Cited by 595Cancer Cells and MetastasisTGF-β signaling in diseasesMechanisms of cancer metastasis

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Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival

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Gjerdrum, Christine, Tiron, Crina, Høiby, Torill, Stefansson, Ingunn, Haugen, Hallvard, Sandal, Tone, Collett, Karin, Li, Shan, McCormack, Emmet, Gjertsen, Bjørn Tore, Micklem, David R., Akslen, Lars A., Glackin, Carlotta, Lorens, James B.·2010·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0909333107PMC PMC2824310

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Abstract

Metastasis underlies the majority of cancer-related deaths. Thus, furthering our understanding of the molecular mechanisms that enable tumor cell dissemination is a vital health issue. Epithelial-to-mesenchymal transitions (EMTs) endow carcinoma cells with enhanced migratory and survival attributes that facilitate malignant progression. Characterization of EMT effectors is likely to yield new insights into metastasis and novel avenues for treatment. We show that the presence of the receptor tyrosine kinase Axl in primary breast cancers independently predicts strongly reduced overall patient survival, and that matched patient metastatic lesions show enhanced Axl expression. We demonstrate that Axl is strongly induced by EMT in immortalized mammary epithelial cells that establishes an autocrine signaling loop with its ligand, Gas6. Epiallelic RNA interference analysis in metastatic breast cancer cells delineated a distinct threshold of Axl expression for mesenchymal-like in vitro cell invasiveness and formation of tumors in foreign and tissue-engineered microenvironments in vivo. Importantly, in two different optical imaging-based experimental breast cancer models, Axl knockdown completely prevented the spread of highly metastatic breast carcinoma cells from the mammary gland to lymph nodes and several major organs and increased overall survival. These findings suggest that Axl represents a downstream effector of the tumor cell EMT that is required for breast cancer metastasis. Thus, the detection and targeted treatment of Axl-expressing tumors represents an important new therapeutic strategy for breast cancer.

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Authors: Gjerdrum, C., Tiron, C., Høiby, T., Stefansson, I., Haugen, H., Sandal, T., Collett, K., Li, S., McCormack, E., Gjertsen, B. T., Micklem, D. R., Akslen, L. A., Glackin, C., & Lorens, J. B.
Affiliations: Department of Biomedicine
The Gade Institute, Pathology Section
Beckman Research Institute (US)
Haukeland University Hospital (NO)
ORCID: Tiron, Crina
Collett, Karin
Li, Shan
McCormack, Emmet
Gjertsen, Bjørn Tore
Micklem, David R.
Akslen, Lars A.
Glackin, Carlotta
Lorens, James B.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2009-12-28
Volume: 107
Issue: 3
Pages: 1124-1129
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0909333107
PMC: PMC2824310
OpenAlex: W2003445065
Cited by: 594
References: 29
Citations by year: 2026: 14 · 2025: 30 · 2024: 21 · 2023: 44 · 2022: 34 · 2021: 37 · 2020: 55 · 2019: 39 · 2018: 37 · 2017: 45 · 2016: 52 · 2015: 42 · 2014: 40 · 2013: 29 · 2012: 27
FWCI: 12.17
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Helse Vest
Universitetet i Bergen
Norges Forskningsråd
National Institutes of Health
National Cancer Institute (R21CA107245, CA107245)
Topics: Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords: AXL, epithelial-mesenchymal transition, breast cancer metastasis, Gas6, autocrine signaling, patient survival, tumor invasion, lymph node metastasis, therapeutic target, mammary epithelial cells
MeSH terms: Axl Receptor Tyrosine Kinase, Animals, Breast Neoplasms, Epithelial Cells, Female, Humans, Mesoderm, Neoplasm Invasiveness, Neoplasm Metastasis, Prognosis, Proto-Oncogene Proteins, Oncogene Proteins, Survival Analysis, Mice, SCID, Mice, Inbred NOD, Receptor Protein-Tyrosine Kinases, Tissue Engineering, RNA Interference, Mice

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Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival

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