Abstract 5180: The neuroreticular axis modulates cell signaling kinases in bone metastasis

Abstract

Abstract Bone metastasis is a main cause of cancer associated pain and mortality. The activation of osteoblasts and osteoclasts by cancer cells generates a vicious cycle of bone destruction and increased tumor growth, causing pain, fractures and spinal cord compression. In this study the microenvironment of human bone metastasis is being examined from a new point of view: the neuroreticular axis. The sympathetic nervous system regulates the homing and survival of bone marrow immune stem cells within a structural bone network called the neuroreticular complex. The neuroendocrine axis permits stem cells to survive in the bone microenvironment, regulates B and T cells and influences mesenchymal stem cells (MSC). Estrogen/androgen ratio is a fundamental regulator of bone development and turnover, inducing osteoblast or osteoclast differentiation. Platelet-derived serotonin (5-HT) is involved in bone metabolism via release from small intestine enterochromaffin cells to induce bone lysis or neuronal release, supporting bone consolidation. The aims are a) identify activated kinase pathway interconnections in each bone metastasis from different primary tumors to identify predictive/prognostic biomarkers, b) identify targets for molecular targeted therapies. 142 bone metastases frozen samples from different types of primary carcinomas (13 head and neck, 45 urogenital, 16 gastro enteric, 14 breast, 25 lung, 7 melanoma and 22 unknown carcinomas) and 24 from primary sarcomas were lysed using Covaris adaptive focused acoustic technology. Levels of 100 post-translationally modified cell signaling kinases were quantified by Reverse Phase Protein Microarray (RPMA). RPMA provides a quantitative “circuit map” of pathways that are activated/deactivated in a sample of tumor cells obtained from a biopsy. The metastasis originating from different primary tumors showed similar levels of cell signaling across tissue types for the majority of proliferation, invasion and adhesion pathway proteins analyzed. Sex hormone receptor expression was found to be similar among the metastasis samples from different carcinoma types, while bone metastasis from sarcomas showed a statistically significant higher expression compared to those originating from carcinomas (ERα Ser118 p<0.001, PR Ser190 p<0.005). No differences were found in serotonin levels among the bone metastasis derived from different tumor types (carcinomas and sarcomas). This data suggests that the bone microenvironment influences the signaling profiles of the metastatic tumor (seed vs. soil hypothesis). Therapies targeting bone metastasis are actually under evaluation but with poor success on prolonging patient survival. The results of this study may provide the opportunity to develop therapies targeting the bone microenvironment via an unexplored pathway, the neuroendocrine axis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5180. doi:10.1158/1538-7445.AM2011-5180