3383

ICAM1

intercellular adhesion molecule 1;ICAM1;intercellular adhesion molecule 1

ICAM-1|cell surface glycoprotein P3.58|intercellular adhesion molecule 1 (CD54), human rhinovirus receptor|major group rhinovirus receptor

19p13.3-p13.2

protein-coding

Endothelial cell adhesion molecules (CAMs) are important in tumorigenesis and host defense mechanism. Their status in breast cancer with regard to nodal invasion is not yet known. Hence we looked at the expression of three important CAMs: VCAM, ICAM and E-selectin. A downregulation of all these CAMs was noted in node positive breast cancer in comparison to node negative cases. This suggests shedding of these molecules in cases with nodal metastasis which might help the tumor cells to escape the host defense mechanism. On multi-variate analysis, VCAM alone emerged as an independent predictor of nodal metastasis.

We identified previously a region on chromosome 19p13.2 spanning the genes encoding the intercellular adhesion molecules (ICAM), ICAM1, ICAM4 and ICAM5 as a breast cancer susceptibility locus. Genetic variants in this region were also associated with indicators of disease severity, including higher rates of metastases to other organs. Based on this association, we set out to explore the role of ICAM1 in proliferation and invasion of human breast cancer cells. We observed that ICAM1 downregulation at the mRNA and protein levels led to a strong suppression of human breast cell invasion through a matrigel matrix. Under the same conditions, no significant effect on cell proliferation in vitro was seen. Incubation of cells with an antibody against ICAM1 blocked invasion of the highly metastatic MDA-MB-435 cell line in a dose-dependent manner without affecting cell migration. We also demonstrated that the level of ICAM1 protein expression on the cell surface positively correlated with metastatic potential of five human breast cancer cell lines and that ICAM1 mRNA levels were elevated in breast tumor compared with adjacent normal tissue. These results corroborate our previous genetic finding that variations in the ICAM region are associated with the occurrence of metastases and establish a causal role of ICAM1 in invasion of metastatic human breast carcinoma cell lines.

BACKGROUND: In this study, we aimed to investigate serum total sialic acid (TSA) and soluble intracellular adhesion molecule-1 (sICAM-1) levels in breast cancer patients to find a correlation with the cancer stage. METHODS: The parameters from sera of 61 patients with breast cancer were measured. The concentrations of serum sICAM-1 and TSA were measured in serum samples from 61 patients with breast cancer and 25 healthy control subjects using enzyme-linked immunoassay and thiobarbituric acid method. RESULTS: Mean serum sICAM-1 and TSA levels were significantly higher in the total patient group than in the control group (p < 0.001). Thus, the correlation between TSA and sICAM-1 became more significant in metastatic breast cancer. There were significant positive correlations between TSA and sICAM-1 in stage I+II (r = 0.59, p < 0.05), stage III (r = 0.47, p < 0.05), and stage IV (r = 0.89, p < 0.01), and total patient group (r = 0.56, p < 0.001). CONCLUSION: SerumsICAM-1 and TSA levels were higher in patients with breast cancer, than that of the control group, and also in the metastatic breast cancer group. Significant correlations between serum sICAM-1 and TSA may reflect the similar function of these molecules as adhesion molecules, and their roles in the carcinogenesis of breast cancer as well as metastasis.

tumor infiltrating neutrophil granulocytes do not only exhibit tumor eliminating functions but also promote tumor progression. We have recently shown that neutrophil granulocytes can serve as linking cells for the adhesion of MDA-MB-468 breast carcinoma cells to pulmonary endothelium. Neutrophil granulocytes but not MDA-MB-468 cells express beta(2)-integrins, the ligands of the intercellular adhesion molecule (ICAM)-1, whereas ICAM-1 is strongly expressed on MDA-MB-468 cells. Consequently, the herein presented study was performed to investigate if this interaction has also an influence on the migratory activity of the tumor cells and whether ICAM-1 signaling plays a role in this process, too. We found that the continuous release of interleukin-8 (IL-8) and GRO-alpha by MDA-MB-468 cells increases the migratory activity of neutrophil granulocytes and attracts these cells towards the tumor cells which enables direct cell-cell interactions. These interactions in turn increase the migratory activity of the tumor cells in an ICAM-1 clustering-dependent mechanism since transfection of the tumor cells with specific siRNA against ICAM-1 abolished the effect. Moreover, ICAM-1 cross-linking on tumor cells induces the phosphorylation of focal adhesion components such as focal adhesion kinase and paxillin via src kinase as well as the activation of the p38 MAPK pathway via Rho kinase in a time-dependent manner. Our results provide evidence that ICAM-1 is coupled to intracellular signaling pathways involved in tumor cell migration. Thus, neutrophil granulocytes can act as modulators of the metastatic capability of tumor cells by ligation of ICAM-1.

AIMS: The aim of this study was to prospectively investigate metastatic pathways of spread to lymph node versus bone marrow and identify biological characteristics that determine these patterns in early invasive breast cancer. PATIENTS AND METHODS: In all, 177 patients with early invasive breast cancer underwent surgical extirpation of the primary tumour with sentinel lymph node biopsy (SLNB). Bone marrow (BM) aspiration was performed to screen for cytokeratin-positive cells by immunocytochemistry. Lymphatic spread was assessed by histopathological examination of lymph nodes (LN). A representative subset of 87 tumours was analysed by tissue microarray (TMA) to evaluate expression of markers that potentially influence haematogenous vs. lymphatic spread. Patients were followed up for a median of 54.7 months. RESULTS: Of the 177 patients, 114 (64%) were BM-/LN-, 38 (22%) BM-/LN+, 19 (11%) BM+/LN- and 6 (3%) BM+/LN+. Multivariate analysis of histopathological characteristics revealed that increasing tumour size was significantly associated with both LN positivity (p = 0.003) and BM positivity (p = 0.01), the presence of lymphovascular invasion significantly correlated with LN+ (p = 0.01), whereas lower histological grade was significantly associated with BM+ (p = 0.03). LN+ and BM+ were non-significantly negatively related to each other. Univariate analysis of the TMA data showed differential expression patterns for several factors; significant differences between effects on the two metastatic pathways (lymphatic vs. haematogenous) were found for expression of CD54 (p = 0.03), osteopontin (p = 0.04), bone sialoprotein (p = 0.04) and CXCR4 (p = 0.009). High expression of CD54, osteopontin and bone sialoprotein (BSP) was positively associated with BM + but was either not associated, or negatively associated, with LN+. High CXCR4 expression was positively associated with LN+ and negatively with BM+. High VEGF-C expression was associated with both LN+ and BM+, although this did not attain statistical significance. Due to the small number of clinical events during clinical follow-up, no associations were identified between metastatic spread patterns, recurrence and/or death. CONCLUSION: These findings suggest that distinct lymphatic and haematogenous metastatic pathways exist in early breast cancer and that these pathways are governed by specific biological markers.

AIM: To investigate the pathogenic mechanism of colon cancer at the molecular level and to elucidate the relationship between intercellular adhesion molecule-1 (ICAM-1) and nm23H(1) genes and Chinese patients with colon cancer. METHODS: DNA was extracted from paraffin-embedded materials. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) was used to analyze MSI and LOH. expression of ICAM-1 was detected by Envision immuno-histochemistry. Experimental results were analyzed with Leica-Qwin computer imaging techniques and SPSS software of statistics. RESULTS: ICAM-1 expression of lymphatic endothelium was negative in normal colon and positive in colon cancer respectively. The number of lymphatics positive for ICAM-1 was gradually increased with degree of cancer invasion (P<0.01). In the group with metastasis of colon cancer, the number of lymphatics positive for ICAM-1 in lymph nodes was more than that in the group with no metastasis (P<0.01). The frequency of MSI, LOH and nm23H(1) protein was 26.67%, 20.00% and 53.33% in colon cancer, respectively. In TNM staging, MSI (43.75%) and nm23H(1) protein (81.25%) in stages I+II were detected more easily than the corresponding indexes (MSI: 7.14%, P<0.05 and nm23H(1): 21.43%, P<0.01) in stages III+IV. By comparison, the frequency of LOH (35.71%) in stages III+IV was more than that of LOH (6.25%, P<0.05) in stages I+II. LOH exhibited a rising trend along with the Dukes staging. nm23H(1) protein in the group of tubular adenocarcinoma (60.00%) was higher expressed than that in the group of mucoid adenocarcinoma (20.00%) (P<0.01), and exhibited a rising trend with the differentiation degrees of tubular adenocarcinoma. nm23H(1) protein in MSI positive group was higher expressed (75%) than that in MSI negative group (45.45%, P<0.05). CONCLUSION: The expression of ICAM-1 in lymphatic vessels is beneficial to the judgement of the invasion and metastasis ability of colon cancer and the anti-tumor immunity function, and shows an important clinical significance in predicting lymphatic metastasis of colon cancer. MSI and LOH may separately control the development of sporadic colon cancer with different pathways. LOH mostly arises in the late period of sporadic colon cancer and endows a high aggressive and poor prognostic phenotype. By compassion, MSI may be an early period molecule marker for sporadic colon cancer, enhanced expression of nm23H(1) protein can effectively inhibit colon cancer metastasis and improve prognosis of sporadic colon cancer patients.

Colorectal cancer (CRC) is one of the most common cancers of the gastrointestinal tract and the fourth cause of cancers death in the world. Soluble adhesion molecules (CAMs) are thought to have an important role in host defense against carcinogenesis. They are biomarkers of inflammation and indicators of the immune response to tumors. The study included 40 CRC patients without remote metastases and 24 control subjects. Serum concentrations of sE-selectin, sICAM and sVCAM in patients with CRC were investigated by ELISA method. The level of the sCAMs decreased significantly after radical tumor resection. Preoperative serum concentrations of sICAM and sVCAM in CRC patients were significantly higher compared to the control group, whereas there were no differences regarding serum sE-selectin. Serum levels of sE-selectin, sICAM and sVCAM correlated significantly with each other. There was a significant correlation of serum levels of sICAM-1 and sVCAM-1, but not sE-selectin, with TNM stage and lymph node involvement. No significant relationship was found between serum concentrations of sICAM-1, sVCAM-1 and sE-selectin in CRC patients and patients' age or gender. Our findings suggest that an improved understanding of the mechanisms of membrane shedding of sICAM, sVCAM and sE-selectin is required to delineate their role in tumor progression.

AIM: To study the expression levels of E- selectin, integrin beta1 and immunoglobulin superfamily member-intercellular adhesion molecule-1 (ICAM-1) in human gastric carcinoma cells, and to explore the relationship between these three kinds of cell adhesion molecules and gastric carcinoma. METHODS: The serum contents of E-selectin, integrin beta1 and ICAM-1 were detected by enzyme-linked immunosorbent assay (ELISA), in 47 healthy individuals (control group) and in 57 patients with gastric carcinoma (gastric carcinoma group) respectively prior to operation and 7 d after operation. RESULTS: The serum E-selectin, ECAM-1 and integrin beta1 were found to be expressed in both control and gastric carcinoma groups. However, they were highly expressed in patients with gastric carcinoma patients before operation or with unresectable tumours. The expression levels of ICAM-1 and integrin beta1 were significantly higher in gastric carcinoma patients than in controls (P < 0.01). A comparison of the E-selectin levels between the two groups showed statistically insignificant difference (P = 0.64). In addition, the expression levels were all decreased substantially in the postoperative patients subjected to radical resection of the tumours, indicating that the high level expressions of these compounds might be the important factor for predicting the prognosis of these patients. CONCLUSION: Serum E-selectin, ICAM-1 and integrin beta1 expression levels are probably related to the metastasis and relapse of gastric cancer.

OBJECTIVES: To explore the effects of E-selectin, ICAM-1 and their ligands on the adhesive metastasis of hepatocellular carcinoma (HCC), and to select possible anti-adhesion drugs for hepatocellular carcinoma metastasis. METHODS: 78 HCC patients were analyzed with the correlation of clinical features to the expression levels of E-selectin, sLeX, sLeA and CD44v6 in the tumor tissue. The adhesion between HepG2 and endothelial cell lines was examined by solid phase adhesion assay in vitro. Two kinds of drugs were accessed for their anti-adhesion ability. RESULTS: The positive rate of E-selectin in vascular endothelia cells adjacent to cancer nest is 70.51%, and which of sLeX, sLeA, CD44v6 within tumor cells is 64.10%, 69.23%, 62.90% respectively. The patients' life span is closely related with the positive expression of sLeX, sLeA, CD44v6 (P = 0.008, 0.001, 0.022). The positive expression of E-selectin, sLeX and sLeA is significantly correlated to portal vein tumor thrombus (PVTT), preoperative extrahepatic metastasis, and satellite foci, but not to the size of tumor and AFP. The level of CD44v6 expression is significantly correlated to patient's survival time. The expression levels of E-selectin and ICAM-1 are remarkably higher after ED25 and ECV304 cell lines be activated. Meanwhile the adhesive ability of HepG2 to endothelial cell is mediated. Dexamethasone, tanshinone IIA are able to block this adhesion at low concentration. CONCLUSION: The expression levels of E-selectin, sLeX, sLeA and CD44v6 are closely correlated with clinical features. E-selectin, ICAM-1 and their ligands are important molecules of hepatocellular carcinoma and endothelial cells to tumor adhesive metastasis. Dexamethasone, tanshinone II A can be hopefully used as anti-adhesion drugs.

BACKGROUND & AIMS: Intercellular adhesion molecule 1 (ICAM-1) is believed to be involved in metastasis of hepatocellular carcinoma (HCC) cells. cancer stem cells promote tumor relapse and metastasis. We investigated whether ICAM-1 is a marker of HCC stem cells. METHODS: Sphere formation and tumor formation assays were performed to investigate the stem cell properties of ICAM-1(+) cells in vitro and in vivo. A specific targeting system that inhibits ICAM-1 expression and hepatitis B virus transgenic mice (M-TgHBV) were used to investigate whether inhibition of ICAM-1 reduced tumor incidence and metastasis in vivo. We used real-time polymerase chain reaction and immunoblot analysis to assess ICAM-1 and Nanog expression in tumor cell lines, and flow cytometry analysis was used to investigate ICAM-1 expression in HCC and blood samples. RESULTS: ICAM-1 was expressed on a minor cell population in HCC tumor cell lines, as well as in tumor tissues and circulating tumor cells isolated from patients and transgenic mice. ICAM-1(+) tumor cells had greater sphere-forming and tumorigenic capacities and increased expression of stemness-related genes compared with ICAM-1(-) tumor cells. The specific inhibition of ICAM-1 reduced formation and metastasis in M-TgHBV mice. ICAM-1 was found to be a marker of circulating tumor cells from patients and M-TgHBV mice. Increased numbers of CD45(-)ICAM-1(+) cells in blood samples of patients with HCC correlated with worse clinical outcomes. The stem cell transcription factor Nanog regulated expression of ICAM-1 in HCC stem cells. CONCLUSIONS: ICAM-1 is a marker of HCC stem cells in humans and mice; ICAM-1 inhibitors slow tumor formation and metastasis in mice. ICAM-1 expression is regulated by the stem cell transcription factor Nanog.

We have shown that administration of a novel anti-CD54 monoclonal antibody (UV3) results in long-term survival of SCID mice bearing human myeloma xenografts. Previous studies have demonstrated a link between the expression of CD54 and the progression of uveal melanoma. Our study assessed the expression of CD54 on 7 human uveal melanoma cell lines and 3 cell lines established from uveal melanoma metastases. In vivo studies examined the efficacy of systemic and local administration of UV3 antibody on the progression of uveal melanoma cells transplanted either heterotopically or orthotopically into SCID mice. Five of the 7 primary uveal melanoma cell lines and all 3 of the metastases cell lines expressed CD54. Intraperitoneal injection of either IgG or F(ab')2 fragments of UV3 significantly inhibited the growth of subcutaneous and intraocular melanomas. Subconjunctival injection of either IgG or F(ab')2 fragments of UV3 produced a significant reduction in the growth of intraocular melanomas, even if the antibody was administered after the appearance of intraocular tumors. The results indicate that both primary and metastatic human uveal melanoma cells express CD54. The marked inhibition of intraocular and subcutaneous uveal melanoma progression suggests that UV3 antibody is a promising therapeutic agent for further evaluation in patients with uveal melanoma. This is especially noteworthy, as no existing therapeutic modality prevents metastasis of uveal melanoma or prolongs the survival of patients with uveal melanoma.

cancer metastasis involves multistep adhesive interactions between tumor cells (TCs) and endothelial cells (ECs), but the molecular mechanisms of intercellular communication in the tumor microenvironment remain elusive. Using static and flow coculture systems in conjunction with flow cytometry, we discovered that certain receptors on the ECs are upregulated on melanoma cell adhesion. Direct contact but not separate coculture between human umbilical endothelial cells (HUVECs) and a human melanoma cell line (Lu1205) increased intercellular adhesion molecule 1 (ICAM-1) and E-selectin expression on HUVECs by 3- and 1.5-fold, respectively, compared with HUVECs alone. The nonmetastatic cell line WM35 failed to promote ICAM-1 expression changes in HUVECs on contact. Enzyme-linked immunosorbent assay (ELISA) revealed that EC-TC contact has a synergistic effect on the expression of the cytokines interleukin (IL)-8, IL-6, and growth-related oncogene alpha (Gro-alpha). By using E-selectin cross-linking and beads coated with CD44 immunopurified from Lu1205 cells, we showed that CD44/selectin ligation was responsible for the ICAM-1 up-regulation on HUVECs. Protein kinase Calpha (PKC-alpha) activation was found to be the downstream target of the CD44/selectin-initiated signaling, as ICAM-1 elevation was inhibited by siRNA targeting PKCalpha or a dominant negative form of PKCalpha (PKCalpha DN). Western blot analysis and electrophoretic mobility shift assays (EMSAs) showed that TC-EC contact mediated p38 phosphorylation and binding of the transcription factor SP-1 to its regulation site. In conclusion, CD44/selectin binding signals ICAM-1 up-regulation on the EC surface through a PKCalpha-p38-SP-1 pathway, which further enhances melanoma cell adhesion to ECs during metastasis.

BACKGROUND: All trans retinoic acid (ATRA) is used as standard of care in promyelocytic leukemia. Not much is known about the gene expression profile in ATRA-treated tongue cancer cells. We performed a genome-wide transcriptional profiling of ATRA-treated tongue cancer cells to understand the pathways that mediate ATRA action in tongue cancer. METHODS: We measured the effects of ATRA on the proliferation of SCC-9 human tongue carcinoma cells. The differential gene expression profile was measured by microarray analysis of untreated and ATRA-treated cells and expression of key genes was validated by real-time RT-PCR. RESULTS: ATRA treatment (24 and 48 hr) significantly inhibited SCC-9 cell proliferation in a dose-dependent manner. SCC-9 cells treated for 48 hr with ATRA showed upregulation of 276 genes, including ANGPTL4, GDF15, ICAM1 and TUSC4, and downregulation of 43 genes, including CXCL10. Validation by real-time PCR showed a significant upregulation of intracellular adhesion molecule 1 (ICAM1) and downregulation of CXCL10 and IL32. CONCLUSIONS: ATRA had an anti-tumor effect in tongue cancer cells. This effect is likely mediated via upregulation of ICAM1 and downregulation of CXCL10 and IL32.