ICAM-1-suPAR-CD11b Axis Is a Novel Therapeutic Target for Metastatic Triple-Negative Breast Cancer
Accumulating evidence demonstrates that circulating tumor cell (CTC) clusters have higher metastatic ability than single CTCs and negatively correlate with cancer patient outcomes. Along with homotypic CTC clusters, heterotypic CTC clusters (such as neutrophil–CTC clusters), which have been identifi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/10/2734 |
| _version_ | 1797600727332290560 |
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| author | Dong Li Hami Hemati Younhee Park Rokana Taftaf Youbin Zhang Jinpeng Liu Massimo Cristofanilli Xia Liu |
| author_facet | Dong Li Hami Hemati Younhee Park Rokana Taftaf Youbin Zhang Jinpeng Liu Massimo Cristofanilli Xia Liu |
| author_sort | Dong Li |
| collection | DOAJ |
| description | Accumulating evidence demonstrates that circulating tumor cell (CTC) clusters have higher metastatic ability than single CTCs and negatively correlate with cancer patient outcomes. Along with homotypic CTC clusters, heterotypic CTC clusters (such as neutrophil–CTC clusters), which have been identified in both cancer mouse models and cancer patients, lead to more efficient metastasis formation and worse patient outcomes. However, the mechanism by which neutrophils bind to CTCs remains elusive. In this study, we found that intercellular adhesion molecule-1 (ICAM-1) on triple-negative breast cancer (TNBC) cells and CD11b on neutrophils mediate tumor cell–neutrophil binding. Consequently, CD11b deficiency inhibited tumor cell–neutrophil binding and TNBC metastasis. Furthermore, CD11b mediated hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) production from neutrophils. Moreover, we found that ICAM-1 in TNBC cells promotes tumor cells to secrete suPAR, which functions as a chemoattractant for neutrophils. Knockdown of uPAR in ICAM-1<sup>+</sup> TNBC cells reduced lung-infiltrating neutrophils and lung metastasis. Bioinformatics analysis confirmed that uPAR is highly expressed in TNBCs, which positively correlates with higher neutrophil infiltration and negatively correlates with breast cancer patient survival. Collectively, our findings provide new insight into how neutrophils bind to CTC to facilitate metastasis and discover a novel potential therapeutic strategy by blocking the ICAM-1-suPAR-CD11b axis to inhibit TNBC metastasis. |
| first_indexed | 2024-03-11T03:52:59Z |
| format | Article |
| id | doaj.art-aad257646ec141e490a67a1f4880aa58 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T03:52:59Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-aad257646ec141e490a67a1f4880aa582023-11-18T00:48:08ZengMDPI AGCancers2072-66942023-05-011510273410.3390/cancers15102734ICAM-1-suPAR-CD11b Axis Is a Novel Therapeutic Target for Metastatic Triple-Negative Breast CancerDong Li0Hami Hemati1Younhee Park2Rokana Taftaf3Youbin Zhang4Jinpeng Liu5Massimo Cristofanilli6Xia Liu7Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USADepartment of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USADepartment of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USADepartment of Medicine, Hematology/Oncology Division, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USADepartment of Medicine, Hematology/Oncology Division, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USAMarkey Cancer Center, University of Kentucky, Lexington, KY 40536, USADepartment of Medicine, Hematology/Oncology Division, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USADepartment of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USAAccumulating evidence demonstrates that circulating tumor cell (CTC) clusters have higher metastatic ability than single CTCs and negatively correlate with cancer patient outcomes. Along with homotypic CTC clusters, heterotypic CTC clusters (such as neutrophil–CTC clusters), which have been identified in both cancer mouse models and cancer patients, lead to more efficient metastasis formation and worse patient outcomes. However, the mechanism by which neutrophils bind to CTCs remains elusive. In this study, we found that intercellular adhesion molecule-1 (ICAM-1) on triple-negative breast cancer (TNBC) cells and CD11b on neutrophils mediate tumor cell–neutrophil binding. Consequently, CD11b deficiency inhibited tumor cell–neutrophil binding and TNBC metastasis. Furthermore, CD11b mediated hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) production from neutrophils. Moreover, we found that ICAM-1 in TNBC cells promotes tumor cells to secrete suPAR, which functions as a chemoattractant for neutrophils. Knockdown of uPAR in ICAM-1<sup>+</sup> TNBC cells reduced lung-infiltrating neutrophils and lung metastasis. Bioinformatics analysis confirmed that uPAR is highly expressed in TNBCs, which positively correlates with higher neutrophil infiltration and negatively correlates with breast cancer patient survival. Collectively, our findings provide new insight into how neutrophils bind to CTC to facilitate metastasis and discover a novel potential therapeutic strategy by blocking the ICAM-1-suPAR-CD11b axis to inhibit TNBC metastasis.https://www.mdpi.com/2072-6694/15/10/2734TNBCmetastasisneutrophilsoluble uPARICAM-1CD11b |
| spellingShingle | Dong Li Hami Hemati Younhee Park Rokana Taftaf Youbin Zhang Jinpeng Liu Massimo Cristofanilli Xia Liu ICAM-1-suPAR-CD11b Axis Is a Novel Therapeutic Target for Metastatic Triple-Negative Breast Cancer Cancers TNBC metastasis neutrophil soluble uPAR ICAM-1 CD11b |
| title | ICAM-1-suPAR-CD11b Axis Is a Novel Therapeutic Target for Metastatic Triple-Negative Breast Cancer |
| title_full | ICAM-1-suPAR-CD11b Axis Is a Novel Therapeutic Target for Metastatic Triple-Negative Breast Cancer |
| title_fullStr | ICAM-1-suPAR-CD11b Axis Is a Novel Therapeutic Target for Metastatic Triple-Negative Breast Cancer |
| title_full_unstemmed | ICAM-1-suPAR-CD11b Axis Is a Novel Therapeutic Target for Metastatic Triple-Negative Breast Cancer |
| title_short | ICAM-1-suPAR-CD11b Axis Is a Novel Therapeutic Target for Metastatic Triple-Negative Breast Cancer |
| title_sort | icam 1 supar cd11b axis is a novel therapeutic target for metastatic triple negative breast cancer |
| topic | TNBC metastasis neutrophil soluble uPAR ICAM-1 CD11b |
| url | https://www.mdpi.com/2072-6694/15/10/2734 |
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