Targeting of adenovirus vectors to tumor cells does not enable efficient transduction of breast cancer metastases.
Targeting of oncolytic adenoviruses to tumors can potentially increase their efficacy and safety profile after systemic application. We have developed recently a capsid-modified vector containing the adenovirus serotype 35 fiber shaft and knob inserted into an Ad5 capsid. This Ad5/35 vector infects cells via a coxsackievirus adenovirus receptor-independent pathway. Here we attempted to exploit this new tropism of Ad5/35 vectors for tumor-specific infection. In vitro, the Ad5/35 vector efficiently transduced human breast cancer cells that were refractory to infection with conventional Ad5-based vectors. Additionally, primary mouse hepatocytes were relatively refractory to Ad5/35 infection in vitro or after systemic vector application to mice. In an animal model of breast cancer metastasis, intraportal infusion of MDA-MB435 cells produced multiple hepatic metastases that were surrounded by extracellular matrix and developed blood vessels confined to the tumor stroma. Tail vein injection of a standard Ad5-based vector into tumor-bearing animals resulted in transduction of mouse hepatocytes but not metastases. However, the capsid-modified Ad5/35 vector transduced only approximately 8% of metastases. The metastases that were susceptible to Ad5/35 infection demonstrated blood vessels in close proximity to tumor nests without extracellular matrix separating endothelial and tumor cells. These findings indicate that transduction of liver metastases not only requires tumor-specific tropism but also new strategies to increase accessibility of tumor cells to systemically applied oncolytic adenoviruses.
Shayakhmetov
Dmitry M
DM
Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA.
Li
Zong-Yi
ZY
Ni
Shaoheng
S
Lieber
André
A
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000821:virology; D002213:Capsid / Q000235:genetics; D005109:Extracellular Matrix / Q000473:pathology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays