Abstract 1100: Macrophage infiltration is associated with release from dormancy in a novel model of dormant prostate cancer

Abstract

Abstract Background: Circulating tumor cells are found in approximately 70% of men with prostate cancer at the time of primary treatment. Less than a third of these men will develop recurrent cancer within 20 years of primary treatment, suggesting that only a subset of dormant tumor cells are able to escape dormancy and develop into clinical metastases. Escape from dormancy, though, is clinically significant since these men are at greatest risk of dying from prostate cancer. Mechanisms by which cancer cells escape dormancy are poorly understood and very few models exist to study dormancy, especially in prostate cancer. We previously found that when a dormant prostate cancer cell line was seeded into a bioscaffold and placed in vivo, tumor formation was detected after 6-8 weeks, whereas no growth was seen up to six months after the dormant cells were injected s.c. with Matrigel. Analysis of the tumors revealed significantly greater macrophage infiltration into the scaffold tumors. Gene expression and cytokine antibody arrays demonstrated increased expression of macrophage associated cytokines in scaffold tumors. While macrophages have been implicated in metastatic spread of various cancers, their role in escape from dormancy has not been elucidated. Objective: To determine if macrophages play a role in escape from tumor dormancy in prostate cancer. Methods: In vitro we cultured a dormant prostate cancer cell line, M12mac25, with macrophage conditioned media and then examined proliferation and gene expression. In vivo, mice were implanted with sphere-templated polyHEMA bioscaffolds pre-seeded with M12mac25 cells. To inhibit macrophage activity, mice received s.c. injections of clondronate liposomes or PBS liposomes as a control for 6 weeks. Results: In vitro culture of M12mac25 cells with macrophage-derived conditioned medium led to increased proliferation of the M12mac25 cells and similarly upregulated genes as those seen the in vivo bioscaffold-derived tumors. In vitro treatment of primary bone-marrow derived macrophages with clondronate liposomes resulted in apoptosis while exposure to PBS liposomes did not affect the macrophages. In contrast, M12mac25 cells were not affected by either PBS or clondronate liposomes. In vivo, clondronate liposomes effectively eliminated macrophages from the M12mac25 seeded scaffolds and prevented tumor growth in these scaffolds. Interpretation: Macrophages contribute to M12mac25 escape from dormancy. Citation Format: Thomas Long, Cynthia C. Sprenger, Ilsa Coleman, Peter Nelson, Buddy Ratner, Stephen Plymate. Macrophage infiltration is associated with release from dormancy in a novel model of dormant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1100. doi:10.1158/1538-7445.AM2014-1100