Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility.
OBJECTIVE
Patients with pancreatic adenocarcinoma have a poor prognosis due to the extraordinary high invasive capacity of this tumor. Altered integrin and tetraspanin expression is suggested to be an important factor. We recently reported that after protein kinase C activation, colocalization of alpha6beta4 with the tetraspanin CO-029 strongly supports migration of a rat pancreatic adenocarcinoma. The finding led us to explore whether and which integrin-tetraspanin complexes influence the motility of human pancreatic tumors.


METHODS
Integrin and tetraspanin expression of pancreatic and colorectal adenocarcinoma was evaluated with emphasis on colocalization and the impact of integrin-tetraspanin associations on tumor cell motility.


RESULTS
The majority of pancreatic and colorectal tumors expressed the alpha2, alpha3, alpha6, beta1, and beta4 integrins and the tetraspanins CD9, CD63, CD81, CD151, and CO-029. Expression of alpha6beta4 and CO-029 was restricted to tumor cells, whereas alpha1, alpha2, alpha3, alpha6, beta1, and CD9, CD81, CD151 were also expressed by the surrounding stroma. CD63, CD81, and beta1 expression was observed at comparably high levels in healthy pancreatic tissue. alpha3beta1 frequently colocalized and coimmunoprecipitated with CD9, CD81, and CD151, whereas alpha6beta4 colocalized and coimmunoprecipitated mostly with CD151 and CO-029. Notably, protein kinase C activation strengthened only the colocalization of CD151 and CO-029 with beta4 and was accompanied by internalization of the integrin-tetraspanin complex, decreased laminin 5 adhesion, and increased cell migration.


CONCLUSIONS
alpha6beta4 is selectively up-regulated in pancreatic and colorectal cancer. The association of alpha6beta4 with CD151 and CO-029 correlates with increased tumor cell motility.
Gesierich
Sabine
S
Department of Tumor Progression and Tumor Defense, German Cancer Research Center, University of Heidelberg, Heidelberg, Germany.
Paret
Claudia
C
Hildebrand
Dagmar
D
Weitz
Jürgen
J
Zgraggen
Kaspar
K
Schmitz-Winnenthal
Friedrich H
FH
Horejsi
Vaclav
V
Yoshie
Osamu
O
Herlyn
Dorothee
D
Ashman
Leonie K
LK
Zöller
Margot
M
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D015703:Antigens, CD / Q000032:analysis; D000951:Antigens, Neoplasm / Q000032:analysis; D045744:Cell Line, Tumor; D002465:Cell Movement; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D016023:Integrins / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D008565:Membrane Proteins / Q000032:analysis*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D060185:Tetraspanin 24; D059470:Tetraspanins
D015703:Antigens, CD; D000951:Antigens, Neoplasm; C554715:CD151 protein, human; C554717:Cd151 protein, rat; D016023:Integrins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C065609:TSPAN8 protein, human; D060185:Tetraspanin 24; D059470:Tetraspanins