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Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells
Published on: January 18, 2017
Transcription factor Fos-related antigen 1 is an effective target for a breast cancer vaccine
Yunping Luo1, He Zhou, Masato Mizutani
1Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Abstract:
Protection against breast cancer was achieved with a DNA vaccine against murine transcription factor Fos-related antigen 1, which is overexpressed in aggressively proliferating D2F2 murine breast carcinoma. Growth of primary s.c. tumor and dissemination of pulmonary metastases was markedly suppressed by this oral DNA vaccine, carried by attenuated Salmonella typhimurium, encoding murine Fos-related antigen 1, fused with mutant polyubiquitin, and cotransformed with secretory murine IL-18. The life span of 60% of vaccinated mice was tripled in the absence of detectable tumor growth after lethal tumor cell challenge. Immunological mechanisms involved activation of T, natural killer, and dendritic cells, as indicated by up-regulation of their activation markers and costimulatory molecules. Markedly increased specific target cell lysis was mediated by both MHC class I-restricted CD8+ T cells and natural killer cells isolated from splenocytes of vaccinated mice, including a significant release of proinflammatory cytokines IFN-gamma and IL-2. Importantly, fluorescence analysis of fibroblast growth factor 2 and tumor cell-induced vessel growth in Matrigel plugs demonstrated marked suppression of angiogenesis only in vaccinated animals. Taken together, this multifunctional DNA vaccine proved effective in protecting against growth and metastases of breast cancer by combining the action of immune effector cells with suppression of tumor angiogenesis.
Insights
This study developed an oral DNA vaccine targeting Fos-related antigen 1 to combat breast cancer. The vaccine significantly suppressed tumor growth and metastasis, tripling lifespan in vaccinated mice.
Area of Science:
- Oncology
- Immunology
- Vaccinology
Background:
- Fos-related antigen 1 (FRA1) is overexpressed in aggressive murine breast carcinoma.
- Developing effective breast cancer therapies remains a critical challenge.
Purpose of the Study:
- To evaluate the efficacy of an oral DNA vaccine against FRA1 for breast cancer treatment.
- To investigate the immunological mechanisms and anti-angiogenic effects of the vaccine.
Main Methods:
- An oral DNA vaccine was constructed using attenuated Salmonella typhimurium, encoding FRA1 fused with mutant polyubiquitin and co-expressing IL-18.
- The vaccine's impact on primary tumor growth, pulmonary metastasis, and survival was assessed in a murine breast cancer model.
- Immunological responses, including immune cell activation, cytokine release, and angiogenesis suppression, were analyzed.
Main Results:
- The DNA vaccine markedly suppressed primary tumor growth and pulmonary metastasis.
- Vaccinated mice exhibited tripled lifespan with no detectable tumor growth after lethal challenge.
- The vaccine activated T cells, NK cells, and dendritic cells, enhancing target cell lysis and proinflammatory cytokine release (IFN-gamma, IL-2).
- Significant suppression of tumor angiogenesis was observed in vaccinated animals.
Conclusions:
- This multifunctional oral DNA vaccine is effective against breast cancer growth and metastasis.
- The vaccine combines immune cell activation with anti-angiogenic properties for comprehensive anti-tumor activity.
- Further research into this novel DNA vaccine strategy holds promise for breast cancer treatment.
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