Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome
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RESEARCH ARTICLE
Open Access
Spontaneous regression of micrometastases following primary tumor excision: a critical role for primary tumor secretome Lee Shaashua1†, Anabel Eckerling1†, Boaz Israeli1, Gali Yanovich2, Ella Rosenne1, Suzana Fichman-Horn3, Ido Ben Zvi4, Liat Sorski1, Rita Haldar1, Ronit Satchi-Fainaro5, Tamar Geiger2, Erica K. Sloan6 and Shamgar Ben-Eliyahu1*
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-MB231HM 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. Keywords: Metastatic regression, Breast cancer, Surgery, Removal of primary tumor, Cancer secretome
* Correspondence: [email protected] † Lee Shaashua and Anabel Eckerling contributed equally to this work. 1 Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, 69978 Tel Aviv, Israel Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to t
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