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An Orthotopic Model of Serous Ovarian Cancer in Immunocompetent Mice for in vivo Tumor Imaging and Monitoring of Tumor Immune Responses
Published on: November 28, 2010
Using sindbis viral vectors for specific detection and suppression of advanced ovarian cancer in animal models
Jen-Chieh Tseng1, Alicia Hurtado, Herman Yee
1New York University Cancer Institute, the Rita J. and Stanley H. Kaplan Comprehensive Cancer Center, and the New York University Gene Therapy Center, New York University School of Medicine, New York, New York 10016, USA.
Abstract:
We studied the therapeutic value of Sindbis vectors for advanced metastatic ovarian cancer by using two highly reproducible and clinically accurate mouse models: a SCID xenograft model, established by i.p. inoculation of human ES-2 ovarian cancer cells, and a syngenic C57BL/6 model, established by i.p. inoculation of mouse MOSEC ovarian cancer cells. We demonstrate through imaging, histologic, and molecular data that Sindbis vectors systemically and specifically infect/detect and kill metastasized tumors in the peritoneal cavity, leading to significant suppression of the carcinomatosis in both animal models. Use of two different bioluminescent genetic markers for the IVIS Imaging System permitted demonstration, for the first time, of an excellent correlation between vector delivery and metastatic locations in vivo. Sindbis vector infection and growth suppression of murine MOSEC tumor cells indicate that Sindbis tumor specificity is not attributable to a species difference between human tumor and mouse normal cells. Sindbis virus is known to infect mammalian cells using the Mr 67,000 laminin receptor. Immunohistochemical staining of tumor cells indicates that laminin receptor is elevated in tumor versus normal cells. Down-regulated expression of laminin receptor with small interfering RNA significantly reduces the infectivity of Sindbis vectors. Tumor overexpression of the laminin receptor may explain the specificity and efficacy that Sindbis vectors demonstrate for tumor cells in vivo. We show that incorporation of antitumor cytokine genes such as interleukin-12 and interleukin-15 genes enhances the efficacy of the vector. These results suggest that Sindbis viral vectors may be promising agents for both specific detection and growth suppression of metastatic ovarian cancer.
Insights
Sindbis viral vectors show therapeutic potential for metastatic ovarian cancer. These vectors specifically target and eliminate tumors in preclinical models, suggesting promise for detection and treatment.
Area of Science:
- Oncology
- Virology
- Gene Therapy
Background:
- Metastatic ovarian cancer presents significant treatment challenges.
- Viral vectors are being explored for targeted cancer therapies.
Purpose of the Study:
- To evaluate the therapeutic efficacy of Sindbis viral vectors in preclinical models of metastatic ovarian cancer.
- To investigate the mechanism of Sindbis vector tumor specificity.
Main Methods:
- Utilized SCID xenograft and syngenic C57BL/6 mouse models of ovarian cancer.
- Employed bioluminescent imaging, histology, and molecular analyses.
- Investigated the role of the laminin receptor in Sindbis vector infectivity.
Main Results:
- Sindbis vectors demonstrated systemic and specific targeting, infection, and killing of metastatic ovarian tumors.
- Excellent correlation between vector delivery and metastatic sites was observed in vivo.
- Tumor-specific infectivity was linked to elevated laminin receptor expression on tumor cells.
Conclusions:
- Sindbis viral vectors show significant promise for the specific detection and growth suppression of metastatic ovarian cancer.
- Laminin receptor overexpression contributes to Sindbis vector tumor cell specificity and efficacy.
- Enhancing vectors with cytokine genes like IL-12 and IL-15 further improves efficacy.
