TACE/ADAM-17: a component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer.
OBJECTIVE
Activation of the epidermal growth factor receptor (EGFR) requires cell surface cleavage of EGFR ligands, uptake of soluble ligand by the receptor, and initiation of EGFR tyrosine kinase activity. We define these collective events as the EGFR axis. Transforming growth factor-alpha (TGF-alpha) and amphiregulin are two EGFR ligands that are delivered preferentially to the basolateral surface of polarized epithelial cells where the EGFR resides. TACE/ADAM-17 (tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloprotease) has been implicated in ectodomain cleavage of TGF-alpha and amphiregulin.


METHODS
Using a human polarizing colorectal cancer (CRC) cell line, HCA-7, and a tissue array of normal colonic mucosa and primary and metastatic CRC, we determined the intracellular localization of TACE and the effects of EGFR axis inhibition in CRC.


RESULTS
Herein, we show that TACE is localized to the basolateral plasma membrane of polarized HCA-7 cells. TACE is overexpressed in primary and metastatic CRC tumors compared with normal colonic mucosa; the intensity of its immunoreactivity is inversely correlated with that of TGF-alpha and amphiregulin. Pharmacologic blockade of HCA-7 cells with an EGFR monoclonal antibody, a selective EGFR tyrosine kinase inhibitor, and a selective TACE inhibitor results in concentration-dependent decreases in cell proliferation and active, phosphorylated mitogen-activated protein kinase. Combining suboptimal concentrations of these agents results in cooperative growth inhibition, increased apoptosis, and reduced mitogen-activated protein kinase pathway activation. Furthermore, an EGFR tyrosine kinase-resistant clone of HCA-7 cells is growth-inhibited by combined monoclonal antibody and TACE inhibition.


CONCLUSIONS
These results implicate TACE as a promising target of EGFR axis inhibition in CRC.
Merchant
Nipun B
NB
Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-8355, USA.
Voskresensky
Igor
I
Rogers
Christopher M
CM
Lafleur
Bonnie
B
Dempsey
Peter J
PJ
Graves-Deal
Ramona
R
Revetta
Frank
F
Foutch
A Coe
AC
Rothenberg
Mace L
ML
Washington
Mary K
MK
Coffey
Robert J
RJ
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D066258:Amphiregulin; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology*; D066255:EGF Family of Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D046888:Tissue Array Analysis; D016211:Transforming Growth Factor alpha / Q000378:metabolism
C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human