Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome
Abstract Background Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive. Here, we present a model of regression and latency of metastases following primary tumor excision and identify potential un...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-11-01
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| Series: | BMC Biology |
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| Online Access: | http://link.springer.com/article/10.1186/s12915-020-00893-2 |
| _version_ | 1818269788426731520 |
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| author | Lee Shaashua Anabel Eckerling Boaz Israeli Gali Yanovich Ella Rosenne Suzana Fichman-Horn Ido Ben Zvi Liat Sorski Rita Haldar Ronit Satchi-Fainaro Tamar Geiger Erica K. Sloan Shamgar Ben-Eliyahu |
| author_facet | Lee Shaashua Anabel Eckerling Boaz Israeli Gali Yanovich Ella Rosenne Suzana Fichman-Horn Ido Ben Zvi Liat Sorski Rita Haldar Ronit Satchi-Fainaro Tamar Geiger Erica K. Sloan Shamgar Ben-Eliyahu |
| author_sort | Lee Shaashua |
| collection | DOAJ |
| description | Abstract Background Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive. Here, we present a model of regression and latency of metastases following primary tumor excision and identify potential underlying mechanisms. Results Using MDA-MB-231HM human breast cancer cells that express highly sensitive luciferase, we monitored early development stages of spontaneous metastases in BALB/c nu/nu mice. Removal of the primary tumor caused marked regression of micro-metastases, but not of larger metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that primary tumor-secreted factors promote early metastatic growth. Correspondingly, MDA-MB-231HM-conditioned medium increased in vitro tumor proliferation and adhesion and reduced apoptosis. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231HM secretome were conducted. The results identified significant enrichment of angiogenesis, growth factor binding and activity, focal adhesion, and metalloprotease and apoptosis regulation processes. Neutralization of MDA-MB-231HM-secreted key mediators of these processes, IL-8, PDGF-AA, Serpin E1 (PAI-1), and MIF, each antagonized secretome-induced proliferation. Moreover, their in vivo simultaneous blockade in the presence of the primary tumor arrested the development of micro-metastases. Interestingly, in the METABRIC cohort of breast cancer patients, elevated expression of Serpin E1, IL-8, or the four factors combined predicted poor survival. Conclusions These results demonstrate regression and latency of micro-metastases following primary tumor excision and a crucial role for primary tumor secretome in promoting early metastatic growth in MDA-MB-231HM xenografts. If generalized, such findings can suggest novel approaches to control micro-metastases and minimal residual disease. |
| first_indexed | 2024-12-12T20:59:57Z |
| format | Article |
| id | doaj.art-c428b1582c5b452882d00c864c28dd9b |
| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-12-12T20:59:57Z |
| publishDate | 2020-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj.art-c428b1582c5b452882d00c864c28dd9b2022-12-22T00:12:10ZengBMCBMC Biology1741-70072020-11-0118111310.1186/s12915-020-00893-2Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretomeLee Shaashua0Anabel Eckerling1Boaz Israeli2Gali Yanovich3Ella Rosenne4Suzana Fichman-Horn5Ido Ben Zvi6Liat Sorski7Rita Haldar8Ronit Satchi-Fainaro9Tamar Geiger10Erica K. Sloan11Shamgar Ben-Eliyahu12Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv UniversitySagol School of Neuroscience and School of Psychological Sciences, Tel Aviv UniversitySagol School of Neuroscience and School of Psychological Sciences, Tel Aviv UniversityDepartment of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv UniversitySagol School of Neuroscience and School of Psychological Sciences, Tel Aviv UniversityPathology Institute, Rabin Medical Center, Tel Aviv UniversityNeurosurgery Department, Rabin Medical Center, Tel Aviv UniversitySagol School of Neuroscience and School of Psychological Sciences, Tel Aviv UniversitySagol School of Neuroscience and School of Psychological Sciences, Tel Aviv UniversityDepartment of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv UniversityDepartment of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv UniversityDrug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash UniversitySagol School of Neuroscience and School of Psychological Sciences, Tel Aviv UniversityAbstract Background Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive. Here, we present a model of regression and latency of metastases following primary tumor excision and identify potential underlying mechanisms. Results Using MDA-MB-231HM human breast cancer cells that express highly sensitive luciferase, we monitored early development stages of spontaneous metastases in BALB/c nu/nu mice. Removal of the primary tumor caused marked regression of micro-metastases, but not of larger metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that primary tumor-secreted factors promote early metastatic growth. Correspondingly, MDA-MB-231HM-conditioned medium increased in vitro tumor proliferation and adhesion and reduced apoptosis. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231HM secretome were conducted. The results identified significant enrichment of angiogenesis, growth factor binding and activity, focal adhesion, and metalloprotease and apoptosis regulation processes. Neutralization of MDA-MB-231HM-secreted key mediators of these processes, IL-8, PDGF-AA, Serpin E1 (PAI-1), and MIF, each antagonized secretome-induced proliferation. Moreover, their in vivo simultaneous blockade in the presence of the primary tumor arrested the development of micro-metastases. Interestingly, in the METABRIC cohort of breast cancer patients, elevated expression of Serpin E1, IL-8, or the four factors combined predicted poor survival. Conclusions These results demonstrate regression and latency of micro-metastases following primary tumor excision and a crucial role for primary tumor secretome in promoting early metastatic growth in MDA-MB-231HM xenografts. If generalized, such findings can suggest novel approaches to control micro-metastases and minimal residual disease.http://link.springer.com/article/10.1186/s12915-020-00893-2Metastatic regressionBreast cancerSurgeryRemoval of primary tumorCancer secretome |
| spellingShingle | Lee Shaashua Anabel Eckerling Boaz Israeli Gali Yanovich Ella Rosenne Suzana Fichman-Horn Ido Ben Zvi Liat Sorski Rita Haldar Ronit Satchi-Fainaro Tamar Geiger Erica K. Sloan Shamgar Ben-Eliyahu Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome BMC Biology Metastatic regression Breast cancer Surgery Removal of primary tumor Cancer secretome |
| title | Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome |
| title_full | Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome |
| title_fullStr | Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome |
| title_full_unstemmed | Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome |
| title_short | Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome |
| title_sort | spontaneous regression of micro metastases following primary tumor excision a critical role for primary tumor secretome |
| topic | Metastatic regression Breast cancer Surgery Removal of primary tumor Cancer secretome |
| url | http://link.springer.com/article/10.1186/s12915-020-00893-2 |
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