ABSTRACT
Bone metastasis of lung adenocarcinoma (AC) is a frequent complication of advanced disease. The purpose of this study was to identify key mediators conferring robust prometastatic activity with clinical significance. We isolated highly metastatic subpopulations (HMS) using a previously described in vivo model of lung AC bone metastasis. We performed transcriptomic profiling of HMS and stringent bioinformatics filtering. Functional validation was assessed by overexpression and lentiviral silencing of single, double and triple combination in vivo and in vitro. We identified HDAC4, PITX1 and ROBO1 that decreased bone metastatic ability after their simultaneous abrogation. These effects were solely linked to defects in osseous colonization. The molecular mechanisms related to bone colonization were mediated by non-cell autonomous effects that include the following: (1) a marked decrease in osteoclastogenic activity in vitro and in vivo, an effect associated with reduced pro-osteoclastogenic cytokines IL-11 and PTHrP expression levels, as well as decreased in vitro expression of stromal rankl in conditions mimicking tumor-stromal interactions; (2) an abrogated response to TGF-ß signaling by decreased phosphorylation and levels of Smad2/3 in tumor cells and (3) an impaired metalloproteolytic activity in vitro. Interestingly, coexpression of HDAC4 and PITX1 conferred high prometastatic activity in vivo. Further, levels of both genes correlated with patients at higher risk of metastasis in a clinical lung AC data set and with a poorer clinical outcome. These findings provide functional and clinical evidence that this metastatic subset is an important determinant of osseous colonization. These data suggest novel therapeutic targets to effectively block lung AC bone metastasis.
Subject(s)
Bone Neoplasms/genetics , Bone Neoplasms/secondary , Gene Expression Profiling , Lung Neoplasms/genetics , Nerve Tissue Proteins/metabolism , Paired Box Transcription Factors/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adenocarcinoma of Lung , Animals , Bone Neoplasms/pathology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Histone Deacetylases/genetics , Histone Deacetylases/metabolism , Humans , Lung Neoplasms/pathology , Mice , Mice, Nude , Neoplasms, Experimental , Nerve Tissue Proteins/genetics , Osteoclasts/metabolism , Osteolysis/genetics , Osteolysis/pathology , Paired Box Transcription Factors/genetics , Survival AnalysisABSTRACT
Bone metastases represent a devastating clinical problem in the most frequent neoplasies, especially in multiple myeloma, tumours breast, prostate and lung. The consequences include pain which is refractory to conventional analgesics, osteolysis often leading to bone-marrow compression and pathological fractures, and metabolic disorders. Recent advances in diagnosis using imaging techniques as well as different biochemical techniques have helped accurate diagnosis and follow-up. The increase in survival has improved through a multimodal approach combining, inhibition of osteolysis, with prophylactic orthopaedic surgery and radiation therapy. Recent advances in basic research have determined the molecular metastatic that can predict its proclivity to metastasize. Basic research will improve understanding of the basic mechanisms and lead to the clarification of molecular targets that will help in the development of medicines capable of preventing, decreasing or blocking the metastatic process.
Subject(s)
Bone Neoplasms/secondary , Biomedical Research/trends , Bone Neoplasms/therapy , Forecasting , HumansABSTRACT
Las metástasis óseas representan un problema clínicodevastador en las neoplasias más frecuentes,especialmente en el mieloma múltiple, mama, próstata,y pulmón. Las consecuencias incluyen dolores refractariosa analgésicos convencionales, osteolisis queconlleva en ocasiones compresión medular, fracturaspatológicas, y trastornos metabólicos. Recientes avancesen el diagnóstico mediante técnicas de imagen, asícomo diversas técnicas bioquímicas, han favorecidoun certero diagnóstico y seguimiento. El aumento de lasupervivencia se ha mejorado mediante una aproximaciónmultimodal en los tratamientos con la combinaciónde la inhibición de la osteolisis, la cirugía ortopédicaprofiláctica y la radioterapia. Recientes progresosen la investigación básica han determinado la huellamolecular de metástasis de un tumor capaz de predecirsu proclividad metastásica. La investigación básicafavorecerá un conocimiento de los mecanismos básicosy llevará a elucidar dianas moleculares que favoreceránel desarrollo de fármacos capaces de prevenir,amortiguar o bloquear el proceso metastático
Bone metastases represent a devastating clinical ;;problem in the most frequent neoplasies, especially ;;in multiple myeloma, tumours breast, prostate ;;and lung. The consequences include pain which is ;;refractory to conventional analgesics, osteolysis ;;often leading to bone-marrow compression and ;;pathological fractures, and metabolic disorders. ;;Recent advances in diagnosis using imaging techniques ;;as well as different biochemical techniques ;;have helped accurate diagnosis and follow-up. The ;;increase in survival has improved through a multimodal ;;approach combining, inhibition of osteolysis, ;;with prophylactic orthopaedic surgery and radiation ;;therapy. Recent advances in basic research have ;;determined the molecular metastatic that can predict ;;its proclivity to metastasize. Basic research will ;;improve understanding of the basic mechanisms and ;;lead to the clarification of molecular targets that will ;;help in the development of medicines capable of preventing, ;;decreasing or blocking the metastatic ;;process
