Abstract B40: Autocrine and paracrine IL-6 and IL-8 drive osteosarcoma lung tropism and facilitate metastasis

Abstract

Abstract Osteosarcoma originates in bone, but metastasizes predictably to the lungs. Patients who develop lung metastases become much more difficult to treat. Metastatic lung disease responds poorly to traditional chemotherapy. We know very little of the mechanisms that mediate this lung tropism, or predilection for spread to lung tissue. A better understanding of this process could facilitate disruption of pathways which drive the metastatic process, potentially preventing or even treating lung metastasis. We thus sought to identify tumor-lung interactions that facilitate extravasation, survival, and growth of tumor cells specifically within the lung environment. Drawing on published signatures of osteosarcoma metastasis, we curated a list of 59 candidate genes that might facilitate lung metastasis. By comparing expression in metastatic lung lesions relative to paired primary tumors, we found that metastatic tumors reliably express two cytokines, IL-6 and IL-8, at much higher levels than matched primary bone tumors. In a mouse model of osteosarcoma, we found that tumors expressing high levels of autocrine IL-6 and IL-8 established lung metastases much more readily than tumors which expressed low or no IL-6 or IL-8. Using immunohistochemistry to identify sources of these cytokines within human metastatic lesions, we found higher levels of IL-6 and IL-8 coming from non-malignant cells within the tumor, especially mononuclear infiltrates and peri-bronchiolar cells. Modelling tumor-lung interactions in vitro using a co-culture system, much higher levels of IL-6 and IL-8 were produced when osteosarcoma cells were cultured with bronchial epithelial cells, smooth muscle cells, or macrophages suggesting that paracrine interactions drive production of these cytokines upon interaction of tumor cells with resident lung cells. In murine models of osteosarcoma metastasis, blocking IL-6 and/or IL-8 production within tumor cells using inducible shRNA-expressing lentiviruses dramatically reduced metastatic efficiency. Our data suggest that IL-6 and IL-8 play a primary role in the development of osteosarcoma lung metastasis. The readily targetable nature of these pathways makes them attractive candidates for therapies designed to prevent and possibly treat osteosarcoma lung metastasis. Citation Format: Ryan D. Roberts, Amy C. Gross, Hemant K. Bid, Doris Phelps, Mary F. Wedekind, Peter J. Houghton. Autocrine and paracrine IL-6 and IL-8 drive osteosarcoma lung tropism and facilitate metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B40.