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Article

Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells

1
Department of Biological Chemistry and Pharmacology, College of Medicine, Ohio State University, Columbus, OH 43210, USA
2
Molecular, Cellular, and Developmental Biology Program, Ohio State University, Columbus, OH 43210, USA
*
Author to whom correspondence should be addressed.
Academic Editor: José L. Quiles
Int. J. Mol. Sci. 2021, 22(19), 10280; https://doi.org/10.3390/ijms221910280
Received: 23 August 2021 / Revised: 14 September 2021 / Accepted: 17 September 2021 / Published: 24 September 2021
(This article belongs to the Special Issue Breast Cancer Chemotherapy)
Previously, we showed that mice treated with cyclophosphamide (CTX) 4 days before intravenous injection of breast cancer cells had more cancer cells in the lung at 3 h after cancer injection than control counterparts without CTX. At 4 days after its injection, CTX is already excreted from the mice, allowing this pre-treatment design to reveal how CTX may modify the lung environment to indirectly affect cancer cells. In this study, we tested the hypothesis that the increase in cancer cell abundance at 3 h by CTX is due to an increase in the adhesiveness of vascular wall for cancer cells. Our data from protein array analysis and inhibition approach combined with in vitro and in vivo assays support the following two-prong mechanism. (1) CTX increases vascular permeability, resulting in the exposure of the basement membrane (BM). (2) CTX increases the level of matrix metalloproteinase-2 (MMP-2) in mouse serum, which remodels the BM and is functionally important for CTX to increase cancer abundance at this early stage. The combined effect of these two processes is the increased accessibility of critical protein domains in the BM, resulting in higher vascular adhesiveness for cancer cells to adhere. The critical protein domains in the vascular microenvironment are RGD and YISGR domains, whose known binding partners on cancer cells are integrin dimers and laminin receptor, respectively. View Full-Text
Keywords: chemotherapy; breast cancer metastasis; vascular microenvironment; cancer cell adhesion; basement membrane; matrix metalloprotease 2 (MMP-2); laminin; integrin β1 chemotherapy; breast cancer metastasis; vascular microenvironment; cancer cell adhesion; basement membrane; matrix metalloprotease 2 (MMP-2); laminin; integrin β1
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MDPI and ACS Style

Middleton, J.D.; Sivakumar, S.; Hai, T. Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells. Int. J. Mol. Sci. 2021, 22, 10280. https://doi.org/10.3390/ijms221910280

AMA Style

Middleton JD, Sivakumar S, Hai T. Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells. International Journal of Molecular Sciences. 2021; 22(19):10280. https://doi.org/10.3390/ijms221910280

Chicago/Turabian Style

Middleton, Justin D., Subhakeertana Sivakumar, and Tsonwin Hai. 2021. "Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells" International Journal of Molecular Sciences 22, no. 19: 10280. https://doi.org/10.3390/ijms221910280

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