Abstract 3943: Cancer cell cooperation in the bone metastatic niche.

Advanced prostate cancer (PCa) frequently spreads to the skeleton and bone metastases are a major cause of morbidity and the main cause of death from this malignancy. The effective treatment of PCa disseminated to the skeleton remains an unmet clinical need. This lack of curative therapeutic approaches stems from our limited knowledge of the molecular interactions underpinning the colonization, survival and growth of cancer cells in the bone microenvironment. In this study, we focused on the autocrine and paracrine interactions involving different phenotypes of Disseminated Tumor Cells (DTCs) and the surrounding bone marrow stroma. These functional interactions are likely to play a crucial role in dictating the fate of DTCs and their disruption could interfere with the supportive role of the metastatic niche. By using comparative gene expression analysis we have demonstrated that IL-1β and CXCL6 determine the bone-metastatic behavior of human prostate cancer cells inoculated in the left cardiac ventricle of SCID mice. Since the tumor-producing cancer cells secrete both signaling molecules, we speculated that their roles include the establishment of cross talk with the surrounding cells of the bone stroma. The stromal cells would reciprocate with an increased or de novo production of trophic factors that promote metastatic progression. These local factors could also support DTC types that would normally be unable to initiate a metastatic niche, resulting in a form of cancer cell cooperation at distant sites. To test this hypothesis, we generated skeletal lesions in mice using Td-Tomato-labeled metastatic cells inoculated via the intracardiac route, followed by a second inoculation with GFP-labeled PCa cells lacking metastatic potential. We found that under these conditions the resulting skeletal lesions were composed of both cell types, indicating that metastasis-initiating cells could support subsequent colonization by cancer cells that normally fail to survive in the bone microenvironment. We then simultaneously inoculated animals with both cell types and discovered that the supportive influence of metastasis-initiating cells on non-metastatic cells is exerted immediately after homing to the skeleton. Further, we used Laser Capture Microdissection (LCM) to confirm high expression of IL-1β and CXCL6 in DTCs in metastatic lesions and then to identify signaling molecules and stromal cell types implicated in this novel cooperation mechanism in bone-metastatic lesions. These data may help identify multiple drug targets that, if clinically exploited, could lead to a substantial reduction in metastatic burden and concomitant increase in quality of life in the advanced prostate cancer patient population. Citation Format: Qingxin Liu, Kristina Shahriari, Marina Sazanovich, Danielle Jernigan, Alessandro Fatatis. Cancer cell cooperation in the bone metastatic niche. [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 3943. doi:10.1158/1538-7445.AM2013-3943