Evidence map›Paper›PMID 25187556›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2014

Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET.

Erinn B Rankin, Katherine C Fuh, Laura Castellini, Kartik Viswanathan, Elizabeth C Finger, Anh N Diep, Edward L LaGory, Mihalis S Kariolis, Andy Chan, David Lindgren and 4 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 178 papers.

0numbers the graph read from it
0cells of the map it votes in
178citing papers in PubMed
9.7field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

178 citing papers in PubMed, 261 citations in OpenAlex.

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  8. Quality of Life Outcomes for Cabozantinib Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma: METEOR Phase III Randomized Trial.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2018
    Trial
  9. Trial
  10. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.The New England journal of medicine · 2015
    Trial
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  16. Clinical and molecular characterization ofJournal for immunotherapy of cancer · 2025
    Article
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118 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 4 institutions in 2 countries.

Erinn B RankinDivision of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
Katherine C FuhDivision of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
Laura CastelliniDivision of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
Kartik ViswanathanDivision of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
Elizabeth C FingerDivision of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
Anh N DiepDivision of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
Edward L LaGoryDivision of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
Mihalis S KariolisDivision of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
Andy ChanDivision of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
David LindgrenDepartment of Laboratory Medicine, Center for Molecular Pathology, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden; and.
Håkan AxelsonDepartment of Laboratory Medicine, Center for Molecular Pathology, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden; and.
Yu R MiaoDivision of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305;
Adam J KriegDepartment of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160.
Amato J GiacciaDivision of Radiation and Cancer Biology and Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA, 94305; giaccia@stanford.edu.
Stanford University · USLund University · SESkåne University Hospital · SEUniversity of Kansas Medical Center · US

Funding

TUMOR HYPOXIA--MOLECULAR STUDIES &CLINICAL EXPLOITATIONP01CA067166 · NCI · STANFORD UNIVERSITY · PI LE, QUYNH-THU XUAN · 1996 to 2017
$25.5M
Leveraging innovative technologies in basic and clinical cancer researchT32CA009302 · NCI · STANFORD UNIVERSITY · PI LAURA D ATTARDI, Aaron M Newman · 1985 to 2026
$19.1M
HYPOXIA AND GENE REPRESSIONR01CA088480 · NCI · STANFORD UNIVERSITY · PI GIACCIA, AMATO J. · 2000 to 2009
$3.4M
Postdoctoral Training in the Radiation ScincesT32CA121940 · NCI · STANFORD UNIVERSITY · PI GRAVES, EDWARD E. · 2007 to 2018
$2.1M
Hypoxia and Gene RepressionR37CA088480 · NCI · STANFORD UNIVERSITY · PI GIACCIA, AMATO J. · 2010 to 2014
$1.6M
NCI NIH HHS CA-088480NCI NIH HHS CA-67166NCI NIH HHS P01 CA067166NCI NIH HHS R01 CA088480NCI NIH HHS R37 CA088480NCI NIH HHS T32 CA009302NCI NIH HHS T32 CA121940PHS HHS ARO65403
6 · The paper itself

Abstract

Dysregulation of the von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) signaling pathway promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis. The protein kinase GAS6/AXL signaling pathway has recently been implicated as an essential mediator of metastasis and receptor tyrosine kinase crosstalk in cancer. Here we establish a molecular link between HIF stabilization and induction of AXL receptor expression in metastatic ccRCC. We found that HIF-1 and HIF-2 directly activate the expression of AXL by binding to the hypoxia-response element in the AXL proximal promoter. Importantly, genetic and therapeutic inactivation of AXL signaling in metastatic ccRCC cells reversed the invasive and metastatic phenotype in vivo. Furthermore, we define a pathway by which GAS6/AXL signaling uses lateral activation of the met proto-oncogene (MET) through SRC proto-oncogene nonreceptor tyrosine kinase to maximize cellular invasion. Clinically, AXL expression in primary tumors of ccRCC patients correlates with aggressive tumor behavior and patient lethality. These findings provide an alternative model for SRC and MET activation by growth arrest-specific 6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma.

Indexed as

Axl Receptor Tyrosine KinaseBasic Helix-Loop-Helix ProteinsCarcinoma, Renal CellCell HypoxiaCell Line, TumorEndothelial PAS Domain-Containing Protein 1Enzyme ActivationGrowth Arrest-Specific Protein 6Hepatocyte Growth FactorHumansHypoxia-Inducible Factor 1, alpha SubunitIntercellular Signaling Peptides and ProteinsKidney NeoplasmsModels, BiologicalNeoplasm InvasivenessPhenotypeAXL protein, humanAxl Receptor Tyrosine KinaseBasic Helix-Loop-Helix ProteinsEndothelial PAS Domain-Containing Protein 1Growth Arrest-Specific Protein 6Hepatocyte Growth FactorHypoxia-Inducible Factor 1, alpha SubunitIntercellular Signaling Peptides and ProteinsMAS1 protein, humanProto-Oncogene MasProto-Oncogene ProteinsProto-Oncogene Proteins c-metReceptor Protein-Tyrosine Kinasessrc-Family KinasesVon Hippel-Lindau Tumor Suppressor Proteinhepatocellular carcinomakidney cancertargeted therapyVHL

Identifiers

PMID25187556
PMCPMC4169907
OpenAlexW2079075723

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.