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Modeling metastasis biology and therapy in real time in the mouse lung
Arnulfo Mendoza, … , Lalage M. Wakefield, Chand Khanna
Arnulfo Mendoza, … , Lalage M. Wakefield, Chand Khanna
Published July 19, 2010
Citation Information: J Clin Invest. 2010;120(8):2979-2988. https://doi.org/10.1172/JCI40252.
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Technical Advance Oncology

Modeling metastasis biology and therapy in real time in the mouse lung

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Abstract

Pulmonary metastasis remains the leading ca use of death for cancer patients. Opportunities to improve treatment outcomes for patients require new methods to study and view the biology of metastatic progression. Here, we describe an ex vivo pulmonary metastasis assay (PuMA) in which the metastatic progression of GFP-expressing cancer cells, from a single cell to the formation of multicellular colonies, in the mouse lung microenvironment was assessed in real time for up to 21 days. The biological validity of this assay was confirmed by its prediction of the in vivo behavior of a variety of high- and low-metastatic human and mouse cancer cell lines and the discrimination of tumor microenvironments in the lung that were most permissive to metastasis. Using this approach, we provide what we believe to be new insights into the importance of tumor cell interactions with the stromal components of the lung microenvironment. Finally, the translational utility of this assay was demonstrated through its use in the evaluation of therapeutics at discrete time points during metastatic progression. We believe that this assay system is uniquely capable of advancing our understanding of both metastasis biology and therapeutic strategies.

Authors

Arnulfo Mendoza, Sung-Hyeok Hong, Tanasa Osborne, Mohammed A. Khan, Kirk Campbell, Joseph Briggs, Ananth Eleswarapu, Lauren Buquo, Ling Ren, Stephen M. Hewitt, El-H. Dakir, Susan Garfield, Renard Walker, Glenn Merlino, Jeffrey E. Green, Kent W. Hunter, Lalage M. Wakefield, Chand Khanna

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Figure 2

Demonstration of a viable and structurally intact pulmonary architecture in PuMA.

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Demonstration of a viable and structurally intact pulmonary architecture...
(A) PuMA yields an intact lung microarchitecture. Day 0: bronchioles (B) were lined by epithelia that contact the basement membrane. Alveoli (A) were uniformly expanded throughout the lung, and the alveolar walls (AW, with arrows) were normal in diameter. The alveolar walls contained small numbers of migratory inflammatory cells, pneumocytes (type I and II), and endothelial cells. Blood vessels and alveolar capillaries were expanded by rbcs. Day 7: alveoli remained expanded. There were decreased numbers of migratory cells, pneumocytes, and endothelial cells in the alveolar walls, and many of those that remained contained pyknotic nuclei. Days 14 and 21: alveoli, airways, and large vessels (PA, pulmonary arteries; PV, pulmonary veins) remained expanded. Alveolar capillaries and rbcs were no longer discernible, and the alveolar walls contained fewer migratory cells and pneumocytes (loss of cellularity). Overall, lung microarchitecture was remarkably unchanged. (B) Movat stain was used to examine the connective tissue components of the lung culture. Black elastin fibers were present in large vessels, in the basement membrane supporting the airway epithelia, and within the alveolar interstitium. Black nuclei were scattered throughout the alveolar interstitium. Red muscle surrounded arteries and larger airways (B) and yellow collagen fibers were in the surrounding vascular submucosa and alveolar interstitium. Each of these components was identified at each time point. (C) TEM. Stromal elements composed of collagen microfibers (C) were evident from day 0 through day 21. Scale bars: 100 μm (A and B); 1 μm (C).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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