Vitronectin in human hepatic tumours contributes to the recruitment of lymphocytes in an alpha v beta3-independent manner.
The degree of lymphocyte infiltration is a prognostic factor in liver cancer, but to date the mechanisms by which lymphocytes infiltrate into and are retained in hepatic tumours are poorly understood. We hypothesised that the extracellular matrix glycoprotein vitronectin, a major component of the stroma of hepatic tumours, might play a role in the recruitment and retention of tumour-infiltrating lymphocytes (TIL). Thus, we investigated the ability of vitronectin to support migration and adhesion of TIL isolated from hepatocellular carcinoma and colorectal hepatic metastases. Soluble vitronectin-induced dose-dependent migration of TIL in in vitro chemotaxis and haptotaxis assays and vitronectin in tissue sections was able to support TIL adhesion to tumour stroma. Neither adhesion nor migration was inhibited by a function blocking mAb against the major vitronectin receptor alpha v beta3 and we were unable to detect alpha v beta3 on TIL in vitro or in vivo on tumour tissue. However, TIL did express high levels of urokinase-type plasminogen activator receptor (uPAR) and inhibitory antibodies and amiloride both significantly inhibited TIL adhesion to vitronectin and reduced transendothelial migration of lymphocytes across liver endothelium in vitro. Thus, we provide evidence that vitronectin in liver tumours can support the recruitment and retention of effector lymphocytes by an uPAR-dependent mechanism.
Edwards
S
S
Liver Research Group, Department of Medicine, 5th Floor, Institute of Biomedical Research, Wolfson Drive, The Medical School, University of Birmingham, Birmingham B15 2TT, UK.
Lalor
P F
PF
Tuncer
C
C
Adams
D H
DH
D002448:Cell Adhesion / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D006801:Humans; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin / Q000378:metabolism*
D039302:Integrin alphaVbeta3; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin