Abstract
Metastatic breast cancer is a fatal disease that responds poorly to treatment. Cancer vaccines targeting antigens expressed by metastatic breast cancer cells and cancer stem cells could function as anticancer therapies. Cripto-1 is an oncofetal protein overexpressed in invasive breast cancer and cancer-initiating cells. In this study, we explored the potential of a Cripto-1-encoding DNA vaccine to target breast cancer in preclinical mouse models. BALB/c mice and BALB-neuT mice were treated with a DNA vaccine encoding mouse Cripto-1 (mCr-1). BALB/c mice were challenged with murine breast cancer 4T1 cells or TUBO spheres; BALB-neuT mice spontaneously developed breast cancer. Tumor growth was followed in all mouse models and lung metastases were evaluated. In vitro assays were performed to identify the immune response elicited by vaccination. Vaccination against mCr-1 reduced primary tumor growth in the 4T1 metastatic breast cancer model and reduced lung metastatic burden. In BALB-neuT mice, because the primary tumors are Cripto-1 negative, vaccination against mCr-1 did not affect primary tumors but did reduce lung metastatic burden. Spheroid-cultured TUBO cells, derived from a BALB/neuT primary tumor, develop a cancer stem cell-like phenotype and express mCr-1. We observed reduced tumor growth in vaccinated mice after challenge with TUBO spheres. Our data indicate that vaccination against Cripto-1 results in a protective immune response against mCr-1 expressing and metastasizing cells. Targeting Cripto-1 by vaccination holds promise as an immunotherapy for treatment of metastatic breast cancer. Cancer Immunol Res; 6(11); 1417-25. ©2018 AACR.
Highlights
Breast cancer is the most common cancer among women in western countries and incidence rates have been rising in developing countries [1]
We aimed to understand if vaccination with pmCr-1 would elicit a protective immune response in a model of murine metastatic breast cancer
EMT enables cells to survive without cell–cell contact, to migrate and to extravasate from the primary tumor
Summary
Breast cancer is the most common cancer among women in western countries and incidence rates have been rising in developing countries [1]. Breast cancer is a heterogeneous disease and insight into its molecular dysregulations has resulted in identification of therapeutic targets. The development of kinase inhibitors and Her targeting monoclonal antibodies led to increased survival rates among breast cancer patients, in particular in patients with local disease [2]. Relapse and metastases remain the most common causes of death among women with breast cancer [3]. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/). K. Witt and M.A. Ligtenberg contributed to this article
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