Adhesion molecules in human pancreatic cancer

BACKGROUND AND OBJECTIVES: Adhesion molecules are cell surface glycoproteins that are important in cell-to-cell and cell-to-extracellular matrix interactions. In the present study, we analyzed the adhesion molecules ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), and ELAM-1 (endothelial leukocyte adhesion molecule-1) in human pancreatic cancer. METHODS: ICAM-1, VCAM-1, and ELAM-1 were analyzed in 20 pancreatic cancer specimens and 20 normal pancreatic tissues. mRNA expression encoding ICAM-, VCAM-1, and ELAM-1 was assessed with Northern blot analysis. The distribution and localization of ICAM-1, VCAM-1, and ELAM-1 was determined in the pancreatic specimens by immunohistochemistry. RESULTS: Northern blot analysis revealed a 5.4-fold increase of ICAM-1 (P<0.01) and a 3.7-fold increase in VCAM-1 (P<0.01) mRNA expression in cancer samples in comparison with normal controls. In contrast, ELAM-1 mRNA levels did not show significant differences between the cancer and the normal tissues. Immunohistochemical analysis of cancer tissues showed strong immunostaining for ICAM-1 and VCAM-1, and faint immunostaining for ELAM-1 in the pancreatic cancer cells. Fibrotic or noncancerous pancreatic tissue adjacent to the cancer mass was devoid of any immunoreactivity for ICAM-1, ELAM-1, and VCAM-1. In contrast, the normal pancreas exhibited no immunoreactivity of ICAM-1, ELAM-1, and VCAM-1. CONCLUSIONS: Enhanced expression of ICAM-1 and VCAM-1 in human pancreatic cancers suggests a role in tumor pathogenesis. The increase of these adhesion molecules might influence the detachment of cancer cells in the primary tumor, might contribute to cancer cell migration and the spread of cancer cells to distant organs, or both.     

Effect of tumour necrosis factor,heat, and radiation on the viability and microfilament organization in cultured endothelial cells

Normal blood vessels are leakage proof, non-adherent to blood cell elements, and participate actively in directional blood flow. These properties rely on the shape of endothelial cells and the integrity of the endothelial cell monolayer. The often observed effects of tumour necrosis factor-α (TNF) and hyperthermia on tumour tissue are the disruption of blood flow and an increase of vascular permeability. These agents are also known to affect the cytoskeletal organization and the cytoskeleton-dependent cellular functions. We observed that TNF (100 U/ml for 60 min) or heat (43°C for 60 min) treatment causes the collapse of actin filaments in human umbilical vein endothelial cells (HUVEC). The combined treatment of TNF and hyperthermia intensifies the change of shape and loss of actin filaments. However, these changes are reversible within 24 h. These transient changes may contribute to the dysfunction and increased leakage of the microvasculature in tumours during and after these treatments despite the fact that the viability determined by MTT assay did not show a significant interaction between TNF and hyperthermia. Radiation (5 Gy) and TNF interact to a lesser extent compared with heat and TNF on cell shape and actin filament organization in HUVEC. Heat or radiation treatment enhances the expression of ELAM-1 mRNA in HUVEC while TNF produces the strongest effect on ELAM-1 mRNA expression. Our study suggests that radiation and heat affect endothelial cells and their subsequent functions differently. Result of an interaction between heat and TNF on endothelial cells supports the common notion that the anti-tumour effect by heat plus TNF treatments may benefit due to the increased disruption of vasculature function in the tumour.     

Effect of tumour necrosis factor, heat, and radiation on the viability and microfilament organization in cultured endothelial cells.

Normal blood vessels are leakage proof, non-adherent to blood cell elements, and participate actively in directional blood flow. These properties rely on the shape of endothelial cells and the integrity of the endothelial cell monolayer. The often observed effects of tumour necrosis factor-alpha (TNF) and hyperthermia on tumour tissue are the disruption of blood flow and an increase of vascular permeability. These agents are also known to affect the cytoskeletal organization and the cytoskeleton-dependent cellular functions. We observed that TNF (100 U/ml for 60 min) or heat (43 degrees C for 60 min) treatment causes the collapse of actin filaments in human umbilical vein endothelial cells (HUVEC). The combined treatment of TNF and hyperthermia intensifies the change of shape and loss of actin filaments. However, these changes are reversible within 24 h. These transient changes may contribute to the dysfunction and increased leakage of the microvasculature in tumours during and after these treatments despite the fact that the viability determined by MTT assay did not show a significant interaction between TNF and hyperthermia. Radiation (5 Gy) and TNF interact to a lesser extent compared with heat and TNF on cell shape and actin filament organization in HUVEC. Heat or radiation treatment enhances the expression of ELAM-1 mRNA in HUVEC while TNF produces the strongest effect on ELAM-1 mRNA expression. Our study suggests that radiation and heat affect endothelial cells and their subsequent functions differently. Result of an interaction between heat and TNF on endothelial cells supports the common notion that the anti-tumour effect by heat plus TNF treatments may benefit due to the increased disruption of vasculature function in the tumour.     

Over-expression of ICAM-1, VCAM-1 and ELAM-1 might influence tumor progression in colorectal cancer

Adhesion molecules might play a role in tumor progression. We investigated expression of the adhesion molecules ICAM-1, VCAM-1 and ELAM-1 in 24 primary colorectal carcinomas using immuno-histochemistry and Northern blot analysis. Normal colonic tissue from the same patients served as controls. ICAM-1 immunostaining was restricted to the intercellular matrix and vascular endothelial cells. The vast majority of normal tissue samples revealed only faint ICAM-1 immunoreactivity. However, moderate to strong immunostaining was found in 86% of cancerous sections. The ICAM-1 immunoreaction was more intense in well-differentiated carcinomas as well as in the adenomatous parts and transition zones of cancers. Similarly, the cancers exhibited markedly enhanced VCAM-1 and ELAM-1 immunostaining in the endothelial cells of small blood vessels. The intense vascular immunostaining by ICAM-1 and VCAM-1 was associated with a strong presence of CD3-positive T lymphocytes, whereas ELAM-1 immunoreactivity did not correlate with round cell infiltration. On Northern blot analysis, ICAM-1, VCAM-1 and ELAM-1 mRNA levels were increased in 67%, 57% and 63% of carcinomas, respectively, in comparison with normal tissue samples. Densitometric analysis of Northern blots revealed an increase in ICAM-1 by 2.1-fold, an increase in VCAM-1 by 3.4-fold and an increase in ELAM-1 by 2.2-fold in cancerous tissues compared to normal controls. Over-expression of ICAM-1 might prevent cell–cell disruption and, hence, tumor dissemination. Furthermore, over-expression of ICAM-1 and VCAM-1, but not ELAM-1, might favor host anti-tumor defense by trafficking of lymphocytes. Int. J. Cancer (Pred. Oncol.) 79:76–81, 1998. © 1998 Wiley-Liss, Inc.     

Cytokine and adhesion molecule expression in primary human endothelial cells stimulated with fever-range hyperthermia

Migration of blood-borne lymphocytes into lymphoid tissues and sites of inflammation is initiated by vascular adhesion molecules and proinflammatory cytokines. Previous in vivo studies have shown that febrile temperatures dynamically stimulate adhesion in differentiated high endothelial venules (HEV), which are portals for lymphocyte extravasation. This report examines the direct effect of fever-range hyperthermia on the expression of adhesion molecules and cytokines by primary cultured endothelial cells. In both macrovascular (HUVEC) and microvascular (HMVEC) endothelial cells, fever-range hyperthermia (40°C for 6-12h) did not affect expression of adhesion molecules (ICAM-1, E-selectin, VCAM-1, P-selectin, PECAM-1, PNAd, MAdCAM-1), cytokine release (IL-1 &#103 , TNF- &#102 , IFN- &#110 , IL-6, IL-11, IL-12, IL-13), or chemokine secretion (IL-8, RANTES, MCP-1, MIP-1 &#103 , MIG). This is in contrast to the stimulatory effects of TNF- &#102 or 43°C heat shock. However, a novel role for fever-range hyperthermia was identified in augmenting actin polymerization in cultured endothelial cells and enhancing the ability of endothelial-derived factors to transactivate the &#102 4 &#103 7 integrin lymphocyte homing receptor. These findings provide insight into the tightly regulated effects of fever-range hyperthermia that exclude induction of adhesion in non-activated endothelium of normal blood vessels. Through these mechanisms, it is proposed that febrile temperatures associated with infection or clinical hyperthermia avoid the unproductive exodus of lymphocytes to non-involved extralymphoid tissues while simultaneously promoting lymphocyte delivery to sites of immune activation.     

PMN adhesion and extravasation as a paradigm for tumor cell dissemination

Summary Current evidence indicates that the localization and extravasation of neutrophils is a complex process involving several adhesion molecules with apparently distinct functions, and a highly coordinated and dynamic interplay between the neutrophil and the endothelial cell that is influenced by the shear forces present at the interface between these two cell types. Chemotactic stimulation of the neutrophil not only induces directed locomotion but markedly alters the surface expression and functions of the neutrophil adhesion molecules, having both an upregulating and downregulating influence. Cytokines such as interleukin 1 induce the synthesis and surface expression of endothelial adhesion molecules such as ICAM-1 and ELAM-1, and stimuli such as thrombin and histamine induce the rapid mobilization to the endothelial surface of another adhesion molecule, GMP-140. Transendothelial migration of neutrophils in most settings both in vitro and in vivo appears to require CD18 integrins on the neutrophil and ICAM-1 on the endothelial cells. This is most clearly demonstrated by the genetic deficiency of CD18 in humans, dogs and cattle, where neutrophil extravasation at most inflammatory sites is almost completely absent. Though the coordinated functions of the various neutrophil and endothelial adhesion molecules are highly efficient in promoting neutrophil extravasation, there has been relatively little investigation of their utilization in tumor cell dissemination. Recent results indicate that such studies may prove fruitful. For example, some adenocarcinoma cell lines express the complex carbohydrate (sialyl Lewis x) recently shown to be a ligand for ELAM-1.     

Lipopolysaccharide induces the interactions of breast cancer and endothelial cells via activated monocytes

The adhesion of circulating cancer cells to vascular endothelium is a key step in hematogenous metastasis. Cancer cell-endothelium interactions are mediated by cell adhesion molecules that can also be involved in the arrest of monocytes and other circulating leukocytes on endothelium in inflammation. Static and microfluidic flow adhesion assays as well as flow cytometry were conducted in this study to elucidate the role of monocytes, bacterial lipopolysaccharide (LPS), and histamine in breast cancer cell adhesion to vascular endothelial cells. Tumor necrosis factor-α (TNF-α) released from LPS-treated monocytes triggered the expression of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells. Histamine augmented the TNF-α effect, leading to a high number of arrested breast cancer cells under both static and shear flow conditions. LPS-treated monocytes were shown to enhance the arrest of breast cancer cells by anchoring the cancer cells to activated endothelial cells. This anchorage was achieved by binding cancer cell ICAM-1 to monocyte β₂ integrins and binding endothelial ICAM-1 and VCAM-1 to monocyte β₁ and β₂ integrins. The results of this study imply that LPS is an important risk factor for cancer metastasis and that the elevated serum level of histamine further increases the risk of LPS-induced cancer metastasis. Preventing bacterial infections is essential in cancer treatment, and it is particularly vital for cancer patients affected by allergy.     

Tanshinone I suppresses growth and invasion of human breast cancer cells, MDA-MB-231, through regulation of adhesion molecules

The role of cell adhesion molecules has been studied extensively in the process of inflammation, and these molecules are critical components of carcinogenesis and cancer metastasis. This study investigated the effect of tanshinone I derived from the traditional herbal medicine, Salvia miltiorrhiza Bunge, on the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tumor necrosis factor-alpha (TNF-alpha)-stimulated endothelial cells. Furthermore, this study investigated the effect of tanshinone I on cancer growth, invasion and angiogenesis on human breast cancer cells MDA-MB-231, both in vitro and in vivo. Tanshinone I dose dependently inhibited ICAM-1 and VCAM-1 expressions in human umbilical vein endothelial cells (HUVECs) that were stimulated with TNF-alpha for 6 h. Pretreatment with tanshinone I significantly reduced adhesion of either monocyte U937 or MDA-MB-231 cells to HUVECs. Interestingly, the inhibitory effect of tanshinone I on monocyte and cancer cell adhesion to HUVECs was mimicked by transfection with ICAM-1 and VCAM-1 small interfering RNA. In addition, tanshinone I effectively inhibited TNF-alpha-induced production of vascular endothelial growth factor (VEGF) and VEGF-mediated tube formation in HUVECs. Tanshinone I also inhibited TNF-alpha-induced VEGF production in MDA-MB-231 cells and migration of MDA-MB-231 cells through extracellular matrix. Additionally, reduction of tumor mass volume and decrease of metastasis incidents by tanshinone I were observed in vivo. In conclusion, this study provides a potential mechanism for the anticancer effect of tanshinone I on breast cancer cells, suggesting that tanshinone I may serve as an effective drug for the treatment of breast cancer.     

Inhibitory Effect of Recombinant Fibronectin Polypeptides on the Adhesion of Liver-metastatic Lymphoma Cells to Hepatic Sinusoidal Endothelial Cells and Tumor Invasion

We have investigated the inhibitory mechanism of the initial arrest of L5178Y-ML25 lymphoma cells in a target organ (liver) by using recombinant fibronectin fragments with cell- and/or heparin-binding domains (C-274, H-271 or the fusion fragment CH-271). Pretreatment of hepatic sinusoidal endothelial (HSE) cell monolayers with lymphoma cells or their conditioned medium for 4 to 6 h resulted in the enhancement of lymphoma cell adhesion to HSE cell monolayer. The increased tumor adhesiveness was completely abolished by preincubation of the conditioned medium with anti interleukin-1β monoclonal antibody (mAb). Synthetic sialyl Le^x (SLe^x) as a ligand for endothelial cell leukocyte adhesion molecule-1 (ELAM-1) adhesion receptor and anti ELAM-1 mAb blocked the conditioned medium-induced enhancement of tumor-endothelial cell interaction, while pretreatment of the activated HSE cell monolayer with anti vascular cell adhesion molecule-1 (VCAM-1) mAb did not affect the enhanced tumor cell adhesion. These results indicate that tumor cell interaction with the stimulated HSE cells is mediated by ELAM-1 molecules on HSE cells. However, the expression of SLe^x and SLe^a on the tumor surface was not observed by flow cytometric analysis. ELAM-1-mediated enhancement of tumor cell adhesion to HSE monolayer was also inhibited in a concentration-dependent manner by CH-271 fusion polypeptide or the sulfated chitin derivative sulfated carboxyntethyl-chitin, which can bind to the heparin-binding domain of CH-271. In addition, CH-271 inhibited not only tumor-endothelium interaction hut also tumor cell invasion into reconstituted basement membrane Matrigel in vitro .     

Expression of the cell adhesion molecules ICAM-1, VCAM-1 and NCAM in uveal melanoma: a clinicopathological study

To investigate the relationship between the expression of the cell adhesion molecules intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and neural cell adhesion molecule (NCAM) in uveal melanoma and the metastatic spread in the first 5 years after diagnosis, we performed a hospital-based case-control study with human tissue from 90 patients who underwent enucleation for primary uveal melanoma (iris melanoma excluded). Thirty-five patients developed metastasis within the first 5 years, and 55 patients lived metastasis-free for at least 5 years after enucleation. The paraffin-embedded and formalin-fixed globes were studied by immunohistochemistry with monoclonal antibodies for ICAM-1, VCAM-1 and NCAM. A strong ICAM-1 positivity (more than 75% of the tumor cells stained positive) was detected in 73 tumors (81%). The expression of 75% or less ICAM-1 positive cells in tumors was strongly associated with the development of metastases (odds ratio: 7.5, p = 0.001). Multiple logistic regression models showed that ICAM-1 is an independent risk factor for metastasis even after control for important prognostic markers like extraocular growth, ciliary body involvement, scleral infiltration and cell type. VCAM-1 was expressed in 24 out of 88 tumors (27.3%) and NCAM only in 14 out of 87 tumors (16%). Only spindle cells stained positive with anti-NCAM. NCAM and VCAM-1 expression was not related to metastasis. Our results show that the loss of ICAM-1 expression is associated with an increased risk of metastasis within the first 5 years after diagnosis.     

人肝癌微血管内皮细胞黏附分子表达特点及其对外周血单个核细胞黏附和跨内皮迁移的影响

目的:研究人肝癌微血管内皮细胞(human liver cancer microvascular endothelial cell,HLCMVEC)上黏附分子表达的特点及其对免疫细胞黏附和迁移的影响.方法:分离培养HLCMVEC,以人肝窦内皮细胞系(liver sinusoid endothelial cell, LSEC)作为正常对照.通过细胞ELISA方法比较多种黏附分子在两种内皮细胞上的表达.外周血单个核细胞(peripheral blood mononuclear cell,PBMC)用荧光染料BCECF标记,将其与HLCMVEC或LSEC共培养,随后采用倒置荧光显微镜和连续光谱荧光仪检测PBMC在两种内皮细胞上的黏附和跨内皮迁移能力;此外,共培养前分别预加各种黏附分子的功能抗体,然后分析各种黏附分子在PBMC与肿瘤微血管内皮细胞黏附和迁移中的作用.结果:HLCMVEC表达CD31、CD34和细胞间黏附分子-3(intercellular adhesion molecule-3,ICAM-3)的水平低于LSEC(P＜0.05),表达ICAM-1和血管细胞黏附分子-1(vascular cell adhesion molecule-l,VCAM-1)的水平明显低于正常LSEC(P＜0.01),但表达整合素αvβ3和αvp5明显高于LSEC(P＜0.01).PBMC在HLCMVEC上的黏附和趋化剂诱导下的跨内皮迁移均显著低于LSEC[黏附:(205.5±46.0) vs (330.5±48.4)个,迁移:(49.0±10.6) vs(110.0±19.2)个,均P＜0.01];该黏附和迁移可被ICAM-1、ICAM-3、VCAM-1抗体明显阻断(P＜0.01),抗CD31抗体对黏附阻断不明显但能阻断跨内皮迁移(P＜0.05).结论:HLCMVEC特有的黏附分子表达特点抑制了PBMC的黏附和跨内皮迁移.     

VLA-4 Molecules on Tumor Cells Initiate an Adhesive Interaction with VCAM-1 Molecules on Endothelial Cell Surface

To elucidate the role of VLA-4 (α4β1 integrin) in tumor metastasis, we have transfected cDNA coding z4 subunit into human flbrosarcoma (HT1080) cells. VLA-4-overexpressing HT-VC1 cells exhibited increased ability to interact with known ligands for VLA-4, such as CS1 peptide and VCAM-1 (vascular cell adhesion molecule-1). In addition, the in vitro invasive ability of HT-VC1 cells was augmented and the mRNA for type IV collagenase was increased in HT-VC1 cells. The induction of VCAM-1 molecules on lung endothelial cells of nude mice by tumor necrosis factor-α treatment resulted in augmentation of in vivo HT-VC1 cell adhesion to the lung endothelial cells. Thus, the VLA-4 molecules on tumor cells initiate an adhesive interaction with VCAM-1 molecules on endothelial cells, that is important for hematogenous metastasis.     

Tumor cell adhesion to endothelial cells: endothelial leukocyte adhesion molecule-1 as an inducible adhesive receptor specific for colon carcinoma cells.

Activation of endothelial cells by the two inflammatory mediators interleukin-1 (IL-1) and tumor necrosis factor strongly increases tumor cell adhesion. We describe antibody inhibition studies showing that the endothelial leukocyte adhesion molecule-1 (ELAM-1), a cell-surface glycoprotein selectively expressed by cytokine-activated endothelial cells and responsible for neutrophil adhesion, is the major, if not the only, mediator of colon carcinoma cell adhesion to activated endothelial cells. Among the different tumor cell lines tested, seven colon carcinoma cell lines were sensitive to ELAM-1 antibodies. Adhesion of melanoma, osteosarcoma, and lung, cervix, or kidney carcinoma cell lines to IL-1-treated endothelial cells was not affected by the ELAM-1 antibody. This result suggests that ELAM-1 is selectively recognized by colon carcinoma cells and that adhesion of tumor cells to activated endothelial cells could be mediated by different and specific mechanisms.     

Cytokine and adhesion molecule expression in primary human endothelial cells stimulated with fever-range hyperthermia.

Migration of blood-borne lymphocytes into lymphoid tissues and sites of inflammation is initiated by vascular adhesion molecules and proinflammatory cytokines. Previous in vivo studies have shown that febrile temperatures dynamically stimulate adhesion in differentiated high endothelial venules (HEV), which are portals for lymphocyte extravasation. This report examines the direct effect of fever-range hyperthermia on the expression of adhesion molecules and cytokines by primary cultured endothelial cells. In both macrovascular (HUVEC) and microvascular (HMVEC) endothelial cells, fever-range hyperthermia (40 degrees C for 6-12 h) did not affect expression of adhesion molecules (ICAM-1, E-selectin, VCAM-1, P-selectin, PECAM-1, PNAd, MAdCAM-1), cytokine release (IL-1beta, TNF-alpha, IFN-gamma, IL-6, IL-11, IL-12, IL-13), or chemokine secretion (IL-8, RANTES, MCP-1, MIP-1beta, MIG). This is in contrast to the stimulatory effects of TNF-alpha or 43 degrees C heat shock. However, a novel role for fever-range hyperthermia was identified in augmenting actin polymerization in cultured endothelial cells and enhancing the ability of endothelial-derived factors to transactivate the alpha4beta7 integrin lymphocyte homing receptor. These findings provide insight into the tightly regulated effects of fever-range hyperthermia that exclude induction of adhesion in non-activated endothelium of normal blood vessels. Through these mechanisms, it is proposed that febrile temperatures associated with infection or clinical hyperthermia avoid the unproductive exodus of lymphocytes to non-involved extralymphoid tissues while simultaneously promoting lymphocyte delivery to sites of immune activation.     

The MHC class-II and CD44 molecules are involved in the induction of tumour necrosis factor (TNF) gene expression by human monocytes stimulated with tumour cells

Tumour necrosis factor alpha (TNF) mRNA is detected in the macrophage infiltrate surrounding the tumour, but the cellular/ molecular interactions leading to TNF gene expression in macrophages are unknown. The in vitro system in which human blood monocytes are stimulated with human cancer cells for TNF release was used to study such interactions. Monoclonal antibodies (MAbs) against various adhesion molecules (LFA-I, LFA-3, (CAM-I, VNR, VLAβI chain) were unable to block TNF production in co-culture of monocytes with a human pancreatic carcinoma (HPC) cell line. However, anti-CD44 and anti-HLA-DR MAbs effectively blocked TNF release and TNF-mRNA induction in monocytes. Pre-incubation of monocytes with anti-HLA-DR and tumour cells with anti-CD44 MAbs had a similar effect. It was concluded that CD44 molecules are involved in tumour-monocyte interactions and that HLA-DR determinants of monocytes are engaged in signal transduction for TNF gene activation. These findings may suggest that certain surface determinants of tumour cells act as ligands for MHC class-II molecules and induce TNF production in monocytes.     

Influence of dose-rate on inflammatory damage and adhesion molecule expression after abdominal radiation in the rat

PURPOSE: The goal of this study was to assess the effects of two clinically relevant radiation dose-rates on endothelial adhesion molecule expression, inflammatory response, and microvascular dysfunction. METHODS AND MATERIALS: Rats were irradiated with 10 Gy at low (0.9 Gy/min) or high (3 Gy/min) dose-rates. Control animals received sham irradiation. Leukocyte rolling, adhesion, emigration, and microvascular permeability were assessed in mesenteric venules by intravital microscopy 6 hours after irradiation. P-selectin and intercellular adhesion molecule-1 (ICAM-1) expression were measured using radiolabeled monoclonal antibodies. RESULTS: Low dose-rate (LDR) abdominal irradiation increased leukocyte adhesion compared with sham-irradiated animals, whereas high dose-rate (HDR) irradiation resulted in enhanced leukocyte rolling, adhesion, and emigration, compared with the LDR or with sham-irradiated rats. Both dose-rates increased microvascular permeability, although this effect was significantly greater after radiation with the high (8-fold) than the low (5-fold) dose-rate. HDR radiation induced significantly larger increments in P-selectin expression in splanchnic organs than LDR, whereas in most organs ICAM-1 expression was only upregulated by the HDR. Blockade of ICAM-1, but not P-selectin, abrogated leukocyte adhesion at both dose-rates. CONCLUSIONS: The magnitude of upregulation of endothelial adhesion molecules, leukocyte recruitment, and endothelial barrier dysfunction elicited by radiation therapy is dependent on the dose-rate at which the radiation is delivered.     

Serum levels of E-selectin, ICAM-1 and VCAM-1 in colorectal cancer patients: correlations with clinicopathological features, patient survival and tumour surgery

The serum concentrations of the cell adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were investigated in 63 patients with colorectal cancer and in 51 controls by an enzyme-linked immunosorbent assay (ELISA). Their relationship to clinicopathological variables and patient survival and changes in their levels after surgery were examined. Colorectal cancer patients showed significantly higher serum levels of E-selectin, ICAM-1 and VCAM-1 compared with healthy controls. There was a significant association between the serum levels of these molecules, disease stage and the presence of both lymph node and distant metastases. Both ICAM-1 and VCAM-1 levels correlated with serum E-selectin and carcinoembryonic antigen (CEA) levels. Serum levels of all three molecules decreased significantly after radical resection of the tumour. Elevated pre-operative E-selectin, ICAM-1 and VCAM-1 levels were significant prognostic factors, although not independent of stage, for patient survival. These findings suggest that serum concentrations of E-selectin, ICAM-1 and VCAM-1 may reflect tumour progression and metastasis. Since these markers are linked to CEA levels, it is uncertain whether their measurement will prove cost-effective in colorectal cancer management.     

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.     

Decrease in ICAM-1 expression on gastric cancer cells is correlated with lymph node metastasis

Background. Lymph node metastasis is a frequent type of metastasis in patients with gastric cancer. The mechanisms responsible for this type of metastasis, however, are not clearly understood. We hypothesize that the immunosurveillance system between cancer cells and lymphocytes may be associated with the lymph node metastatic process. In this study, we examined the correlation between lymph node metastasis and intercellular adhesion molecule-1 (ICAM-1), which mediates the immunosurveillance system between tumor cells and cytotoxic lymphocytes, in gastric cancer. Methods. One hundred and forty-three specimens resected from patients with gastric cancer were investigated by staining with a monoclonal antibody against ICAM-1. We studied the correlation between the expression of ICAM-1 and various clinicopathologic factors, as well as infiltration of tumor-infiltrating lymphocytes (TILs). Results. ICAM-1 expression on gastric cancer cells was significantly decreased in patients with lymph node metastasis. The infiltration of TILs was associated with ICAM-1 expression level. The prognosis of patients with ICAM-1-negative tumors was poorer than the prognosis of those with ICAM-1-positive tumors. Conclusions. These findings suggest that ICAM-1 expression on cancer cells is closely associated with lymph node metastasis in gastric cancer, under the influence of the host immunosurveillance system. Received on Aug. 20, 1999; accepted on Jan. 5, 2000