ABSTRACT: Numerous case studies have reported spontaneous regression of metastases following tumor excision, but underlying mechanisms are elusive. Here we present a model of metastases regression and latency elicited by the removal of a primary tumor, and identify underlying mechanisms. Human breast cancer cells, expressing highly sensitive luciferase, were implanted into the mammary fat-pad of mice, and the progression of early stage micrometastases, was monitored. Upon establishment of micrometastases, the primary tumor was excised, inducing a robust regression of metastatic signal, resulting in latent foci. In vivo supplementation of tumor secretome immediately upon tumor excision diminished this regression, implicating primary tumor secreted factors in promotion of metastatic growth. In vitro, cancer cell conditioned medium reduced apoptosis and enhanced adhesion of non-confluent cancer cells, and induced angiogenesis in endothelial cells. Cytokine array and proteomic analysis of cancer cells secretome identified 359 extracellular secreted factors, with significant enrichment of angiogenic factors, growth factors activity, focal adhesion, apoptosis, and metalloprotease processes. In vivo blockade of four key potential mediators of these processes, IL-8, PDGFaa, Serpin E1 (PAI-1), and MIF, arrested development of micrometastases. Moreover, high protein levels of these four factors were correlated with poor patient outcome. These results demonstrate regression and latency of metastases following tumor excision and a crucial role for primary tumor secretome in promoting early metastatic stages, suggesting novel mechanisms to control minimal residual disease.
Tamar Geiger 
