Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs
Abstract The premetastatic niche hypothesis proposes an active priming of the metastatic site by factors secreted from the primary tumor prior to the arrival of the first cancer cells. We investigated several extracellular matrix (ECM) structural proteins, ECM degrading enzymes, and ECM processing p...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-45832-7 |
| _version_ | 1797636941700661248 |
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| author | Ruoqing Cai Caitlin M. Tressler Menglin Cheng Kanchan Sonkar Zheqiong Tan Santosh Kumar Paidi Vinay Ayyappan Ishan Barman Kristine Glunde |
| author_facet | Ruoqing Cai Caitlin M. Tressler Menglin Cheng Kanchan Sonkar Zheqiong Tan Santosh Kumar Paidi Vinay Ayyappan Ishan Barman Kristine Glunde |
| author_sort | Ruoqing Cai |
| collection | DOAJ |
| description | Abstract The premetastatic niche hypothesis proposes an active priming of the metastatic site by factors secreted from the primary tumor prior to the arrival of the first cancer cells. We investigated several extracellular matrix (ECM) structural proteins, ECM degrading enzymes, and ECM processing proteins involved in the ECM remodeling of the premetastatic niche. Our in vitro model consisted of lung fibroblasts, which were exposed to factors secreted by nonmalignant breast epithelial cells, nonmetastatic breast cancer cells, or metastatic breast cancer cells. We assessed ECM remodeling in vivo in premetastatic lungs of female mice growing orthotopic primary breast tumor xenografts, as compared to lungs of control mice without tumors. Premetastatic lungs contained significantly upregulated Collagen (Col) Col4A5, matrix metalloproteinases (MMPs) MMP9 and MMP14, and decreased levels of MMP13 and lysyl oxidase (LOX) as compared to control lungs. These in vivo findings were consistent with several of our in vitro cell culture findings, which showed elevated Col14A1, Col4A5, glypican-1 (GPC1) and decreased Col5A1 and Col15A1 for ECM structural proteins, increased MMP2, MMP3, and MMP14 for ECM degrading enzymes, and decreased LOX, LOXL2, and prolyl 4-hydroxylase alpha-1 (P4HA1) for ECM processing proteins in lung fibroblasts conditioned with metastatic breast cancer cell media as compared to control. Taken together, our data show that premetastatic priming of lungs by primary breast tumors resulted in significant ECM remodeling which could facilitate metastasis by increasing interstitial fibrillar collagens and ECM stiffness (Col14A1), disruptions of basement membranes (Col4A5), and formation of leaky blood vessels (MMP2, MMP3, MMP9, and MMP14) to promote metastasis. |
| first_indexed | 2024-03-11T12:41:21Z |
| format | Article |
| id | doaj.art-0c8c852b1b174baa99e81e68549380fe |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-11T12:41:21Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-0c8c852b1b174baa99e81e68549380fe2023-11-05T12:15:16ZengNature PortfolioScientific Reports2045-23222023-10-0113111210.1038/s41598-023-45832-7Primary breast tumor induced extracellular matrix remodeling in premetastatic lungsRuoqing Cai0Caitlin M. Tressler1Menglin Cheng2Kanchan Sonkar3Zheqiong Tan4Santosh Kumar Paidi5Vinay Ayyappan6Ishan Barman7Kristine Glunde8The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of MedicineThe Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of MedicineThe Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of MedicineThe Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of MedicineThe Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineThe Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of MedicineThe Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of MedicineThe Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of MedicineAbstract The premetastatic niche hypothesis proposes an active priming of the metastatic site by factors secreted from the primary tumor prior to the arrival of the first cancer cells. We investigated several extracellular matrix (ECM) structural proteins, ECM degrading enzymes, and ECM processing proteins involved in the ECM remodeling of the premetastatic niche. Our in vitro model consisted of lung fibroblasts, which were exposed to factors secreted by nonmalignant breast epithelial cells, nonmetastatic breast cancer cells, or metastatic breast cancer cells. We assessed ECM remodeling in vivo in premetastatic lungs of female mice growing orthotopic primary breast tumor xenografts, as compared to lungs of control mice without tumors. Premetastatic lungs contained significantly upregulated Collagen (Col) Col4A5, matrix metalloproteinases (MMPs) MMP9 and MMP14, and decreased levels of MMP13 and lysyl oxidase (LOX) as compared to control lungs. These in vivo findings were consistent with several of our in vitro cell culture findings, which showed elevated Col14A1, Col4A5, glypican-1 (GPC1) and decreased Col5A1 and Col15A1 for ECM structural proteins, increased MMP2, MMP3, and MMP14 for ECM degrading enzymes, and decreased LOX, LOXL2, and prolyl 4-hydroxylase alpha-1 (P4HA1) for ECM processing proteins in lung fibroblasts conditioned with metastatic breast cancer cell media as compared to control. Taken together, our data show that premetastatic priming of lungs by primary breast tumors resulted in significant ECM remodeling which could facilitate metastasis by increasing interstitial fibrillar collagens and ECM stiffness (Col14A1), disruptions of basement membranes (Col4A5), and formation of leaky blood vessels (MMP2, MMP3, MMP9, and MMP14) to promote metastasis.https://doi.org/10.1038/s41598-023-45832-7 |
| spellingShingle | Ruoqing Cai Caitlin M. Tressler Menglin Cheng Kanchan Sonkar Zheqiong Tan Santosh Kumar Paidi Vinay Ayyappan Ishan Barman Kristine Glunde Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs Scientific Reports |
| title | Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs |
| title_full | Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs |
| title_fullStr | Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs |
| title_full_unstemmed | Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs |
| title_short | Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs |
| title_sort | primary breast tumor induced extracellular matrix remodeling in premetastatic lungs |
| url | https://doi.org/10.1038/s41598-023-45832-7 |
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