Exploring the Role of RGD-Recognizing Integrins in Cancer
Abstract
:1. Introduction
2. Integrin Activation upon Conformational Rearrangements
3. Integrins in Cancer Progression and Metastasis
3.1. Integrin-Mediated Cell Adhesion, Migration, and Invasion
3.1.1. Integrin αvβ3 and α5β1
3.1.2. Integrin αvβ6
3.1.3. Integrin αvβ8
3.2. Impact of Integrins on Cellular Proliferation
3.2.1. Integrin αvβ3
3.2.2. Integrin αvβ6
3.2.3. Integrin αvβ8
3.3. Integrin Effects on Cell Survival and Apoptosis
3.4. Integrins αvβ3, αvβ5, and α5β1 in Tumor Angiogenesis
3.5. TGF-β1 and Its Integration with Integrin Signaling
4. Challenges for the Design of Novel Integrin Ligands and Their Translation into Clinical Applications
5. Improving the Activity and Selectivity of Integrin Ligands
6. In Vivo Targeting of Integrins for Cancer Imaging and Therapy
6.1. Integrin αvβ3 and α5β1
6.2. Integrin αvβ6
7. Integrins in Cancer Therapy
8. Conclusions
Acknowledgments
Conflicts of Interest
Abbreviations
RGD | Arg-Gly-Asp |
BM | Basement membrane |
BMP | Bone morphogenetic protein |
CAM | Cell adhesion molecule |
CD | Crohn’s disease |
COPD | Chronic obstructive pulmonary disease |
DC | Dendritic cells |
ECM | Extracellular matrix |
ERK | Extracellular signal regulated kinase |
FA | Focal adhesion |
TGF-β | Transforming growth factors-β |
MAP | Mitogen-activated protein kinases |
PI3K | Phosphoinositide kinase |
GTP | Guanosine-5′-triphosphate |
EGF-R | Epidermal growth factor receptor |
VEGF | Vascular endothelial growth factor |
PDGF-R | Platelet-derived growth factor |
FAK | Focal adhesion kinase |
CAS | Crk-associated substrate |
LAP | Latency-associated peptide |
MMP | Matrix metalloproteases |
uPA | Urokinase-type plasminogen activator |
HREs | Hypoxia response elements |
HAX-1 | Hematopoietic lineage cell-specific protein-1 (HS1) associated protein |
HIF | Hypoxia-inducible factor |
OSCC | Oral squamous cell carcinoma |
BCC | Basal cell carcinomas |
Shh | Sonic hedgehog |
SPECT | Single-photon emission computed tomography |
tTregs | T regulatory cells |
SLC | Small latent complex |
LLC | Large latent complex |
LTBP | Latent TGF- β binding proteins |
FMDV | Foot-and-mouth disease virus |
HNSCC | Head and neck squamous cell carcinoma |
NSCLC | Non-small-cell lung carcinoma |
PDAC | Pancreatic carcinoma |
SPECT | Single photon emission computed tomography |
PET | Positron emission tomography |
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αvβ3 [nM] | αvβ5 [nM] | αvβ6 [nM] | αvβ8 [nM] | α5β1 [nM] | αIIbβ3 [nM] | Ref. | |
---|---|---|---|---|---|---|---|
1a | >10,000 | >10,000 | 433 ± 101 | 37 ± 3 | 2.3 ± 0.02 | >10,000 | [220] |
2a | 0.65 ± 0.05 | 199 ± 21 | >10,000 | >10,000 | 108 ± 27.5 | >10,000 | [221] |
3 | >10,000 | >10,000 | 23 ± 3.4 | 8.2 ± 0.52 | 2.5 ± 0.4 | >10,000 | [222] |
4a | 0.61 ± 0.06 | 8.4 ± 2.1 | 2050 ± 640 | 2350 ± 438 | 14.9 ± 3.1 | 5400 ± 814 | [216] |
5a | 1200 ± 240 | >10,000 | 0.28 ± 0.019 | 24 ± 3.1 | 73 ± 6 | >10,000 | [223] |
6a | 1.1 ± 0.1 | 16.7 ± 2.1 | >10,000 | >10,000 | 820 ± 156 | >10,000 | [224] |
Integrin | Cancer Type | Cell Type | Main Expression Feature | Reference |
---|---|---|---|---|
αvβ3 | gastric cancer | tumor, endothelial and stromal cells | low to moderate expression frequency in tumor cells, high frequency in stroma and endothelia, correlates with phenotype, endothelial expression correlates with survival | [60] |
glioma | endothelial and tumor cells | expression correlates with grade | [61] | |
lung cancer brain metastases | endothelial and tumor cells | high expression frequency in endothelial, low frequency in tumor cells | [62] | |
non small cell lung cancer | endothelial and tumor cells | high expression frequency in endothelia, low frequency in tumor cells, no correlation with survival | [63] | |
oral squamous cell carcinoma | endothelial cells | higher expression in intratumoral endothelia compared with control tissue | [64] | |
pancreatic cancer | tumor cells | moderate expression frequency, involved in lymph node metastasis | [65] | |
prostate cancer | endothelial cells | high expression frequency peritumoral | [66] | |
αvβ5 | gastric cancer | tumor, endothelial and stromal cells | moderate (to high) frequency in tumor cells, high frequency in stroma and endothelial cells, independent prognostic factor in intestinal-type | [60] |
lung cancer (with brain metastases) | vessel endothelia and tumor cells | high expression frequency in endothelia, low frequency in tumor cells | [62] | |
non small cell lung cancer | tumor cells and stroma | high frequency in tumor and stroma cells, no correlation with survival | [63] | |
oral squamous cell carcinoma | tumor cells and stroma | [64] | ||
prostate cancer | tumor cells | expression influenced by differentiation | [66] | |
αvβ6 | basal cell carcinoma | tumor cells | higher expression frequency in infiltrative subtype | [67] |
breast cancer | expression correlates with prognosis | [68] | ||
colon cancer | upregulated at invasive front and in budding tumor cells | [69] | ||
endometrial cancer | often overexpressed without correlation with occurrence of lymph node metastasis | [70] | ||
gastric cancer | potential prognostic marker in early stage carcinoma | [53] | ||
liver | differentiates cholangiocarcinoma from hepatocellular carcinoma | [52] | ||
non small cell lung cancer | high expression frequency with intratumoral heterogeneity, no correlation with survival | [71] | ||
lung cancer brain metastases | high expression frequency | [62] | ||
oral squamous cell carcinoma | expression at invasive front | [72] | ||
ovarian cancer | expression correlates with grade | [55] | ||
pancreatic cancer | high expression frequency | [51] [73] | ||
prostate cancer | not/weakly expressed | [66] | ||
αvβ8 | non small cell lung cancer | tumor cells | low to moderate expression frequency, no correlation with survival | [63] |
prostate cancer | not expressed | [66] | ||
α5β1 | oral squamous cell carcinoma | tumor, endothelial cells, stroma | strong expression in stroma, expressed also in tumor and endothelial cells | [64] |
ovarian cancer | tumor cells | moderate expression frequency, correlates with survival | [74] |
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Nieberler, M.; Reuning, U.; Reichart, F.; Notni, J.; Wester, H.-J.; Schwaiger, M.; Weinmüller, M.; Räder, A.; Steiger, K.; Kessler, H. Exploring the Role of RGD-Recognizing Integrins in Cancer. Cancers 2017, 9, 116. https://doi.org/10.3390/cancers9090116
Nieberler M, Reuning U, Reichart F, Notni J, Wester H-J, Schwaiger M, Weinmüller M, Räder A, Steiger K, Kessler H. Exploring the Role of RGD-Recognizing Integrins in Cancer. Cancers. 2017; 9(9):116. https://doi.org/10.3390/cancers9090116
Chicago/Turabian StyleNieberler, Markus, Ute Reuning, Florian Reichart, Johannes Notni, Hans-Jürgen Wester, Markus Schwaiger, Michael Weinmüller, Andreas Räder, Katja Steiger, and Horst Kessler. 2017. "Exploring the Role of RGD-Recognizing Integrins in Cancer" Cancers 9, no. 9: 116. https://doi.org/10.3390/cancers9090116