Integrin-free tetraspanin CD151 can inhibit tumor cell motility upon clustering and is a clinical indicator of prostate cancer progression.
Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins α3β1 and α6β1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151(free)) correlates clinically with tumor progression and metastasis. Clustering CD151(free) through its integrin-binding domain promotes accumulation in areas of cell-cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151(free) clustering is a strong regulator of motility even in the absence of α3 expression but requires PKCα, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151(free) in prostate cancer correlates with poor patient outcome. When CD151(free) is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151(free) as an independent predictor of survival. Moreover, the detection of CD151(free) can stratify survival among patients with elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151(free) with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression.
Authors' Affiliations:Departments of Pathology, Microbiology and Immunology and Cancer Biology, Vanderbilt University, Nashville, Tennessee; Department of Oncology, University of Alberta, Edmonton, Alberta; Translational Prostate Cancer Research Group, London Regional Cancer Program; and Department of Pathology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario Canada.
Trenis D
TD
Palmer
Carlos H
CH
Martínez
Catalina
C
Vasquez
Katie E
KE
Hebron
Celestial
C
Jones-Paris
Shanna A
SA
Arnold
Susanne M
SM
Chan
Venu
V
Chalasani
Jose A
JA
Gomez-Lemus
Andrew K
AK
Williams
Joseph L
JL
Chin
Giovanna A
GA
Giannico
Tatiana
T
Ketova
John D
JD
Lewis
Andries
A
Zijlstra
D000818:Animals; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002642:Chick Embryo; D015331:Cohort Studies; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D039422:Integrin alpha3 / Q000378:metabolism; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D010974:Platelet Aggregation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012189:Retrospective Studies; D060185:Tetraspanin 24 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D059470:Tetraspanins / Q000235:genetics / Q000378:metabolism*
C554715:CD151 protein, human; D039422:Integrin alpha3; D012333:RNA, Messenger; D060185:Tetraspanin 24; D059470:Tetraspanins