Abstract # 1800 Promotion of micrometastases by primary tumor secretome, and the deleterious effects of inflammatory surgical-stress responses on dormant metastases

Abstract

Surgical excision of a primary tumor was repeatedly shown to promote metastatic growth. However, several case studies have reported regression of metastases following tumor excision. Here we studied a luciferase-2-labelled human breast cancer cell line (MDA-MB-231) orthotopically implanted in nude mice. Primary tumors and metastatic progression were continuously monitored by bioluminescence imaging, and the primary tumor was excised shortly following metastases identification. Intriguingly, a reliable and robust 10–100 fold decrease in metastatic signal occurred gradually within 24 h of tumor excision. Subcutaneous implantation of osmotic minipumps containing conditioned medium from tumor cells, simultaneously with tumor excision, significantly attenuated this metastatic regression, indicating a stimulating signal from the primary tumor to remote malignant foci. Independently of this cross-talk, NK cells also mediated this regression of metastases, as indicated by two approaches of NK-depletion. Importantly, following tumor excision, the metastatic foci regressed into dormant micrometastases; however, extensive surgery simultaneously with tumor excision attenuated this regression and elicited an outbreak of these dormant micrometastases. Based on our previous work, we hypothesized that surgical inflammatory stress responses underlie this metastatic progression. Indeed, a short perioperative β -adrenergic blockade and COX-2 inhibition (using propranolol and etodolac) prevented this metastatic outbreak. This is a first model for post-excision metastatic regression into dormancy, and for the perioperative efficacy of this combined drug regimen in the context of evident micrometastases of a human malignancy.