MMTV-NeuT/ATTAC mice: a new model for studying the stromal tumor microenvironment
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Hongyan Yuan1, Xiaoyi Wang1, Jin Lu1, Qiongsi Zhang1, Irina Brandina2, Ilya Alexandrov2 and Robert I. Glazer1
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
2ActivSignal, LLC, Natick, MA 01760, USA
Robert I. Glazer, email: [email protected]
Keywords: fibrosis; mammary tumorigenesis; NeuT; adipose tissue; chemokines
Received: May 12, 2017 Accepted: January 09, 2018 Published: January 15, 2018
One of the central challenges in cancer prevention is the identification of factors in the tumor microenvironment (TME) that increase susceptibility to tumorigenesis. One such factor is stromal fibrosis, a histopathologic negative prognostic criterion for invasive breast cancer. Since the stromal composition of the breast is largely adipose and fibroblast tissue, it is important to understand how alterations in these tissues affect cancer progression. To address this question, a novel transgenic animal model was developed by crossing MMTV-NeuT mice containing a constitutively active ErbB2 gene into the FAT-ATTAC (fat apoptosis through targeted activation of caspase 8) background, which expresses an inducible caspase 8 fusion protein targeted to mammary adipose tissue. Upon caspase 8 activation, lipoatrophy of the mammary gland results in stromal fibrosis and acceleration of mammary tumor development with an increase in tumor multiplicity. Fibrosis was accompanied by an increase in collagen deposition, α-smooth muscle actin and CD31 expression in the tumor stroma as well as an increase in PD-L1-positive tumor cells, and infiltration by regulatory T cells, myeloid-derived suppressor cells and tumor-associated macrophages. Gene expression and signal transduction profiling indicated upregulation of pathways associated with cytokine signaling, inflammation and proliferation. This model should be useful for evaluating new therapies that target desmoplasia in the TME associated with invasive cancer.
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