TY - JOUR
T1 - A tissue-engineered 3d microvessel model reveals the dynamics of mosaic vessel formation in breast cancer
AU - Silvestri, Vanesa L.
AU - Henriet, Elodie
AU - Linville, Raleigh M.
AU - Wong, Andrew D.
AU - Searson, Peter C.
AU - Ewald, Andrew J.
N1 - Funding Information:
We thank the Ewald and Searson laboratories for helpful comments. We thank Veena Padmanaban for in vivo work, Juan Carlos Ramirez for image scans, and Seyvonne Ip for image analysis. A.J. Ewald received support from: The Breast Cancer Research Foundation (BCRF-19-048), the Metastatic Breast Cancer Network, the Commonwealth Foundation, and the NIH/NCI (U01CA217846, U01CA221007, U54CA2101732, 3P30CA006973). P.C. Searson received support for this work from DTRA (HDTRA1-15-1-0046) and NIH (R01NS106008). V.L. Silvestri received support from the Isaac and Lucille Hay Graduate Fellowship. R.M. Linville acknowledges a NSF Graduate Fellowship (DGE1746891).
Funding Information:
R.M. Linville reports grants from NSF during the conduct of the study. P.C. Searson reports grants from the NIH and Defense Threat Reduction Agency. A.D. Wong reports a patent issued for US20140142370A1. A.J. Ewald reports grants from Breast Cancer Research Foundation, Metastatic Breast Cancer Network, Commonwealth Foundation, and NCI during the conduct of the study; in addition, A.J. Ewald has a patent issued for US20140336282A1 and his wife is an employee of Immunocore. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - In solid tumors, vascular structure and function varies from the core to the periphery. This structural heterogeneity has been proposed to influence the mechanisms by which tumor cells enter the circulation. Blood vessels exhibit regional defects in endothelial coverage, which can result in cancer cells directly exposed to flow and potentially promoting intravasation. Consistent with prior reports, we observed in human breast tumors and in a mouse model of breast cancer that approximately 6% of vessels consisted of both endothelial cells and tumor cells, so-called mosaic vessels. Due, in part, to the challenges associated with observing tumor-vessel interactions deep within tumors in real-time, the mechanisms by which mosaic vessels form remain incompletely understood. We developed a tissue-engineered model containing a physiologically realistic microvessel in coculture with mammary tumor organoids. This approach allows real-time and quantitative assessment of tumor-vessel interactions under conditions that recapitulate many in vivo features. Imaging revealed that tumor organoids integrate into the endothelial cell lining, resulting in mosaic vessels with gaps in the basement membrane. While mosaic vessel formation was the most frequently observed interaction, tumor organoids also actively constricted and displaced vessels. Furthermore, intravasation of cancer cell clusters was observed following the formation of a mosaic vessel. Taken together, our data reveal that cancer cells can rapidly reshape, destroy, or integrate into existing blood vessels, thereby affecting oxygenation, perfusion, and systemic dissemination. Our novel assay also enables future studies to identify target-able mechanisms of vascular recruitment and intravasation.
AB - In solid tumors, vascular structure and function varies from the core to the periphery. This structural heterogeneity has been proposed to influence the mechanisms by which tumor cells enter the circulation. Blood vessels exhibit regional defects in endothelial coverage, which can result in cancer cells directly exposed to flow and potentially promoting intravasation. Consistent with prior reports, we observed in human breast tumors and in a mouse model of breast cancer that approximately 6% of vessels consisted of both endothelial cells and tumor cells, so-called mosaic vessels. Due, in part, to the challenges associated with observing tumor-vessel interactions deep within tumors in real-time, the mechanisms by which mosaic vessels form remain incompletely understood. We developed a tissue-engineered model containing a physiologically realistic microvessel in coculture with mammary tumor organoids. This approach allows real-time and quantitative assessment of tumor-vessel interactions under conditions that recapitulate many in vivo features. Imaging revealed that tumor organoids integrate into the endothelial cell lining, resulting in mosaic vessels with gaps in the basement membrane. While mosaic vessel formation was the most frequently observed interaction, tumor organoids also actively constricted and displaced vessels. Furthermore, intravasation of cancer cell clusters was observed following the formation of a mosaic vessel. Taken together, our data reveal that cancer cells can rapidly reshape, destroy, or integrate into existing blood vessels, thereby affecting oxygenation, perfusion, and systemic dissemination. Our novel assay also enables future studies to identify target-able mechanisms of vascular recruitment and intravasation.
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U2 - 10.1158/0008-5472.CAN-19-1564
DO - 10.1158/0008-5472.CAN-19-1564
M3 - Article
C2 - 32665356
AN - SCOPUS:85092514312
SN - 0008-5472
VL - 80
SP - 4288
EP - 4301
JO - Cancer Research
JF - Cancer Research
IS - 19
ER -