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

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 +6 more·2010·Proceedings of the National Academy of Sciences

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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Registry

Crossref · 10.1073/pnas.0909333107

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  • A growing body of literature supports an essential role for AXL in promoting metastasis within many tumor types, including breast, ovarian, and lung.

    “A growing body of literature supports an essential role for AXL in promoting metastasis within many tumor types, including breast (81), ovarian (82), and lung (83).”

    From Hypoxic control of metastasis (2016) · cites this paper as [81]

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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)
Venue
Proceedings of the National Academy of Sciences
Published
2009-12-28
Volume
107
Issue
3
Pages
1124-1129
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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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