Abstract 5065: Interleukin-1β secreted into the bone metastatic niche by androgen receptor-negative prostate cancer cells enables skeletal metastasis

Abstract

Abstract Advanced prostate cancer (PCa) frequently leads to bone metastasis, a major cause of morbidity and mortality. Limited knowledge of the molecular interactions underpinning the behavior of cancer cells in the bone microenvironment has stymied the development of curative therapies. Signaling between cancer cells and stroma likely plays a crucial role in dictating the fate of disseminated tumor cells (DTCs), and its disruption could interfere with the supportive role of the metastatic niche and thus hamper tumor growth. We previously identified interleukin-1β (IL-1β) as a major mediator of the bone-metastatic behavior of human prostate cancer cells inoculated into the left cardiac ventricle of SCID mice. Here, we show not only that pharmacologic disruption of IL-1β signaling using the IL-1 receptor (IL-1R) antagonist anakinra diminishes the metastatic potential of PCa cells in vivo, but also that IL-1β secreted by PCa cells can prompt bone stromal cells to acquire a carcinoma-associated fibroblast (CAF) phenotype. Emphasizing the role of the stroma, we demonstrate that SCID mice null for IL-1R display diminished formation of bone metastases relative to wild-type when inoculated with highly metastatic IL-1β-expressing PCa cells. In this same model we find that IL-1β supports early survival of DTCs in the bone. Interestingly, while the aggressively-metastatic androgen receptor (AR)-negative PC3-ML cell line expresss high levels of IL-1β, the numerous AR(+) PCa cell lines we examined each lack IL-1β expression. This was recapitulated in human tissue specimens of PCa bone metastases examined by a combination of Laser Capture Microdissection and qPCR. In these lesions, a relevant fraction of PCa cells lack AR transcript and express IL-1β, whereas AR(+) cells were uniformly negative for this cytokine. As AR(+) PCa cells are consistently non-metastatic in our pre-clinical model, we speculated that IL-1β-mediated induction of CAFs in the bone may enable growth of AR(+) PCa cells that would otherwise be unable to initiate a metastatic niche. To test this hypothesis, we co-inoculated PC3-ML and AR(+) PCa cells and evaluated their metastatic abilities using two-color labeling in both multispectral microscopy and bioluminescence imaging. We found that the presence of AR(-), IL-1β-expressing cells allowed AR(+) PCa cells both to colonize the bone and persist in macroscopic mixed tumors in the long term. Our study thus conclusively confirms the existence of AR(-) PCa cells in skeletal metastases, describes a negative correlation between AR and IL-1β expression, and implicates this cytokine in a form of metastatic cooperation between phenotypically distinct cancer cells. These discoveries may be exploited therapeutically to alter the microenvironment of the metastatic niche, with the aim to impair establishment and progression of bone metastatic disease in PCa patients. Citation Format: Kristina S. Shahriari, Fei Shen, QingXin Liu, Danielle L. Jernigan, Ramanpreet Kaur, Alessandro Fatatis. Interleukin-1β secreted into the bone metastatic niche by androgen receptor-negative prostate cancer cells enables skeletal metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5065. doi:10.1158/1538-7445.AM2015-5065