Biochemical and Biophysical Research Communications
c-Src-dependent cross-talk between CEACAM6 and αvβ3 integrin enhances pancreatic adenocarcinoma cell adhesion to extracellular matrix components
Section snippets
Materials and methods
Cell culture. BxPC3 pancreatic ductal adenocarcinoma cells were obtained from ATCC (Rockville, MD). BxPC3 was specifically chosen as these cells inherently overexpress CEACAM6 [14]. Cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM) containing 10% fetal bovine serum (FBS, Gibco-BRL, Gaithersburg, MD). Cells were incubated in a humidified (37 °C, 5% CO2) incubator and passaged upon reaching 80% confluence.
CEACAM6 crosslinking. The By114 mouse monoclonal antibody (Innogenex, San
CEACAM6 crosslinking promotes pancreatic adenocarcinoma cellular adhesion to ECM components
Antibody-mediated crosslinking of CEACAM6 was performed by exposing BxPC3 cells to anti-CEACAM6 primary antibody, followed by anti-mouse IgG secondary antibody F(ab′)2. F(ab′)2 was used to exclude Fc-mediated effects, although use of intact secondary antibody produced identical results (data not shown). CEACAM6 crosslinking induced a marked increase in cellular adhesion to both fibronectin and vitronectin. The effect of anti-CEACAM6 antibody alone was minimal and secondary antibody F(ab′)2
Discussion
In this study, we have shown that antibody-induced crosslinking of CEACAM6 enhances αvβ3 integrin-mediated adhesion to ECM components. We have also shown that c-Src is required for this cross-talk between CEACAM6 and αvβ3 integrin to occur. Despite lacking an intracellular domain, CEACAM6 is capable of independently activating neutrophil adhesion to human vascular endothelial cells (HUVECs) [23] and crosslinking of the GPI-linked CEACAM family members has been reported to induce a respiratory
Acknowledgements
The authors gratefully acknowledge the technical assistance of Jan Rounds. This work was supported by The National Pancreas Foundation and departmental funds from the Department of Surgery, Brigham and Women’s Hospital.
References (51)
- et al.
Carcinoembryonic antigen family members CEACAM6 and CEACAM7 are differentially expressed in normal tissues and oppositely deregulated in hyperplastic colorectal polyps and early adenomas
Am. J. Pathol.
(2000) - et al.
Deregulated expression of the human tumor marker CEA and CEA family member CEACAM6 disrupts tissue architecture and blocks colonocyte differentiation
Neoplasia
(2002) - et al.
Adhesion of neutrophils to fibronectin: role of the cd66 antigens
Cell. Immunol.
(2001) Integrins: versatility, modulation, and signaling in cell adhesion
Cell
(1992)Fibronectin and its integrin receptors in cancer
Adv. Cancer Res.
(1999)- et al.
Integrins and cancer
Curr. Opin. Cell. Biol.
(1996) - et al.
Differential display of expressed genes in pancreatic cancer cells
Biochem. Biophys. Res. Commun.
(2002) - et al.
Involvement of gangliosides in glycosylphosphatidylinositol-anchored neuronal cell adhesion molecule TAG-1 signaling in lipid rafts
J. Biol. Chem.
(2000) - et al.
Inhibition of tyrosine kinase Src suppresses pancreatic cancer invasiveness
Surgery
(2003) - et al.
Integrin affinity modulation
Trends Cell Biol.
(1998)
Integrin cytoplasmic interactions and bidirectional transmembrane signalling
Curr. Opin. Cell. Biol.
Integrin activation by R-ras
Cell
Characterization of the integrin alpha v beta 6 as a fibronectin-binding protein
J. Biol. Chem.
Overexpression and activation of the tyrosine kinase Src in human pancreatic carcinoma
Biochem. Biophys. Res. Commun.
Lipopolysaccharide induces activation of CD14-associated protein tyrosine kinase p53/56lyn
J. Biol. Chem.
Src kinase plays an essential role in integrin-mediated tyrosine phosphorylation of Crk-associated substrate p130Cas
Biochem. Biophys. Res. Commun.
Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation
J. Biol. Chem.
Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels
Cell
Origin and biology of cancer metastasis
Cytometry
The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited
Nat. Rev. Cancer
General mechanisms of metastasis
Cancer
The immunoglobulin superfamily-domains for cell surface recognition
Annu. Rev. Immunol.
CEACAM6 gene silencing imparis anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells
Oncogene
CD66: role in the regulation of neutrophil effector function
Eur. J. Immunol.
Role of integrins in cancer: survey of expression patterns
Proc. Soc. Exp. Biol. Med.
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