A novel lung cancer signature mediates metastatic bone colonization by a dual mechanism.

Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and a dismal prognosis. To identify and functionally characterize genes involved in the mechanisms of osseous metastasis, we developed a murine lung cancer model. Comparative transcriptomic analysis identified genes encoding signaling molecules (such as TCF4 and PRKD3) and cell anchorage-related proteins (MCAM and SUSD5), some of which were basally modulated by transforming growth factor-beta (TGF-beta) in tumor cells and in conditions mimicking tumor-stromal interactions. Triple gene combinations induced not only high osteoclastogenic activity but also a marked enhancement of global metalloproteolytic activities in vitro. These effects were strongly associated with robust bone colonization in vivo, whereas this gene subset was ineffective in promoting local tumor growth and cell homing activity to bone. Interestingly, global inhibition of metalloproteolytic activities and simultaneous TGF-beta blockade in vivo led to increased survival and a remarkable attenuation of bone tumor burden and osteolytic metastasis. Thus, this metastatic gene signature mediates bone matrix degradation by a dual mechanism of induction of TGF-beta-dependent osteoclastogenic bone resorption and enhancement of stroma-dependent metalloproteolytic activities. Our findings suggest the cooperative contribution of host-derived and cell autonomous effects directed by a small subset of genes in mediating aggressive osseous colonization.

[1]  G. Oster,et al.  The Cost of Treatment of Skeletal-Related Events in Patients with Bone Metastases from Lung Cancer , 2005, Oncology.

[2]  J. Minna,et al.  NCI‐navy medical oncology branch cell line data base , 1996, Journal of cellular biochemistry. Supplement.

[3]  M. Tammi,et al.  Hyaluronan-Cell Interactions in Cancer and Vascular Disease* , 2002, The Journal of Biological Chemistry.

[4]  B F Boyce,et al.  Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. , 1996, The Journal of clinical investigation.

[5]  Carlos L. Arteaga,et al.  Targeting the TGFβ signaling network in human neoplasia , 2003 .

[6]  E. Ogata,et al.  Involvement of parathyroid hormone–related protein in experimental cachexia induced by a human lung cancer–derived cell line established from a bone metastasis specimen , 2001, International journal of cancer.

[7]  A. Balmain,et al.  TGF-β signaling in tumor suppression and cancer progression , 2001, Nature Genetics.

[8]  J. Chirgwin,et al.  Transforming Growth Factor-Stimulates Parathyroid Hormone-related Protein and Osteolytic Metastases via Smad and Mitogen-activated Protein Kinase Signaling Pathways * , 2002 .

[9]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Kathleen R. Cho,et al.  ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with beta-catenin defects and promotes neoplastic transformation. , 2002, Cancer cell.

[11]  J. Massagué,et al.  TGFβ Signaling in Growth Control, Cancer, and Heritable Disorders , 2000, Cell.

[12]  C. Cordon-Cardo,et al.  A multigenic program mediating breast cancer metastasis to bone. , 2003, Cancer cell.

[13]  T. Jacks,et al.  Modeling human lung cancer in mice: similarities and shortcomings , 1999, Oncogene.

[14]  조남훈,et al.  MMP expression profiling in recurred stage IB lung cancer , 2004 .

[15]  Allan Balmain,et al.  TGF-β signaling in tumor suppression and cancer progression , 2001, Nature Genetics.

[16]  A. Jemal,et al.  Cancer Statistics, 2004 , 2004, CA: a cancer journal for clinicians.

[17]  S Paget,et al.  THE DISTRIBUTION OF SECONDARY GROWTHS IN CANCER OF THE BREAST. , 1889 .

[18]  Tomoyuki Shirai,et al.  MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. , 2005, Cancer cell.

[19]  L. Wakefield,et al.  Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. , 2002, The Journal of clinical investigation.

[20]  P. Brennan,et al.  Cigarette smoking and risk of large cell carcinoma of the lung: a case-control study in Uruguay. , 2004, Lung cancer.

[21]  Quynh-Thu Le,et al.  Non-small cell lung cancer: Clinical practice guidelines in oncology , 2006 .

[22]  T. Speed,et al.  Summaries of Affymetrix GeneChip probe level data. , 2003, Nucleic acids research.

[23]  M. V. Dinther,et al.  The Tumor Suppressor Smad 4 Is Required for Transforming Growth Factor B – Induced Epithelial to Mesenchymal Transition and Bone Metastasis of Breast Cancer Cells , 2006 .

[24]  J. Johnson,et al.  Expression of MCAM/MUC18 by human melanoma cells leads to increased tumor growth and metastasis. , 1997, Cancer research.

[25]  M. Cher,et al.  Third North American symposium on skeletal complications of malignancy , 2003, Cancer.

[26]  R Wieser,et al.  TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. , 1999, The Journal of clinical investigation.

[27]  J. Rivas,et al.  Transcriptional networks of knockout cell lines identify functional specificities of H-Ras and N-Ras: significant involvement of N-Ras in biotic and defense responses , 2007, Oncogene.

[28]  J. Massagué,et al.  TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. , 2005, Cancer cell.

[29]  Suyun Huang,et al.  Fully human antibodies to MCAM/MUC18 inhibit tumor growth and metastasis of human melanoma. , 2002, Cancer research.

[30]  Wei He,et al.  Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[32]  E. Rozengurt,et al.  Protein Kinase D Signaling* , 2005, Journal of Biological Chemistry.

[33]  E. Álava,et al.  EWS/FLI-1 oncoprotein subtypes impose different requirements for transformation and metastatic activity in a murine model , 2007, Journal of Molecular Medicine.

[34]  R. Coleman.  Skeletal complications of malignancy , 1997, Cancer.

[35]  K. Uematsu,et al.  Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells , 2004, Oncogene.

[36]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[37]  D. Winchester,et al.  The National Cancer Data Base report on lung cancer , 1996, Cancer.

[38]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[39]  M. Doucet,et al.  TGF-beta promotes the establishment of renal cell carcinoma bone metastasis. , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[40]  J. Prieto,et al.  Identification of peptide inhibitors of transforming growth factor beta 1 using a phage-displayed peptide library. , 2007, Cytokine.

[41]  J. Prieto,et al.  A synthetic peptide from transforming growth factor beta type III receptor inhibits liver fibrogenesis in rats with carbon tetrachloride liver injury. , 2003, Cytokine.

[42]  G. Mundy.  Metastasis: Metastasis to bone: causes, consequences and therapeutic opportunities , 2002, Nature Reviews Cancer.

[43]  B. Asselain,et al.  4-year mortality in patients with non-small-cell lung cancer: development and validation of a prognostic index. , 2006, The Lancet. Oncology.