Systemic Instigation: A Mouse Model to Study Breast Cancer as a Systemic Disease
Little is known about the mechanisms that cause indolent tumors – such as micrometastases, occult primary tumors, or minimal residual disease – to erupt into overt, malignant cancers. As a result, predicting which patients are likely to experience disease relapse and treating patients with metastatic disease has been frustratingly limited. We developed an in vivo xenograft model system that provided us with fundamental insights into processes that govern indolent tumor growth and represented a new paradigm for translational cancer research. We learned that systemic endocrine factors and circulating bone marrow-derived cells support the acquisition of malignant traits by otherwise indolent tumors. As a result, we now think of cancer as a systemic disease by which tumors actively perturb as well as respond to the host systemic environment. First, we found that certain human breast carcinoma cell lines (we term “instigators”) facilitate the growth of otherwise-indolent tumor cells (we term “responders”) located at distant anatomical sites within host mice – a process we term “systemic instigation”. Second, systemic instigation is accompanied by incorporation of bone marrow-derived cells into the stroma of the distant once-indolent tumors. Importantly, bone marrow cells (BMCs) of hosts bearing instigating tumors are functionally activated in the marrow prior to their mobilization into the circulation. Third, instigating tumor-derived osteopontin (OPN), a cytokine that is elevated in the plasma of patients with metastatic cancers and is predicitive of poor outcome, is necessary but not sufficient for systemic instigation. Although there may be alternative explanations, this systemic communication between tumors might explain why patients diagnosed with one malignant neoplasm are at an increased risk of presenting with multiple, independent primary cancers or why patients with recurrent disease often present with multiple metastases that appear to arise suddenly and synchronously. In this review, I address the methods by which the systemic instigation model was established, what we’ve learned by using this model, the implications of our studies, and some of the questions that have yet to be answered.
KeywordsNude Mouse Bone Marrow Cell Minimal Residual Disease Contralateral Breast Cancer Immunocompromised Mouse
I thank Dr. Robert A. Weinberg and members of his laboratory for intellectual contributions and critical discussions during the design and implementation of the experiments reviewed herein. Additionally, I thank Ann M. Gifford and Hanna Kuznetsov for technical support and contributions toward unpublished observations mentioned in this review. Finally, I wish to acknowledge Drs. Zafira Castaño Corsino and Moshe Elkabets for helpful discussions.
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