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    2020-03-17


    Of note, the abdominal wall puncture site AngiotensinI model documents reproducible establishment of a primary intraperitoneal
    66 Port site metastasisWilkinson-Ryan et al. Translational Oncology Vol. 12, No. 1, 2019
    A B
    Figure 3. EOC metastases within the abdominal wall at the puncture sites and not the control sites of C57BL/6 mice. (A) Microscopic images of abdominal wall samples from C57BL/6 mice with H + E staining. The first two rows show intra-abdominal wall metastases at the puncture sites. The third row shows an example of a control site with tumor on the peritoneal wall, but no invasive component. Black boxes indicate the area that is enhanced under 10× power and shown on AngiotensinI the right. (B) Tumor was identified in 16/24 (66.7% ± 10.77) of puncture site biopsies and 0/14 (0%) of control site biopsies (P b .0003, CI 41.16–90.84).
    tumor followed by secondary development of a metastatic site at a predictable location. Thus, this system closely mirrors the process of port site tumor metastasis in humans and allows for tracking of a
    developing metastasis by inducing the tumor in an identifiable and reproducible location. We utilize a transplantable murine EOC cell line. Another syngeneic model to which researchers could
    A B
    Figure 4. Qualitative and quantitative evaluation demonstrate metastases within the abdominal wall at the puncture sites and not the control sites of NSG mice. (A) Microscopic images of abdominal wall samples from NSG mice with H + E staining. The first two rows show examples of intra-abdominal wall metastasis at the puncture site. The third row shows an example of a control site with peritoneal tumor, but no invasive component. Black boxes indicate the area that is enhanced under 10× power and shown on the right. (B) Tumor was identified in 12/18mice (70% ± 10) of puncture site biopsies and 0/18 (0%) of control site biopsies (P b .002, CI 42.24–97.76).
    Port site metastasisWilkinson-Ryan et al. 67
    A Mouse 1 Mouse 2 Mouse 3
    B
    Figure 5. T-cells and leukocytes infiltrate the stroma of puncture site metastases. (A) Immunochemistry of puncture site metastases in three different C57BL/6 mice showing H + E staining (top), anti-CD3 staining of T cells (middle), and anti-CD11b staining of leukocytes (bottom), all taken at 10× power. (B) In all four samples stained (100%) from different C57BL/6 mice there was evidence of intratumoral and/or tumor stroma infiltration of CD3+ cells and CD11b+ cells.
    potentially apply the port site model is the MISIIR transgenic mice which develop spontaneous syngeneic murine ovarian malignancy and frequently form intraperitoneal metastasis. [8,9] Overall, our model closely reflects the mechanical process of metastasis described in women with EOC who undergo laparoscopic surgery [2–5,7–9,13].
    In summary, the puncture site mouse model of port site metastasis represents a novel tool that can be used in animal studies of ovarian cancer. Importantly, this model mirrors a clinical process well described in ovarian cancer patients and is easily reproducible in both wild type (immunocompetent) and genetically modified (immuno-deficient) mice. Specifically, we propose that this model can be used as a secondary outcome for therapeutic studies in mice or for mechanistic studies of tumor metastasis. Currently, EOC patients are in need of targeted, efficacious therapies including immune therapies. 
    Models such as this one will be valuable to assess both the biological underpinnings and the potential efficacy of targeted therapies in preclinical studies.
    Acknowledgements
    Research reported in this publication was supported by Friends of the Norris Cotton Cancer Center, Norris Cotton Cancer Center Core Grant P30CA023108, the Foundations for Women's Cancer, Dartmouth Immunology COBRE P20GM103506, and The Dart-mouth Clinical and Translational Science Institute, under award number UL1TR001086 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). We acknowledge experimental assistance from the NCCC Mouse Modeling and Immune Monitoring shared resources. The