin is an effective approach for lung cancer treatment
Summary
Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. 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. 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. Previous reports on the therapeutic effects of vasostatin were based solely on subcutaneous tumor models, whereas the key challenge in cancer therapy lies in eradicating metastases at the subclinical and advanced stages, wherein the tumor microenvironment affects induction of tumor angiogenesis [10]. Producing secretory proteins, allowing persistent expression of the transgene product They have been successfully used for delivery of angiogenesis inhibitors for cancer therapy in different murine models (15 – 17). Cross-packaging AAV2 vector genome into AAV5 capsid, which results in pseudotyped rAAV2/5 vector that share a similar safety profile as AAV2, can mediate efficient gene transfer to the lung [14, 19]
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