Angiogenic activity of human soluble intercellular adhesion molecule-1.

Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) are elevated in a number of pathological conditions associated with angiogenesis, including tumor growth. Because the increased levels of sICAM-1 suggested that it may be angiogenic, we tested the ability of sICAM-1 to promote angiogenesis. Human recombinant sICAM-1 stimulates chemokinetic endothelial cell migration, endothelial cell tube formation on Matrigel, and sprouting of aortic rings. sICAM-1 also mediates angiogenesis in the chick chorioallantoic membrane assay. Additionally, we found a Mr 49,000 molecule that binds to sICAM-1 that may be the surface ligand on endothelial cells. The evidence that sICAM-1 has angiogenic activity suggests a possible role linking inflammation and neovascularization. Furthermore, sICAM-1 may enhance tumor growth by promoting angiogenesis and escape from immunosurveillance.     

ICAM-1在肿瘤中的研究进展

细胞间黏附分子(Intercellular adhesion molecule-1,ICAM-1)又称CD54,是免疫球蛋白超家族的一种跨膜糖蛋白,参与肿瘤细胞免疫调节、血管生成、侵袭和远处转移。国内外诸多研究证明ICAM-1在多种恶性肿瘤中异常高表达,促进了肿瘤的发生、发展并影响其预后,同时对预测个别肿瘤放化疗敏感性有一定的作用。因此ICAM-1可能为恶性肿瘤的诊断和治疗提供参考依据。本文就近年来ICAM-1在恶性肿瘤中的研究做一综述。     

Amphiregulin enhances intercellular adhesion molecule-1 expression and promotes tumor metastasis in human osteosarcoma

Osteosarcoma is a common, high malignant, and metastatic bone cancer. Amphiregulin (AREG) has been associated with cancer cellular activities. However, the effect of AREG on metastasis activity in human osteosarcoma cells has yet to be determined. We determined that AREG increases the expression of intercellular adhesion molecule-1 (ICAM-1) through PI3K/Akt signaling pathway via its interaction with the epidermal growth factor receptor, thus resulting in the enhanced cell migration of osteosarcoma. Furthermore, AREG stimulation increased the association of NF-κB to ICAM-1 promoter which then up-regulated ICAM-1 expression. Finally, we observed that shRNA silencing of AREG decreased osteosarcoma metastasis in vivo. Our findings revealed a relationship between osteosarcoma metastatic potential and AREG expression and the modulating effect of AREG on ICAM-1 expression.     

结直肠癌患者血清可溶性E-选择素和细胞内黏附分子-1浓度的临床意义

目的:探讨结直肠癌患者可溶性E选择素(sEselectin)和细胞内黏附分子1(ICAM1)的血清浓度与结直肠癌转移的关系。方法:采用酶联免疫吸附实验方法(ELISA法)测定了64例结直肠癌患者可溶性E选择素和细胞内黏附分子1的血清浓度。同时测定癌胚抗原(CEA)的血清浓度。结果:可溶性E选择素的浓度和可溶性sICAM1的血清浓度显著增高,P=0001和P=0032,伴有远处转移者增高显著,P=0004和P=0015。可溶性E选择素的浓度和可溶性sICAM1的血清浓度与血清癌胚抗原的水平有相关性,P=0025和P=0038。结论:可溶性E选择素的浓度和sICAM1的血清浓度的升高可能与结直肠癌的发展和广泛转移有关。     

Expression of intercellular adhesion molecule-1 in hepatocellular carcinoma

The expression of intercellular adhesion molecule-1 (ICAM-1) was investigated in frozen sections obtained from 40 resected liver specimens of patients with hepatocellular carcinoma using immunoperoxidase techniques and immunoelectron microscopy. ICAM-1 was expressed in 80% of the HCC specimens on the membrane of cancer cells. In noncancerous regions characterized by cirrhosis in 28 cases and chronic hepatitis in 12 cases, ICAM-1 was rarely expressed on hepatocytes but was expressed mainly on the endothelium of portal vessels and sinusoidal lining cells. These results suggest that expression of ICAM-1 in hepatocellular carcinoma may be induced by malignant transformation of hepatocytes. © 1993 Wiley-Liss, Inc.     

Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications

Tumors can escape from immunity by repressing leukocyte adhesion molecule expression on tumor endothelial cells and by rendering endothelial cells unresponsive to inflammatory activation. This endothelial cell anergy is induced by angiogenic growth factors and results in reduced leukocyte-vessel wall interactions, thereby attenuating infiltration of leukocytes into the tumor. This report describes a novel mechanism of endothelial cell anergy regulation. We recently reported that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors have angiostatic activity. Here, we studied whether epigenetic mechanisms regulate this angiogenesis-mediated escape from immunity. We found that DNMT inhibitors 5-aza-2'-deoxycytidine and zebularine, as well as HDAC inhibitor trichostatin A, reexpressed intercellular adhesion molecule-1 (ICAM-1) on tumor-conditioned endothelial cells in vitro, resulting in restored leukocyte-endothelial cell adhesion. In addition, treatment with DNMT or HDAC inhibitors in vivo also restored ICAM-1 expression on tumor endothelial cells from two different mouse tumor models. Furthermore, leukocyte-vessel wall interactions in mouse tumors were increased by these compounds, as measured by intravital microscopy, resulting in enhanced leukocyte infiltration. We show that ICAM-1 down-regulation in tumor endothelial cells is associated with ICAM-1 promoter histone H3 deacetylation and loss of histone H3 Lys(4) methylation but not with DNA hypermethylation. In conclusion, our data show that ICAM-1 is epigenetically silenced in tumor endothelial cells by promoter histone modifications, which can be overcome by DNMT and HDAC inhibitors, suggesting a new molecular mechanism based on which novel therapeutic approaches for cancer can be pursued.     

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

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.     

Expression and modulation by cytokines of the intercellular adhesion molecule-1 (ICAM-1) in human central nervous system tumor cell cultures

The intercellular adhesion molecule (ICAM-1) has been shown to be important in interactions involving cells of the immune system and to be upregulated in a number of cell culture systems by cytokines, including immune interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). In the present study, we have determined by fluorescence-activated cell sorter (FACS) analysis and the anti-ICAM-1 monoclonal antibody (MAb) CL203.4 the base-line expression of ICAM-1 and its modulation by recombinant IFN-beta, IFN-gamma and TNF-alpha in early passage (less than 15) human central nervous system (CNS) tumor-derived cell cultures. These cultures were established from various malignancies, including glioblastoma multiforme (GBM), astrocytoma (AST), ganglioglioma, medulloblastoma, meningioma and a pineal tumor. ICAM-1 expression was highest in the GBM- and AST-derived cell cultures and was lowest in the ganglioglioma and normal pineal cell cultures. Variable ICAM-1 expression was found, however, in tumors of the same histological group. In several cell cultures the variable expression observed by FACS was substantiated by the intensity of the molecular species immunoprecipitated by the anti-ICAM-1 MAb CL203.4 from these cells. All the cell cultures displayed variable but consistent increases in ICAM-1 expression following treatment with IFN-gamma or TNF-alpha. In general, the degree of increase in ICAM-1 expression was greatest in cultures exposed to TNF-alpha. Upregulation of ICAM-1 expression in an established glioblastoma multiforme cell line was of greater magnitude and more rapid following TNF-alpha treatment (within 2 to 3 hr) than exposure to IFN-gamma (by 24 hr). In several cultures, IFN-beta also increased ICAM-1 expression and enhanced the increase induced by TNF-alpha. The results of the present study indicate that variable expression of ICAM-1 is a common property of early passage cultures of CNS tumors and recombinant interferons and TNF-alpha can differentially upregulate ICAM-1 expression in these CNS tumor cell cultures.     

Circulating soluble adhesion molecules E-cadherin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in patients with gastric cancer.

The concentrations of the soluble adhesion molecules E-cadherin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were investigated in 45 patients with gastric cancer before treatment and their correlation with clinical, histological and routine laboratory parameters was examined. Data were collected on tumour stage at presentation, presence and sites of metastatic disease, tumour pathology, survival and results of routine laboratory tests. Serum concentrations of ICAM-1 and VCAM-1 were significantly elevated in the patients with gastric cancer in comparison with the group of healthy subjects (P < 0.00001 and P < 0.0001 respectively). Increased serum concentrations of VCAM-1 were associated with locally advanced and metastatic disease whereas ICAM-1 was significantly elevated both in local and in advanced/metastatic disease. Soluble E-cadherin and E-selectin concentrations did not show any significant elevation in gastric cancer patients. Concentrations of soluble adhesion molecules showed significant correlation with each other (except E-selectin and VCAM-1) and with alkaline phosphatase. Soluble ICAM-1 and VCAM-1 were significantly associated with an elevated total white cell count. Patients with elevated VCAM-1 had significantly poorer survival in comparison with patients with normal serum levels (P = 0.0361).     

Detection of circulating intercellular adhesion molecule-1 in hepatocellular carcinoma

Serum levels of circulating intercellular adhesion molecule-1 (cICAM-1) were measured in 23 patients with chronic hepatitis (CH), 22 with liver cirrhosis (LC) and 45 with hepatocellular carcinoma (HCC) using an ELISA. Serum samples from all patients showed significantly higher cICAM-1 levels than serum from 50 normal controls. The cICAM-l level was significantly increased in LC or HCC when compared with CH, but no differences were noted between LC and HCC. Levels of cICAM-1 correlated well with serum bilirubin, retention rate of indocyanine green, hyaluronic acid, type IV collagen 7-S and type III procollagen peptide levels but not with tumor size or circulating tumor markers (α-fetoprotein and des-γ-carboxyprothrombin). Our findings indicate that the measurement of cICAM-l is useful for the determination of the severity of liver disease and hepatic fibrosis. HCC tissues obtained from 10 patients were immunohistochemically stained for ICAM-I. Enhanced ICAM-I expression was found on the tumor cell membranes. Sequential measurements of cICAM-1 levels showed that they changed in a similar manner to those of a-fetoprotein during the course of treatment of HCC in a patient with very high pretreatment levels of both markers. These results suggest that HCC cells shed ICAM-1 into the circulation. We conclude that cICAM-1 is not a diagnostic marker for HCC, but may be useful for monitoring the response to treatment.     

Levels of soluble intercellular adhesion molecule-1 and total sialic acid in serum of patients with colorectal cancer

BACKGROUND AND OBJECTIVES: Serum soluble intercellular adhesion molecule-1 (sICAM-1) and total sialic acid (TSA) are related to the metastatic potential of cancer cells. The purpose of the present investigation was to determine sICAM-1 and TSA levels in colorectal carcinoma and correlate their levels with the cancer stage. METHODS: The sera from 65 patients with colorectal cancer (18 at Dukes' B, 24 at Dukes' C, 23 at Dukes' D) were extracted before treatment. The concentrations of sICAM-1 and TSA were measured by enzyme-linked immunoassay and the thiobarbituric acid method, respectively, and compared with those from a healthy control group (n = 42). RESULTS: Mean serum sICAM-1 and TSA levels were found to be higher in the total patient group than in the control group (P < 0.0001). The concentrations of sICAM-1 and TSA were significantly higher in patients with Dukes' C and Dukes' D. The correlations between sICAM-1 and TSA became more significant as the stage of the disease increased (r = 0.58, P < 0.05 in Dukes' B, r = 0.88, P < 0.01 in Dukes' C and r = 0.81, P < 0.01 in Dukes' D). CONCLUSIONS: The results of this investigation indicate that sICAM-1 and TSA are the best of the tested markers. These markers should prove useful for monitoring malignant disease stage and for evaluating the effectiveness of various therapeutic approaches for colorectal carcinomas.     

Levels of soluble intercellular adhesion molecule-1 and total sialic acid in serum of patients with laryngeal cancer

BACKGROUND: Adhesion molecules have been implicated in tumor progression. In this study, we aimed to investigate serum soluble intercellular adhesion molecule-1 (sICAM-1) and total sialic acid (TSA) levels in laryngeal carcinoma and correlate their levels with the cancer stage. METHOD: The sera from 35 patients with laryngeal cancer (10 at stage II, 12 at stage III and 13 at stage IV) were extracted before treatment. The concentrations of sICAM-1 and TSA were measured by enzyme-linked immunoassay and the thiobarbituric acid method, respectively and compared with those from a healthy control group (n = 34). RESULTS: Mean serum sICAM-1 and TSA levels were found to be higher in the total patient group (the lowest level belonging to stage II) than in the control group (p < 0.001, control versus total patient group). As the stage of the disease increased, higher levels of sICAM-1 and TSA were determined. The correlations between TSA and sICAM-1 became more significant as the stage of the disease increased (r= 0.67, p < 0.05 in stage II, r= 0.86, p < 0.001 in stage III and r = 0.90, p < 0.001 in stage IV). CONCLUSION: These data reveal that the significant correlations between sICAM-1 and TSA in laryngeal cancer, more prominent at advanced stage, might reflect the similar nature of these molecules, which function as adhesion molecules.     

Expression of intercellular adhesion molecule-1 and prognosis in colorectal cancer

Intercellular adhesion molecule-1 (ICAM-1) is a 90-kDa cell surface glycoprotein and is known to be a member of the immunoglobulin gene superfamily of adhesion molecules. It has been suggested that ICAM-1 expression on cancer cells might have a role as a suppressor of tumor progression under the host immune surveillance system. We studied the correlation between the expression of ICAM-1 and clinicopathological factors, as well as infiltration of tumor infiltrating lymphocytes (TILs) in colorectal cancer. Resected specimens from 96 patients with colorectal carcinoma were investigated using immunohistochemical staining with a monoclonal antibody against ICAM-1. As a result, the incidence of lymph node or liver metastasis was significantly lower in patients with ICAM-1-positive tumors than in those with ICAM-1-negative tumors. Infiltration of TILs was more frequently observed in the ICAM-1-positive tumors than in the ICAM-1-negative tumors. The prognosis of the patients with ICAM-1-negative tumors was significantly poorer than that of those with ICAM-1-positive tumors. In conclusion, these findings suggested that ICAM-1 expression is closely associated with metastasis and may be a useful indicator of prognosis in patients with colorectal cancer.     

Reduced expression of intercellular adhesion molecule-1 in ovarian adenocarcinomas.

Ovarian adenocarcinomas develop as the result of multiple genetic and epigenetic changes in the precursor ovarian surface epithelial (OSE) cells which result in a malignant phenotype. We investigated changes in gene expression in ovarian adenocarcinoma using a cDNA array containing 588 known human genes. We found that intercellular adhesion molecule-1 (ICAM-1) was expressed at lower levels in the ovarian tumour cell lines OAW42, PEO1 and JAM than in the immortalised human ovarian surface epithelial cell line HOSE 17.1. Further investigation revealed ICAM-1 was expressed in the surface epithelium of normal ovaries and both mRNA and protein expression levels were reduced in the majority of ovarian adenocarcinoma cell lines and primary tumours. ICAM-1 expression was increased in 8/8 cell lines treated with the de novo methyltransferase inhibitor 5-aza-2'-deoxycytidine, indicating that methylation of CpG islands may play a role in the down-regulation of its expression in primary tumours. There was a significant association between patients whose tumours expressed ICAM-1 and survival (P = 0.03), suggesting that expression levels of ICAM-1 may have clinical relevance.     

Expression and release of intercellular adhesion molecule-1 in renal-cancer patients

We examined ICAM-1 expression in 37 freshly dissociated renal-cancer cell populations. Immunoperoxidase analysis revealed that 31 of the 37 renal tumors expressed ICAM-I to various degrees; ICAM-1 expression was significantly lower in tumor cells obtained from patients remaining tumor-free after a median follow-up of 60 months (mean value 24.4% ± 21) than in tumor cells obtained from the relapsed patients (mean value 40.8% ± 22), and the low expression of this molecule on the cell surface seemed to correlate with favorable clinical behavior. In 41 patients, the mean level of sICAM-1 was 551 ± 260 ng/ml, significantly higher than normal. However, sICAM-1 levels were significantly lower in the 20 tumor-free (mean 467 ± 158 ng/ml) than in the 21 metastatic patients (mean 631 ± 318 ng/ml). Eleven renal-cancer cell populations were cultured in order to examine the expression and release of ICAM-1. All of these cells were positive for ICAM-1 expression, which was elevated in 6 cases (> 50%) and low in the remaining 5 cases (18–35%). However, only the 5 cell populations expressing low levels of ICAM-1 released this molecule, showing an inverse correlation with cellular expression. Five of the cell populations were treated for 48 hr with rIFN-γ; in these cells, both ICAM-1 expression and sICAM-1 levels increased, although sICAM-1 levels in the supernatants of the cell populations with constitutive high ICAM-1 expression remained very low. © 1995 Wiley-Liss Inc.     

细胞间黏附分子-1对恶性肿瘤影响的临床研究进展

细胞间黏附分子 -1(intercellularadhesionmolecule 1,ICAM 1或CD54)是免疫球蛋白超家族成员及跨膜糖蛋白 ,也是淋巴细胞功能相关抗原 -1(LFA 1)的主要配体 ,涉及细胞分化、黏附及迁移。细胞表面ICAM 1可脱落进入血循环 ,成为可溶性形式ICAM 1(sICAM 1)。sICAM 1仍具有结合LFA 1的活性 ,sICAM 1/LFA 1介导多种病理过程。研究表明 :sICAM 1水平升高与多种恶性肿瘤患者的不良结局有关     

Differential levels of soluble intercellular adhesion molecule-1 (sICAM-1) in early breast cancer and benign breast lesions

To date, no soluble markers can discriminate benign from malignant breast lesion; therefore, to assess the diagnostic potential of circulating intercellular adhesion molecule-1 (sICAM-1), serum concentrations of sICAM-1 were quantitated in 230 consecutive patients that underwent surgery for breast neoplasias, utilizing an enzyme-linked immunosorbent assay. Histological diagnosis revealed that 177 patients had breast cancer and 53 had a benign breast disease. In the cancer patient group, 90 subjects had pTl tumors without (pT1N0M0, n=46) or with (pT1N1M0, n=41; pT1N2M0, n=3) regional lymph node metastases. Mean levels of serum sICAM-1 of patients with pT1 breast cancer, without or with regional lymph node involvement, were significantly (P<0.05) higher than those of patients with benign breast lesions and of 49 age-matched control subjects. Elevated levels of serum sICAM-1 were detected in 27/90 (30%) pTl breast tumors and in 1/53 (2%) benign breast lesions; thus, among subjects with high levels of sICAM-1, 96% had breast cancer. No significant correlation was found between levels of serum sICAM-1 and breast cancer progression. These observations, altogether, suggest that in the presence of a suspicious breast neoplasm the quantitative analysis of serum sICAM-1 can orient clinical diagnosis towards malignancy.     

Stimulation of anchorage-independent growth of human tumor cells by interleukin 1

Human peripheral blood monocytes and tumor-associated macrophages release a factor that enhances the clonal growth of a human epithelial tumor cell line (SW-13) in soft agar. We now demonstrate that purified interleukin 1 (IL-1) may account for part of this colony-stimulating activity. Purified IL-1 (0.5 to 8 units/ml) was added to SW-13 cells cultured in soft agar. IL-1 increased colony growth in a dose-dependent manner and did not inhibit colony formation at the highest doses tested. Other purified human monocyte products (alpha-interferon, tumor necrosis factor, transforming growth factor beta, fibronectin) did not stimulate colony growth. Antibody to IL-1 only partially inhibited the ability of monocyte-conditioned medium to stimulate SW-13 colony growth. This antibody did, however, completely inhibit the ability of purified IL-1 to support the growth of SW-13 colonies in soft agar. IL-1 increased growth of quiescent SW-13 cells cultured in monolayers as assessed by tritiated thymidine incorporation assays. The results of this study indicate that IL-1 can enhance clonogenic growth of an epithelial cell line in soft agar. However, other uncharacterized activities in monocyte conditioned medium also promote colony growth. These studies add to an increasing body of evidence indicating that inflammatory products play a role in maintaining the transformed phenotype.