An integrin αvβ3–c-Src oncogenic unit promotes anchorage-independence and tumor progression
Open accessAbstract
Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin alpha(v)beta(3) is associated with progression of a variety of human tumors. Here we reveal a previously undescribed adhesion-independent role for integrin alpha(v)beta(3) in pancreatic cancer and other carcinomas. Specifically, alpha(v)beta(3) expressed in carcinoma cells enhanced anchorage-independent tumor growth in vitro and increased lymph node metastases in vivo. These effects required recruitment of c-Src to the beta(3) integrin cytoplasmic tail, leading to c-Src activation, Crk-associated substrate (CAS) phosphorylation and tumor cell survival that, unexpectedly, was independent of cell adhesion or focal adhesion kinase (FAK) activation. Pharmacological blockade of c-Src kinase activity or decreased expression of endogenous alpha(v)beta(3) integrin or c-Src not only inhibited anchorage-independent growth but also suppressed metastasis in vivo, yet these manipulations did not affect tumor cell migration or invasion. These data define an unexpected role for an integrin as a mediator of anchorage independence, suggesting that an alpha(v)beta(3)-c-Src signaling module may account for the aggressive behavior of integrin alpha(v)beta(3)-expressing tumors in humans.
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Integrin αvβ3 can induce apoptosis, tumor progression, and tumor stemness in an anchorage-independent manner.
“In fact, integrin αvβ3 can induce apoptosis (Stupack et al., 2001), tumor progression (Desgrosellier et al., 2009), and tumor stemness (Seguin et al., 2014) in an anchorage-independent manner.”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Desgrosellier et al., 2009
Integrins can mediate signaling cascades independent of ligand binding.
“Interestingly, integrins can also mediate signaling cascades independent of ligand binding.”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Desgrosellier et al., 2009
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- Authors
- Desgrosellier, J. S., Barnes, L. A., Shields, D. J., Huang, M., Lau, S. K., Prévost, N., Tarin, D., Shattil, S. J., & Cheresh, D. A.
- Affiliations
- Moores Cancer Center (US)
- University of California San Diego (US)
- Corresponding author
- Cheresh, David A
- ORCID
- Venue
- Nature Medicine
- Published
- 2009-09-06
- Volume
- 15
- Issue
- 10
- Pages
- 1163-1169
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2759406
- OpenAlex
- W2201926879
- Cited by
- 293
- References
- 51
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 12 · 2023: 15 · 2022: 7 · 2021: 15 · 2020: 20 · 2019: 20 · 2018: 15 · 2017: 21 · 2016: 17 · 2015: 13 · 2014: 24 · 2013: 17 · 2012: 26
- FWCI
- 19.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 57900, P01HL057900)
- National Cancer Institute (F32CA123774, CA-45726, R01CA045726, R21CA129660, CA 78045, CA129660, R37CA050286, P01CA078045, CA95262, CA123774, R01CA095262, T32CA121938)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- integrin αvβ3, Src kinase, anchorage-independent growth, tumor progression, lymph node metastasis, pancreatic cancer, carcinoma, integrin cytoplasmic tail, tumor cell survival, focal adhesion kinase
- MeSH terms
- CSK Tyrosine-Protein Kinase, Animals, Breast Neoplasms, Carcinoma, Cell Adhesion, Female, Fibronectins, Humans, Lymphatic Metastasis, Mice, Nude, Neoplasm Invasiveness, Pancreatic Neoplasms, Protein-Tyrosine Kinases, Substrate Specificity, Time Factors, Transfection, Transplantation, Heterologous, Tumor Cells, Cultured, Apoptosis, src-Family Kinases, Ki-67 Antigen, In Situ Nick-End Labeling, RNA, Small Interfering, Integrin alphaVbeta3, Cell Proliferation, Green Fluorescent Proteins, Mice, Focal Adhesion Protein-Tyrosine Kinases
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