Abstract 4585: Breaking metastatic dormancy during surgical resection of a primary tumor and implications for treatment strategies.

Abstract

At the time of a cancer diagnosis, most patients have localized tumors. Despite elaborate staging schemas for each cancer type in an attempt to stratify patients, the vast majority of patients that die will do so from metastatic disease. We hypothesized that surgery augments the already ongoing activation and mobilization of bone marrow-derived progenitor cells that are critical to colonizing tumor cells at distant sites. These bone marrow-derived cells, by inducing a local inflamed tumor microenvironment, provide survival signals to these seeding tumor cells. Our data show increased metastatic burden in the lung after surgical resection of the primary tumor using two murine cancer models, B16 melanoma and E0771 breast carcinoma. In these models, we also show a surge in hematopoietic and endothelial progenitor cells in the hours and days immediately following resection of the primary tumor, which is not similarly observed in control mice, where surgery was performed in the absence of the primary tumor. We also confirmed that a factor specific to the plasma of the tumor-bearing mice is responsible for this mobilization by using in vitro migration assays, whereby plasma from tumor-bearing mice and surgically resected mice induced an increased migration of lineage negative bone marrow cells compared to the plasma of wild type mice. We confirmed increased levels of MCP-1 and MCSF, both known to mobilize progenitor cells, in the plasma of mice with surgical resection. Additionally, targeting these bone marrow derived hematopoietic and endothelial progenitor cells with Pazopanib prevents the surge in bone marrow-derived cells into the circulation, abolishes the enhanced metastatic spread in mice undergoing surgical resection of the primary tumor, and provides a significant prolongation of survival. Finally, we correlated these data to a cohort of breast cancer patients where circulating levels of progenitor cells were analyzed at time points before and after surgery, which confirmed the mobilization of progenitor cells with surgery. Together, these results provide evidence for the increased risk of metastatic spread after surgical resection of the primary tumor and suggest that blocking progenitor cell mobilization by adjuvant treatment during or immediately following surgery, the incidence of metastatic recurrence may be reduced.

Citation Format: Selena R. Granitto, Amber Giles, Simon Lavotshkin, Daniel Rutigliano, David Lyden, Rosandra N. Kaplan. Breaking metastatic dormancy during surgical resection of a primary tumor and implications for treatment strategies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4585. doi:10.1158/1538-7445.AM2013-4585