title: The calcineurin-NFAT-angiopoietin-2 signaling axis in lung endothelium is critical for the establishment of lung metastases.
abstract: The premetastatic niche is a predetermined site of metastases, awaiting the influx of tumor cells. However, the regulation of the angiogenic switch at these sites has not been examined. Here, we demonstrate that the calcineurin and nuclear factor of activated T cells (NFAT) pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. Upregulation of the calcineurin pathway via deletion of its endogenous inhibitor Dscr1 leads to a significant increase in lung metastases due to increased expression of a newly identified NFAT target, Angiopoietin-2 (ANG2). Increased VEGF levels specifically in the lung, and not other organ microenvironments, trigger a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR1 or the ANG2 receptor, soluble TIE2, prevents the activation of lung endothelium, inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the premetastatic niche and offer targets for lung metastases.
authors: Division of Vascular Biology, RCAST, the University of Tokyo, Tokyo 153-8904, Japan. minami@med.rcast.u-tokyo.ac.jp
authors: Takashi
authors: T
authors: Minami
authors: Shuying
authors: S
authors: Jiang
authors: Keri
authors: K
authors: Schadler
authors: Jun-Ichi
authors: J
authors: Suehiro
authors: Tsuyoshi
authors: T
authors: Osawa
authors: Yuichi
authors: Y
authors: Oike
authors: Mai
authors: M
authors: Miura
authors: Makoto
authors: M
authors: Naito
authors: Tatsuhiko
authors: T
authors: Kodama
authors: Sandra
authors: S
authors: Ryeom
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D059016:Tumor Microenvironment
chemical_list: D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C099439:Ang2 protein, mouse; D012259:Ribonuclease, Pancreatic; D019703:Calcineurin
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