| Popis: |
Breast cancer liver metastasis (BCLM) is encountered in >50% of breast cancer patients with advanced disease and is associated with the poorest disease prognosis. Unlike primary tumors and metastatic lesions in other organs, BCLM growth relies heavily on the liver vasculature, leading to lesions that are hypo-vascularized. Consequently, most BCLM clinically appear as hypoattenuating spots. This under-vascularization prevents systemically administered agents from reaching all of the cells in these lesions, causing physiological, transport-related resistance to therapy. The liver is an organ enriched in macrophages, which play important roles by affecting tumor growth, angiogenesis, metastasis and chemoresistance. These phagocytic cells remain in close proximity to BCLM and have been clinically utilized for imaging with nanomaterials. We have previously shown (T. Tanei etal, Cancer Res. 2016) that drug transport barriers can be overcome using macrophages as carriers for nanotherapeutics, leading to an efficient therapy for BCLM. The prerequisite for this therapy is the ability of BCLM to attract macrophages from surrounding liver tissue. The drug-carrying macrophages can escape host defense mechanisms, hence extending the therapeutic agent half-life and releasing it in close proximity of tumor cells under-exposed to vascular-borne drugs. In the present study, we aimed to evaluate the ability of different breast cancer cells to attract macrophages, further exploiting these cells as a viable candidate for targeted delivery of lipid nanoparticles. For this purpose, we evaluated the transport phenomena of macrophages in the presence of a variety of human breast cancer cells, including, MCF7 (ER+, PR+/-, HER2-), T-47D (ER+, PR+/-, HER2-), MDA-MB-231 (TNBC), SUM-159 (TNBC). The studies were conducted in tumor cell-macrophage co-cultures in 2-dimensional (2D) and 3-dimensional (3D, hypovascularized model) settings. Human macrophages were derived from buffy coats from healthy donors and prelabelled for the co-culture experiments. The majority of macrophages were M0 phenotype. The following parameters were assessed for macrophage infiltration: a) static (confocal) and kinetic (Incucyte) microscopy imaging of cell transport, b) cell counts for migration assay, c) immunofluorescence, d) directionality/path length. The datapoint towards the variability in behaviors of macrophage transport towards the tumor cells in both 2D and 3D settings. MDA-MB-231 (triple negative breast cancer cell line) was more prominent in recruiting macrophages, which can be clinically correlated to higher tumor grade and reduced overall and relapse-free survival. These findings were further utilized to mathematically model and experimentally evaluate BCLM therapeutic response to nanocarriers loaded with high molecular weight (HMW) therapeutics. Longer term, this work provides a methodology for macrophage-mediated targeting of particular patient hypo-vascularized BCLM. Acknowledgement: This research is partial support by Department of Defense/U.S. Army Medical Research grant Citation Format: Anjana Tiwari, Eric Chau, Karem A. Court, Jenna Carr, Dylan Goodin, Hermann Frieboes, Biana Godin. Overcoming drug transport barriers in breast cancer liver metastasis by using macrophages as carriers: valuation in 2D and 3D models [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-14. |
