The onset of distant organ metastasis from primary breast cancer marks the transition to a stage IV diagnosis. Standard imaging modalities often detect distant metastasis when the burden of disease is high, underscoring the need for improved methods of detection to allow for interventions that would impede disease progression. Here, microporous poly(ε-caprolactone) scaffolds were developed that capture early metastatic cells and thus serve as a sentinel for early detection. These scaffolds were used to characterize the dynamic immune response to the implant spanning the acute and chronic foreign body response. The immune cell composition had stabilized at the scaffold after approximately 1 month and changed dramatically within days to weeks after tumor inoculation, with CD11b+Gr1hiLy6C- cells having the greatest increase in abundance. Implanted scaffolds recruited metastatic cancer cells that were inoculated into the mammary fat pad in vivo, which also significantly reduced tumor burden in the liver and brain. Additionally, cancer cells could be detected using a label-free imaging modality termed inverse spectroscopic optical coherence tomography, and we tested the hypothesis that subsequent removal of the primary tumor after early detection would enhance survival. Surgical removal of the primary tumor following cancer cell detection in the scaffold significantly improved disease-specific survival. The enhanced disease-specific survival was associated with a systemic reduction in the CD11b+Gr1hiLy6C- cells as a consequence of the implant, which was further supported by Gr-1 depletion studies. Implementation of the scaffold may provide diagnostic and therapeutic options for cancer patients in both the high-risk and adjuvant treatment settings.
Bibliographical noteFunding Information:
The authors would like to thank Dr. Ji Yi (Northwestern University) for help with scanning electron microscopy, Rohit Maramraju (University of Michigan) for help with sectioning, and Dr. Mark Hoenerhoff (University of Michigan Medical School) for providing fluorescent images. Technical support for the orthotopic tumor model was provided by V. Cryns, A. Mazar, and the Northwestern University Developmental Therapeutics Core. The authors acknowledge financial support from the National Institutes of Health NIH-Director's Transformative Research Award-R01CA173745 (L.D. Shea, V. Backman, and J.S. Jeruss) and the Northwestern H Foundation Cancer Research Award (L.D. Shea). B.A. Aguado and G.G. Bushnell are recipients of NSF Graduate Research Fellowship. Flow cytometry was supported by the Northwestern University Flow Cytometry Facility and a Cancer Center Support Grant (NCI CA060553). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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