title: Elevated TNFR1 and serotonin in bone metastasis are correlated with poor survival following bone metastasis diagnosis for both carcinoma and sarcoma primary tumors.
abstract: OBJECTIVE
  There is an urgent need for therapies that will reduce the mortality of patients with bone metastasis. In this study, we profiled the protein signal pathway networks of the human bone metastasis microenvironment. The goal was to identify sets of interacting proteins that correlate with survival time following the first diagnosis of bone metastasis.
  
  
  METHODS
  Using Reverse Phase Protein Microarray technology, we measured the expression of 88 end points in the bone microenvironment of 159 bone metastasis tissue samples derived from patients with primary carcinomas and sarcomas.
  
  
  RESULTS
  Metastases originating from different primary tumors showed similar levels of cell signaling across tissue types for the majority of proteins analyzed, suggesting that the bone microenvironment strongly influences the metastatic tumor signaling profiles. In a training set (72 samples), TNF receptor 1, alone (P = 0.0013) or combined with serotonin (P = 0.0004), TNFα (P = 0.0214), and RANK (P = 0.0226), was associated with poor survival, regardless of the primary tumor of origin. Results were confirmed by (i) analysis of an independent validation set (71 samples) and (ii) independent bioinformatic analysis using a support vector machine learning model. Spearman rho analysis revealed a highly significant number of interactions intersecting with ERα S118, serotonin, TNFα, RANKL, and matrix metalloproteinase in the bone metastasis signaling network, regardless of the primary tumor. The interaction network pattern was significantly different in the short versus long survivors.
  
  
  CONCLUSIONS
  TNF receptor 1 and neuroendocrine-regulated protein signal pathways seem to play an important role in bone metastasis and may constitute a novel drug-targetable mechanism of seed-soil cross talk in bone metastasis.
authors.affiliation: Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Chiechi
authors.forename: Chiara
authors.initials: C
authors.lastname: Novello
authors.forename: Giovanna
authors.initials: G
authors.lastname: Magagnoli
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.forename: Jianghong
authors.initials: J
authors.lastname: Deng
authors.forename: Maria S
authors.initials: MS
authors.lastname: Benassi
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.forename: Iosif
authors.initials: I
authors.lastname: Vaisman
authors.forename: Virginia
authors.initials: V
authors.lastname: Espina
authors.forename: Lance A
authors.initials: LA
authors.lastname: Liotta
mesh_terms: D019540:Area Under Curve; D001859:Bone Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D002277:Carcinoma / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008954:Models, Biological; D011379:Prognosis; D060066:Protein Interaction Maps; D020543:Proteome / Q000378:metabolism; D012372:ROC Curve; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D012509:Sarcoma / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction; D060388:Support Vector Machine; D059016:Tumor Microenvironment
chemical_list: D020543:Proteome; D047888:Receptors, Tumor Necrosis Factor, Type I; D012701:Serotonin