Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells
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,...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/19/10280 |
| _version_ | 1797516340365361152 |
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| author | Justin D. Middleton Subhakeertana Sivakumar Tsonwin Hai |
| author_facet | Justin D. Middleton Subhakeertana Sivakumar Tsonwin Hai |
| author_sort | Justin D. Middleton |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T07:00:46Z |
| format | Article |
| id | doaj.art-6798df170420483cbe60d6ec714cf79c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T07:00:46Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6798df170420483cbe60d6ec714cf79c2023-11-22T16:07:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-0122191028010.3390/ijms221910280Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer CellsJustin D. Middleton0Subhakeertana Sivakumar1Tsonwin Hai2Department of Biological Chemistry and Pharmacology, College of Medicine, Ohio State University, Columbus, OH 43210, USADepartment of Biological Chemistry and Pharmacology, College of Medicine, Ohio State University, Columbus, OH 43210, USADepartment of Biological Chemistry and Pharmacology, College of Medicine, Ohio State University, Columbus, OH 43210, USAPreviously, 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.https://www.mdpi.com/1422-0067/22/19/10280chemotherapybreast cancer metastasisvascular microenvironmentcancer cell adhesionbasement membranematrix metalloprotease 2 (MMP-2) |
| spellingShingle | Justin D. Middleton Subhakeertana Sivakumar Tsonwin Hai 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 chemotherapy breast cancer metastasis vascular microenvironment cancer cell adhesion basement membrane matrix metalloprotease 2 (MMP-2) |
| title | Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells |
| title_full | Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells |
| title_fullStr | Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells |
| title_full_unstemmed | Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells |
| title_short | Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells |
| title_sort | chemotherapy induced changes in the lung microenvironment the role of mmp 2 in facilitating intravascular arrest of breast cancer cells |
| topic | chemotherapy breast cancer metastasis vascular microenvironment cancer cell adhesion basement membrane matrix metalloprotease 2 (MMP-2) |
| url | https://www.mdpi.com/1422-0067/22/19/10280 |
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