|Title:||ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway||Authors:||Lin C.-Y.
|Issue Date:||2014||Publisher:||American Association for Cancer Research Inc.||Journal Volume:||74||Journal Issue:||18||Start page/Pages:||5229-5243||Source:||Cancer Research||Abstract:||
The transmembrane cell adhesion protein ADAM9 has been implicated in cancer cell migration and lung cancer metastasis to the brain, but the underpinning mechanisms are unclear and clinical support has been lacking. Here, we demonstrate that ADAM9 enhances the ability of tissue plasminogen activator (tPA) to cleave and stimulate the function of the promigratory protein CDCP1 to promote lung metastasis. Blocking this mechanism of cancer cell migration prolonged survival in tumor-bearing mice and cooperated with dexamethasone and dasatinib (a dual Src/Abl kinase inhibitor) treatment to enhance cytotoxic treatment. In clinical specimens, high levels of ADAM9 and CDCP1 correlated with poor prognosis and high risk of mortality in patients with lung cancer. Moreover, ADAM9 levels in brain metastases derived from lung tumors were relatively higher than the levels observed in primary lung tumors. Our results show how ADAM9 regulates lung cancer metastasis to the brain by facilitating the tPA-mediated cleavage of CDCP1, with potential implications to target this network as a strategy to prevent or treat brain metastatic disease. ? 2014 American Association for Cancer Research.
|ISSN:||0008-5472||DOI:||10.1158/0008-5472.CAN-13-2995||metadata.dc.subject.other:||ADAM protein; ADAM9 protein, human; CDCP1 protein, human; cell adhesion molecule; dasatinib; dexamethasone; leukocyte antigen; membrane protein; plasminogen activator; pyrimidine derivative; thiazole derivative; tumor protein; adenocarcinoma; animal; Brain Neoplasms; deficiency; disease model; gene silencing; genetics; human; Lung Neoplasms; metabolism; metastasis; mouse; pathology; SCID mouse; secondary; tumor cell line; xenograft; ADAM Proteins; Adenocarcinoma; Animals; Antigens, CD; Brain Neoplasms; Cell Adhesion Molecules; Cell Line, Tumor; Dexamethasone; Disease Models, Animal; Gene Knockdown Techniques; Heterografts; Humans; Lung Neoplasms; Membrane Proteins; Mice; Mice, SCID; Neoplasm Metastasis; Neoplasm Proteins; Plasminogen Activators; Pyrimidines; Thiazoles
|Appears in Collections:||生理學科所|
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