Circulating intercellular adhesion molecule-1 (ICAM-1), E-selectin and vascular cell adhesion molecule-1 (VCAM-1) in human malignancies

Abstract

Summary Cellular adhesion molecules have been implicated in tumour progression and metastasis. This study examines for the first time the serum concentrations of circulating VCAM-1 and E-selectin in a consecutive series of 110 cancer patients seen in a general medical oncology clinic, and confirms and extends previous studies reporting measurement of circulating ICAM-1. Soluble ICAM-1 and VCAM-1 levels were significantly higher in all the patient groups compared with the controls whereas soluble E-selectin was significantly higher in the ovarian, breast and GI cancer groups and lower in the myeloma group. The significance of these results together with the possible sources and stimuli for release of these adhesion molecules are discussed. Sera and patientsBlood samples were obtained from a consecutive series of all patients being seen in a general medical oncology clinic, including those with both localised or advanced disease and those on active therapy or during follow-up. The following malignancies were represented: bladder (n = 6), breast (n = 13), gastrointestinal (n = 18), ovarian (n = 15), renal (n = 12), Hodgkin's disease (n = 15), non-Hodgkin's lymphoma (n = 13), and myeloma (n = 18). Approximately 85% of those with epithelial cancers had clinical evidence of metastases. Samples were allowed to clot, and the serum stored at -70'C until assayed. Samples were also obtained from 89 healthy laboratory and clinical personnel and blood donors (age range 18-60 years) and assayed for E-selectin and VCAM-1. In the case of ICAM-1, a sub-group of 27 of the control samples (age range 24-54 years) were assayed.Assay of soluble adhesion molecules Levels of circulating ICAM-1 were measured with a commercial ELISA kit (British Bio-technology Products, Oxford, UK). Concentrations of circulating E-selectin and VCAM-1 were measured using dual monoclonal antibody two-site ELISAs Pigott et al., 1992). Briefly, microtitre ELISA plates (Nunc Immunoplates, Life Technologies, Paisley, Scotland) were coated overnight with a specific capture antibody (BBIG-E2 for E-selectin, BBIG-V4 for VCAM-1) at a final concentration of 10 tg ml-' in 0.1 M bicarbonate buffer pH 8.9. Standards and samples were added to the plate, incubated for 2 h at room temperature and the bound soluble adhesin of interest was detected by sequential incubation with a specific biotin-labelled antibody (BBIG-E5 for E-selectin, BBIG-V3 for VCAM-1) followed by horseradish peroxidase-conjugated streptavidin (Amersham International, Amersham, UK) and finally tetramethylbenzidine (Universal Biologicals, Kingston-upon-Thames, UK). The reaction was stopped by the addition of 1 M HCI to each well and the O.D. 450 nm measured using a Titertek MS-2 reader (ICN Flow, Rickmansworth, UK). The assays were standardised using a recombinant soluble form of Eselectin or VCAM-1 (Pigott et al., 1991) lacking their transmembrane and cytoplasmic domains and given an arbitrary unitage against which all samples were measured.Statistical analysis Data was analysed using SPSS/PC + . Res...

Circulating intercellular adhesion molecule-1 and E-selectin levels in gastric cancer

“…They also demonstrated that both expression and shedding of ICAM-I antigen increased when cultured gastric carcinoma cells were treated with interferon-y. Banks et al (1993) examined the serum concentrations of adhesion molecules sE-selectin, sICAM-1 and cVCAM-1 in randomly selected cancer patients. The levels of all three adhesion receptors were found to be elevated in patients with gastrointestinal cancer, but the exact localization of the tumours were not specified.…”

“…Adhesion molecules can be detected in soluble forms in the circulation, and raised levels have been reported in several conditions, including different neoplastic conditions, higher concentrations being associated with liver metastases in gastrointestinal cancers (Haming et al, 1991;Tsujisaki et al, 1991;Banks et al, 1993;Gearing and Newman, 1993;Pui et al, 1993;Christiansen et al, 1996). However, effect on survival was determined only in patients with malignant melanoma, lymphomas and Hodgkin's disease (Harning et al, 1991;Pui et al, 1993;Christiansen et al, 1996).…”

Surrogate markers in antiangiogenesis clinical trials

“…Elevated levels of angiogenic growth factors, proteases, and endothelial adhesion molecules have been detected in sera of patients with malignant disease (Dirix et al, 1997). These important promoters of tumour angiogenesis include VEGF (Takahashi et al, 1994), bFGF (Fujimoto et al, 1995), urokinase-type plasminogen activator and its soluble receptor (Xu et al, 1997), E-selectin and vascular cell adhesion molecule-1 (VCAM-1) (Banks et al, 1993), and von Willebrand's factor (vWF) (Gadducci et al, 1994). Of the many mediators of angiogenesis, VEGF and bFGF are thought to play the most important roles and thus have been frequently measured as potential surrogate markers of antiangiogenic activity in many Phase I/II studies.…”

Tumour-derived interleukin 1α (IL-1α) up-regulates the release of soluble intercellular adhesion molecule-1 (sICAM-1) by endothelial cells

“…Furthermore, high levels of sICAM-1 are detectable in malignancies of different histotype and correlate with disease progression (Tsujisaki et al, 1991;Altomonte et al, 1992;Banks et al, 1993;Pui et al, 1993). This latter finding suggested that elevated levels of sICAM-1 represent an unfavourable prognostic marker in human neoplasias and that sICAM-1 can be used to monitor the clinical course of disease (Altomonte et al, 1992).…”

“…Nevertheless, elevated levels of sICAM-1 are also present in patients affected by ICAM-1-negative malignancies, such as sarcomas (Natali et al, 1990;Pui et al, 1993), and ovary (Vainky et al, 1990;Banks et al, 1993) and bladder (Banks et al, 1993;Nouri et al, 1996) carcinomas. Moreover, higher levels of sICAM-1 have been found in sera of patients affected by ICAM-1-negative renal cell carcinomas than ICAM-1-positive tumours of similar histotype (Heicappell et al, 1994).…”