Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome

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-231(HM) 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-231(HM)-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-231(HM) 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-231(HM)-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-231(HM) xenografts. If generalized, such findings can suggest novel approaches to control micro-metastases and minimal residual disease.