VCAM1; vascular cell adhesion molecule 1 (1p32-p31)

Gene Summary

Gene:VCAM1; vascular cell adhesion molecule 1
Aliases: CD106, INCAM-100
Summary:This gene is a member of the Ig superfamily and encodes a cell surface sialoglycoprotein expressed by cytokine-activated endothelium. This type I membrane protein mediates leukocyte-endothelial cell adhesion and signal transduction, and may play a role in the development of artherosclerosis and rheumatoid arthritis. Three alternatively spliced transcripts encoding different isoforms have been described for this gene. [provided by RefSeq, Dec 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:vascular cell adhesion protein 1
Updated:12 December, 2014


What does this gene/protein do?
Show (34)


What pathways are this gene/protein implicaed in?
- Adhesion and Diapedesis of Lymphocytes BIOCARTA
- Cells and Molecules involved in local acute inflammatory response BIOCARTA
- Cell adhesion molecules (CAMs) KEGG
- Leukocyte transendothelial migration KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 12 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cancer Gene Expression Regulation
  • Genetic Association Studies
  • Phenotype
  • Childhood Cancer
  • Cell Adhesion
  • Gene Expression
  • Chromosomes, Human, Pair None
  • Immunohistochemistry
  • Western Blotting
  • Cell Survival
  • Base Sequence
  • Staging
  • Breast Cancer
  • Venous Thrombosis
  • Sodium-Hydrogen Antiporter
  • Young Adult
  • Inflammation
  • Renal Cell Carcinoma
  • Adolescents
  • Microarray Analysis
  • Gene Expression Profiling
  • Tissue Array Analysis
  • Single Nucleotide Polymorphism
  • Cell Proliferation
  • Up-Regulation
  • NF-kappa B
  • Liver Cancer
  • Valproic Acid
  • Genetic Predisposition
  • Neoplasm Proteins
  • Cell Movement
  • Messenger RNA
  • Tumor Markers
  • Oligonucleotide Array Sequence Analysis
  • Vascular Cell Adhesion Molecule-1
  • Kidney Cancer
  • Cell Adhesion Molecules
  • Cluster Analysis
  • Brain Tumours
Tag cloud generated 12 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (4)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Brain Tumours, ChildhoodVCAM1 and Brain Tumours View Publications2
Liver CancerVCAM1 and Liver Cancer View Publications2
Kidney CancerVCAM1 and Kidney Cancer View Publications2
Breast CancerVCAM1 and Breast Cancer View Publications2

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: VCAM1 (cancer-related)

Lu Y, Yu T, Liang H, et al.
Nitric oxide inhibits hetero-adhesion of cancer cells to endothelial cells: restraining circulating tumor cells from initiating metastatic cascade.
Sci Rep. 2014; 4:4344 [PubMed] Free Access to Full Article Related Publications
Adhesion of circulating tumor cells (CTCs) to vascular endothelial bed becomes a crucial starting point in metastatic cascade. We hypothesized that nitric oxide (NO) may prevent cancer metastasis from happening by its direct vasodilation and inhibition of cell adhesion molecules (CAMs). Here we show that S-nitrosocaptopril (CAP-NO, a typical NO donor) produced direct vasorelaxation that can be antagonized by typical NO scavenger hemoglobin and guanylate cyclase inhibitor. Cytokines significantly stimulated production of typical CAMs by the highly-purified human umbilical vein endothelial cells (HUVECs). CAP-NO inhibited expression of the stimulated CAMs (particularly VCAM-1) and the resultant hetero-adhesion of human colorectal cancer cells HT-29 to the HUVECs in a concentration-dependent manner. The same concentration of CAP-NO, however, did not significantly affect cell viability, cell cycle and mitochondrial membrane potential of HT-29, thus excluding the possibility that inhibition of the hetero-adhesion was caused by cytotoxicity by CAP-NO on HT-29. Hemoglobin reversed the inhibition of CAP-NO on both the hetero-adhesion between HT-29 and HUVECs and VCAM-1 expression. These data demonstrate that CAP-NO, by directly releasing NO, produces vasorelaxation and interferes with hetero-adhesion of cancer cells to vascular endothelium via down-regulating expression of CAMs. The study highlights the importance of NO in cancer metastatic prevention.

Related: Cytokines

Gialeli Ch, Viola M, Barbouri D, et al.
Dynamic interplay between breast cancer cells and normal endothelium mediates the expression of matrix macromolecules, proteasome activity and functional properties of endothelial cells.
Biochim Biophys Acta. 2014; 1840(8):2549-59 [PubMed] Related Publications
BACKGROUND: Breast cancer-endothelium interactions provide regulatory signals facilitating tumor progression. The endothelial cells have so far been mainly viewed in the context of tumor perfusion and relatively little is known regarding the effects of such paracrine interactions on the expression of extracellular matrix (ECM), proteasome activity and properties of endothelial cells.
METHODS: To address the effects of breast cancer cell (BCC) lines MDA-MB-231 and MCF-7 on the endothelial cells, two cell culture models were utilized; one involves endothelial cell culture in the presence of BCCs-derived conditioned media (CM) and the other co-culture of both cell populations in a Transwell system. Real-time PCR was utilized to evaluate gene expression, an immunofluorescence assay for proteasome activity, and functional assays (migration, adhesion and invasion) and immunofluorescence microscopy for cell integrity and properties.
RESULTS: BCC-CM decreases the cell migration of HUVEC. Adhesion and invasion of BCCs are favored by HUVEC and HUVEC-CM. HA levels and the expression of CD44 and HA synthase-2 by HUVEC are substantially upregulated in both cell culture approaches. Adhesion molecules, ICAM-1 and VCAM-1, are also highly upregulated, whereas MT1-MMP and MMP-2 expressions are significantly downregulated in both culture systems. Notably, the expression and activity of the proteasome β5 subunit are increased, especially by the action of MDA-MB-231-CM on HUVEC.
CONCLUSIONS AND GENERAL SIGNIFICANCE: BCCs significantly alter the expression of matrix macromolecules, proteasome activity and functional properties of endothelial cells. Deep understanding of such paracrine interactions will help to design novel drugs targeting breast cancer at the ECM level. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.

Related: Breast Cancer MMP2

Laureys G, Gerlo S, Spooren A, et al.
β₂-adrenergic agonists modulate TNF-α induced astrocytic inflammatory gene expression and brain inflammatory cell populations.
J Neuroinflammation. 2014; 11:21 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The NF-κB signaling pathway orchestrates many of the intricate aspects of neuroinflammation. Astrocytic β₂-adrenergic receptors have emerged as potential regulators in central nervous system inflammation and are potential targets for pharmacological modulation. The aim of this study was to elucidate the crosstalk between astrocytic β₂-adrenergic receptors and the TNF-α induced inflammatory gene program.
METHODS: Proinflammatory conditions were generated by the administration of TNF-α. Genes that are susceptible to astrocytic crosstalk between β₂-adrenergic receptors (stimulated by clenbuterol) and TNF-α were identified by qPCR-macroarray-based gene expression analysis in a human 1321 N1 astrocytoma cell line. Transcriptional patterns of the identified genes in vitro were validated by RT-PCR on the 1321 N1 cell line as well as on primary rat astrocytes. In vivo expression patterns were examined by intracerebroventricular administration of clenbuterol and/or TNF-α in rats. To examine the impact on the inflammatory cell content of the brain we performed extensive FACS analysis of rat brain immune cells after intracerebroventricular clenbuterol and/or TNF-α administration.
RESULTS: Parallel transcriptional patterns in vivo and in vitro confirmed the relevance of astrocytic β₂-adrenergic receptors as modulators of brain inflammatory responses. Importantly, we observed pronounced effects of β2-adrenergic receptor agonists and TNF-α on IL-6, CXCL2, CXCL3, VCAM1, and ICAM1 expression, suggesting a role in inflammatory brain cell homeostasis. Extensive FACS-analysis of inflammatory cell content in the brain demonstrated that clenbuterol/TNF-α co-administration skewed the T cell population towards a double negative phenotype and induced a shift in the myeloid brain cell population towards a neutrophilic predominance.
CONCLUSIONS: Our results show that astrocytic β₂-adrenergic receptors are potent regulators of astrocytic TNF-α-activated genes in vitro and in vivo, and ultimately modulate the molecular network involved in the homeostasis of inflammatory cells in the central nervous system. Astrocytic β₂-adrenergic receptors and their downstream signaling pathway may serve as potential targets to modulate neuroinflammatory responses.

Related: Cytokines TNF

Matsui T, Higashimoto Y, Yamagishi S
Laminin receptor mediates anti-inflammatory and anti-thrombogenic effects of pigment epithelium-derived factor in myeloma cells.
Biochem Biophys Res Commun. 2014; 443(3):847-51 [PubMed] Related Publications
Pigment epithelium-derived factor (PEDF) has anti-inflammatory and anti-thrombogenic properties both in cell culture and animal models. Although adipose triglyceride lipase (ATGL) and laminin receptor (LR) are two putative receptors for PEDF, which receptor mainly mediates the beneficial effects of PEDF is largely unknown. In this study, we addressed the issue. siRNA raised against LR (siLR) and siATGL transfection dramatically decreased LR and ATGL levels in human cultured myeloma cells, respectively. Ten nM PEDF significantly reduced vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) mRNA levels in siCon- or siATGL-transfected myeloma cells, whereas PEDF increased rather than decreased these gene expressions in siLR-transfected cells. Neutralizing antibody directed against LR (LR-Ab) or LR antagonist actually bound to LR and reduced mRNA levels of VEGF, MCP-1, ICAM-1 and PAI-1 in myeloma cells. Further, pre-treatment of LR-Ab or LR antagonist suppressed the binding of PEDF to LR and resultantly blocked the effects of PEDF in myeloma cells. In addition, high concentration of LR agonist mimicked the actions of PEDF on these gene expressions in myeloma cells. This study indicates that PEDF causes anti-angiogenic, anti-inflammatory and anti-thrombogenic reactions in myeloma cells through the interaction with LR. Target domain of LR agonist and antagonist might be involved in the PEDF-signaling to gene suppression in myeloma cells.

Related: Myeloma Myeloma - Molecular Biology VEGFA

Joo YN, Eun SY, Park SW, et al.
Honokiol inhibits U87MG human glioblastoma cell invasion through endothelial cells by regulating membrane permeability and the epithelial-mesenchymal transition.
Int J Oncol. 2014; 44(1):187-94 [PubMed] Related Publications
Glioblastoma is one of the most lethal and prevalent malignant human brain tumors, with aggressive proliferation and highly invasive properties. There is still no effective cure for patients with glioblastoma. Honokiol, derived from Magnolia officinalis, can cross the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), making it a strong candidate for an effective drug for the treatment of brain tumors, including glioblastoma. In our previous study, we demonstrated that honokiol effectively induced apoptotic cell death in glioblastoma. Metastasis poses the largest problem to cancer treatment and is the primary cause of death in cancer patients. Thus, in this study, we investigated the effect of honokiol on the cell invasion process of U87MG human glioblastoma cells through brain microvascular endothelial cells (BMECs) and its possible mechanisms. Honokiol dose-dependently inhibited TNF-α-induced VCAM-1 expression in BMECs and adhesion of U87MG to BMECs. Moreover, honokiol effectively blocked U87MG invasion through BMEC-Matrigel-coated transwell membranes. Increased phosphorylation of VE-cadherin and membrane permeability by TNF-α were suppressed by honokiol in BMECs. Furthermore, we investigated the effect of honokiol on the epithelial-mesenchymal transition (EMT) in U87MG cells. Honokiol reduced the expression levels of Snail, N-cadherin and β-catenin, which are mesenchymal markers, but increased E-cadherin, an epithelial marker. In conclusion, these results suggest that honokiol inhibits metastasis by targeting the interaction between U87MG and BMECs, regulating the adhesion of U87MG to BMECs by inhibiting VCAM-1, and regulating the invasion of U87MG through BMECs by reducing membrane permeability and EMT processes of U87MG cells.

Related: Apoptosis

Hu Y, Cheng P, Ma JC, et al.
Platelet-derived growth factor BB mediates the glioma-induced migration of bone marrow-derived mesenchymal stem cells by promoting the expression of vascular cell adhesion molecule-1 through the PI3K, P38 MAPK and NF-κB pathways.
Oncol Rep. 2013; 30(6):2755-64 [PubMed] Related Publications
Platelet-derived growth factor BB (PDGFBB) has been shown to activate the migration of bone marrow-derived mesenchymal stem cells (BM-MSCs), and to contribute to mediating the tropism of BM-MSCs towards gliomas. However, the exact mechanism of this migratory behavior remains to be elucidated. The present study investigated the role of vascular cell adhesion molecule-1 (VCAM-1) in the PDGFBB-induced migration of BM-MSCs, the effect of PDGFBB on VCAM-1 expression of BM-MSCs and related signaling pathways involved in this process. Rat BM-MSCs were isolated and cultured by their characteristics of adherence to plastics. The concentrations of PDGFBB in the conditioned medium of C6 and U87 cells were measured using the ELISA method. In vitro migration assays using a VCAM-1 blocking antibody were performed to evaluate the role of VCAM-1 in PDGFBB-induced migration of BM-MSCs. The effect of rat recombinant PDGFBB on VCAM-1 expression of BM-MSCs was studied by RT-PCR and western blotting. LY294002, SB203580, PD98059, SP600125 and BAY11-7082 were used to explore the role of PI3K, p38 MAPK, MEK, JNK and NF-κB in the related intracellular signal transduction of PDGFBB stimulation on VCAM-1 expression of BM-MSCs. The data demonstrated that the neutralization of VCAM-1 inhibited the migration of BM-MSCs induced by PDGFBB. Additionally, PDGFBB stimulation increased VCAM-1 expression of BM-MSCs, which could be inhibited by LY294002, SB203580 and BAY11-7082. It is reasonable to conclude that PDGFBB significantly enhanced the expression of VCAM-1 in BM-MSCs, which facilitated the migration of BM-MSCs towards PDGFBB. PI3K, p38 MAPK and NF-κB were involved in the signal transduction of this process.

Related: PDGFB gene Signal Transduction

Zheng Y, Yang W, Aldape K, et al.
Epidermal growth factor (EGF)-enhanced vascular cell adhesion molecule-1 (VCAM-1) expression promotes macrophage and glioblastoma cell interaction and tumor cell invasion.
J Biol Chem. 2013; 288(44):31488-95 [PubMed] Free Access to Full Article Related Publications
Activated EGF receptor (EGFR) signaling plays an instrumental role in glioblastoma (GBM) progression. However, how EGFR activation regulates the tumor microenvironment to promote GBM cell invasion remains to be clarified. Here, we demonstrate that the levels of EGFR activation in tumor cells correlated with the levels of macrophage infiltration in human GBM specimens. This was supported by our observation that EGFR activation enhanced the interaction between macrophages and GBM cells. In addition, EGF treatment induced up-regulation of vascular cell adhesion molecule-1 (VCAM-1) expression in a PKCε- and NF-κB-dependent manner. Depletion of VCAM-1 interrupted the binding of macrophages to GBM cells and inhibited EGF-induced and macrophage-promoted GBM cell invasion. These results demonstrate an instrumental role for EGF-induced up-regulation of VCAM-1 expression in EGFR activation-promoted macrophage-tumor cell interaction and tumor cell invasion and indicate that VCAM-1 is a potential molecular target for improving cancer therapy.

Related: EGFR

Scalici JM, Thomas S, Harrer C, et al.
Imaging VCAM-1 as an indicator of treatment efficacy in metastatic ovarian cancer.
J Nucl Med. 2013; 54(11):1883-9 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: The inability to successfully treat women with ovarian cancer is due in large part to the advanced stage of disease at diagnosis, the development of platinum resistance, and the lack of sensitive methods to monitor tumor progression and response to treatment. Vascular cell adhesion molecule-1 (VCAM-1) is expressed on the mesothelium of ovarian cancer patients. We investigated VCAM-1 expression as a marker of peritoneal metastasis and tumor response to platinum-based chemotherapy.
METHODS: Peritoneal or omental biopsies obtained from women diagnosed with stage I, stage II, or stage III/IV ovarian cancer were evaluated by immunohistochemistry. The effects of carboplatin on mesothelial VCAM-1 expression were determined in cultured cells by Western blot. Radiolabeled VCAM-1-specific peptide imaging probes and SPECT were used in a mouse model of ovarian cancer peritoneal metastasis to identify VCAM-1 as a viable imaging target.
RESULTS: VCAM-1 expression correlated with tumor stage. All specimens from stage I patients were negative, whereas 29% of stage II patients and 73% of stage III/IV patients were positive. Although most women with advanced stage disease expressed VCAM-1, the incidence of expression was reduced among women who received neoadjuvant chemotherapy, suggesting a role for chemotherapy in regulating VCAM-1 expression. Treatment of mesothelial cells in culture with carboplatin resulted in a transient decrease in VCAM-1 expression 4 h after treatment that returned to baseline within 16-24 h. In vivo imaging of VCAM-1 also demonstrated an acute decrease in expression 4 h after carboplatin administration that recovered within 48 h in mice harboring platinum-resistant tumors. Chronic VCAM-1 expression reflected the effect of platinum-based treatment on tumor burden. Specifically, carboplatin treatment of mice with platinum-sensitive tumors showed reduced VCAM-1 expression, which correlated with reduced tumor burden; mice with platinum-resistant tumors retained elevated VCAM-1 expression and tumor burden after treatment.
CONCLUSION: Clinically relevant VCAM-1-specific imaging probes identify VCAM-1 expression as an indicator of ovarian cancer peritoneal metastasis and therapeutic response to platinum-based agents. These observations support testing the utility of VCAM-1 imaging probes to monitor treatment response in ovarian cancer patients, thus providing the potential to improve management of women with this disease.

Related: Ovarian Cancer

Jin H, Lee WS, Yun JW, et al.
Flavonoids from Citrus unshiu Marc. inhibit cancer cell adhesion to endothelial cells by selective inhibition of VCAM-1.
Oncol Rep. 2013; 30(5):2336-42 [PubMed] Related Publications
Citrus fruits have been used as edible fruit and a component of traditional medicine for various diseases including cancer since ancient times. Herein, we investigated the anticancer activity of flavonoids of Citrus unshiu Marc. (FCM) focusing on anti-metastatic effects. We prepared FCM and performed experiments using MDA-MB-231 human breast cancer cells. FCM inhibited TNF-induced cancer cell adhesion to human umbilical vein endothelial cells (HUVECs) without showing any toxicity. FCM inhibited the expression of VCAM-1, but not of ICAM-1, on MDA-MB-231 cells as well as HUVECs. FCM inhibited protein kinase C (PKC) phosphorylation, but not Akt phosphorylation. FCM also inhibited cancer cell invasion in a dose-dependent manner, but not MMP-9 expression. In conclusion, this study suggested that FCM inhibits TNF-induced cancer cell adhesion to HUVECs by inhibiting VCAM-1 through inhibition of PKC, providing evidence that FCM have anti-metastatic activity by inhibiting adhesion molecules and invasion on human breast cancer cells.

Related: Breast Cancer

Boerkamp KM, van der Kooij M, van Steenbeek FG, et al.
Gene expression profiling of histiocytic sarcomas in a canine model: the predisposed flatcoated retriever dog.
PLoS One. 2013; 8(8):e71094 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The determination of altered expression of genes in specific tumor types and their effect upon cellular processes may create insight in tumorigenesis and help to design better treatments. The Flatcoated retriever is a dog breed with an exceptionally high incidence of histiocytic sarcomas. The breed develops two distinct entities of histiocytic neoplasia, a soft tissue form and a visceral form. Gene expression studies of these tumors have value for comparable human diseases such as histiocytic/dendritic cell sarcoma for which knowledge is difficult to accrue due to their rare occurrence. In addition, such studies may help in the search for genetic aberrations underlying the genetic predisposition in this dog breed.
METHODS: Microarray analysis and pathway analyses were performed on fresh-frozen tissues obtained from Flatcoated retrievers with localized, soft tissue histiocytic sarcomas (STHS) and disseminated, visceral histiocytic sarcomas (VHS) and on normal canine spleens from various breeds. Expression differences of nine genes were validated with quantitative real-time PCR (qPCR) analyses.
RESULTS: QPCR analyses identified the significantly altered expression of nine genes; PPBP, SpiC, VCAM1, ENPEP, ITGAD (down-regulated), and GTSF1, Col3a1, CD90 and LUM (up-regulated) in the comparison of both the soft tissue and the visceral form with healthy spleen. DAVID pathway analyses revealed 24 pathways that were significantly involved in the development of HS in general, most of which were involved in the DNA repair and replication process.
CONCLUSIONS: This study identified altered expression of nine genes not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Exploration of the downside effect of canine inbreeding strategies for the study of similar sarcomas in humans might also lead to the identification of genes related to these rare malignancies in the human.

Sales MF, Sóter MO, Candido AL, et al.
Correlation between plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G polymorphism and metabolic/proinflammatory factors in polycystic ovary syndrome.
Gynecol Endocrinol. 2013; 29(10):936-9 [PubMed] Related Publications
Polycystic Ovary Syndrome (PCOS) is the most common cause of subfertility associated to metabolic disorders. The aim of this study was to correlate metabolic and proinflammatory factors in women with PCOS. The frequency of Plasminogen Activator Inhibitor-1 (PAI-1) promoter 4 G/5 G polymorphism was also compared to healthy controls. We evaluated 79 PCOS and 79 healthy women. PAI-1 levels are positively correlated with proinflammatory factors in PCOS group. 4 G allele in PAI-1 gene was more frequent in PCOS and the 4G/4 G genotype was associated with increased PAI-1 levels. A correlation between insulin resistance and proinflammatory and overweight was also observed. C-reactive protein, serum levels of vascular cell adhesion molecule-1 (sVCAM-1), Lipid Accumulation Product (LAP) and vitamin D are good tools to evaluated factors associated to cardiovascular risk in women with PCOS.

Related: Polymorphisms

Mulrooney DA, Ness KK, Huang S, et al.
Pilot study of vascular health in survivors of osteosarcoma.
Pediatr Blood Cancer. 2013; 60(10):1703-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cardiovascular-related toxicities have been reported among survivors of osteosarcoma.
METHODS: Fasting blood samples from 24 osteosarcoma survivors were analyzed for high-sensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, high-density lipoprotein (HDL), apolipoprotein-ß, lipoprotein (a), fibrinogen, circulating endothelial cells (CECs), and surface expression of vascular cell adhesion molecule-1 (VCAM-1). Values were compared to subjects in the natural history Coronary Artery Risk Development in Young Adults (CARDIA) cohort study except for CECs and VCAM-1 expression, which were compared to controls studied at the University of Minnesota Lillehei clinical trials unit.
PROCEDURE: Survivors (54.2% male), median age 18 years (9-32) at diagnosis, 36.5 years (20-56) at evaluation were treated with a variety of chemotherapeutic exposures, all but one were exposed to doxorubicin (median dose 450 mg/m(2) ; range: 90-645 mg/m(2)), 14 (58.3%) received cisplatin, and 3 (12.5%) were exposed to carboplatin. Two survivors (8.3%) received radiation therapy for disease relapse. Compared to CARDIA subjects, mean hsCRP (3.0 mg/L ± 2.0 vs. 1.6 ± 2.3), triglycerides (151 mg/dl ± 81.7 vs. 95.4 ± 101.3), lipoprotein (a) (34.9 mg/dl ± 17.7 vs. 13.8 ± 22.0), and fibrinogen (315.0 mg/dl ± 49.3 vs. 252.4 ± 61.7) were significantly elevated. The number of CECs (0.47 cells/ml ± 2.5 vs. 0.92 ± 2.5) did not differ while surface expression of VCAM-1 (86.4% ± 34.0 vs. 42.1 ± 33.8) was significantly elevated compared to controls.
CONCLUSIONS: Among survivors of osteosarcoma, assessed a median of 14 years from diagnosis, there is evidence of vascular inflammation, dyslipidemia, and early atherogenesis.

Related: Osteosarcoma

Li JY, Zhang Y, Zhang WH, et al.
Effects of differential distribution of microvessel density, possibly regulated by miR-374a, on breast cancer prognosis.
Asian Pac J Cancer Prev. 2013; 14(3):1715-20 [PubMed] Related Publications
BACKGROUND: The discovery that microRNAs (miRNAs) regulate proliferation, invasion and metastasis provides a principal molecular basis of tumor heterogeneity. Microvessel distribution is an important characteristic of solid tumors, with significant hypoxia occurring in the center of tumors with low blood flow. The distribution of miR-374a in breast tumors was examined as a factor likely to be important in breast cancer progression.
METHODS: Breast tissue samples from 40 patients with breast cancer were classified into two groups: a highly invasive and metastatic group (HIMG) and a low-invasive and metastatic Group (LIMG). Samples were collected from the center and edge of each tumor. In each group, six specimens were examined by microRNA array, and the remaining 14 specimens were used for real-time RT-qPCR, Western blot and immunohistochemical analyses. Correlation analysis was performed for the miRNAs and target proteins. Follow-up was carried out during 28 months to 68 months after surgery, and survival data were analyzed.
RESULTS: In the LIMG, the relative content of miR-374a was lower in the center of the tumor than at its edge; in the HIMG, it was lower at the edge of the tumor, and miR-374a levels were lower in breast cancer tissues than in normal tissues. There was no difference between VEGF-A and VCAM-1 mRNA levels at the edge and center of the tumor; however, we observed a significant difference between VEGF-A and VCAM-1 protein expression levels in these two regions. There was a negative correlation between miR-374a and target protein levels. The microvessel density (MVD) was lower in the center of the tumor than at its edge in HIMG, but the LIMG vessels were uniformly distributed. There was a significant positive correlation between MVD and the number of lymph node metastases (Pearson correlation, r=0.912, P<0.01). The median follow-up time was 48.5 months. LIMG had higher rate of disease-free survival (100%, P=0.013) and longer median survival time (66 months) than HIMG, which had a lower rate of 75% and shorter median survival time (54 months).
CONCLUSIONS: Our data demonstrated miR-374a to be differentially distributed in breast cancer; VEGF-A and VCAM-1 mRNA had coincident distribution, and the distribution of teh respective proteins was uneven and opposite to that for the miR-374a. These data might explain the differences in the distribution of MVD in breast cancer and variation in breast cancer prognosis.

Related: Breast Cancer VEGFA

Garmy-Susini B, Avraamides CJ, Desgrosellier JS, et al.
PI3Kα activates integrin α4β1 to establish a metastatic niche in lymph nodes.
Proc Natl Acad Sci U S A. 2013; 110(22):9042-7 [PubMed] Free Access to Full Article Related Publications
Lymph nodes are initial sites of tumor metastasis, yet whether the lymph node microenvironment actively promotes tumor metastasis remains unknown. We show here that VEGF-C/PI3Kα-driven remodeling of lymph nodes promotes tumor metastasis by activating integrin α4β1 on lymph node lymphatic endothelium. Activated integrin α4β1 promotes expansion of the lymphatic endothelium in lymph nodes and serves as an adhesive ligand that captures vascular cell adhesion molecule 1 (VCAM-1)(+) metastatic tumor cells, thereby promoting lymph node metastasis. Experimental induction of α4β1 expression in lymph nodes is sufficient to promote tumor cell adhesion to lymphatic endothelium and lymph node metastasis in vivo, whereas genetic or pharmacological blockade of integrin α4β1 or VCAM-1 inhibits it. As lymph node metastases accurately predict poor disease outcome, and integrin α4β1 is a biomarker of lymphatic endothelium in tumor-draining lymph nodes from animals and patients, these results indicate that targeting integrin α4β1 or VCAM to inhibit the interactions of tumor cells with the lymph node microenvironment may be an effective strategy to suppress tumor metastasis.

Miaskowski C, Dodd M, Paul SM, et al.
Lymphatic and angiogenic candidate genes predict the development of secondary lymphedema following breast cancer surgery.
PLoS One. 2013; 8(4):e60164 [PubMed] Free Access to Full Article Related Publications
The purposes of this study were to evaluate for differences in phenotypic and genotypic characteristics in women who did and did not develop lymphedema (LE) following breast cancer treatment. Breast cancer patients completed a number of self-report questionnaires. LE was evaluated using bioimpedance spectroscopy. Genotyping was done using a custom genotyping array. No differences were found between patients with (n = 155) and without LE (n = 387) for the majority of the demographic and clinical characteristics. Patients with LE had a significantly higher body mass index, more advanced disease and a higher number of lymph nodes removed. Genetic associations were identified for four genes (i.e., lymphocyte cytosolic protein 2 (rs315721), neuropilin-2 (rs849530), protein tyrosine kinase (rs158689), vascular cell adhesion molecule 1 (rs3176861)) and three haplotypes (i.e., Forkhead box protein C2 (haplotype A03), neuropilin-2 (haplotype F03), vascular endothelial growth factor-C (haplotype B03)) involved in lymphangiogensis and angiogenesis. These genetic associations suggest a role for a number of lymphatic and angiogenic genes in the development of LE following breast cancer treatment.

Related: Breast Cancer VEGFC

Al-Husein B, Goc A, Somanath PR
Suppression of interactions between prostate tumor cell-surface integrin and endothelial ICAM-1 by simvastatin inhibits micrometastasis.
J Cell Physiol. 2013; 228(11):2139-48 [PubMed] Free Access to Full Article Related Publications
Cancer micrometastasis relies on the ability of cancer cells to secrete angiogenic modulators, to interact with the vascular endothelium, and to overcome the resistance offered by the endothelial-barrier. Being an essential step prior to metastasis, blockage of micrometastasis can have potential applications in cancer therapy and metastasis prevention. Due to poorly known molecular mechanisms leading to micrometastasis, developing therapeutic strategies to target prostate cancer utilizing drugs that block micrometastasis is far from reality. Here, we demonstrate the potential benefits of simvastatin in the inhibition of prostate cancer micrometastasis and reveal the novel molecular mechanisms underlying this process. First, we showed that simvastatin inhibited the ability of human PC3 prostate cancer cells for transendothelial migration in vitro. Second, our data indicated that simvastatin modulates the expression of tumor-derived factors such as angiopoietins and VEGF-A at the mRNA and protein levels by the PC3 cells, thus preventing endothelial-barrier disruption. Third, simvastatin directly activated endothelial cells and enhances endothelial-barrier resistance. Apart from this, our study revealed that simvastatin-mediated effect on PC3 micrometastasis was mediated through inhibition of integrin αv β3 activity and suppression of interaction between prostate cancer cell integrin αv β3 with endothelial ICAM-1.

Related: Angiogenesis and Cancer Prostate Cancer CTNNB1 gene

Vacca M, Murzilli S, Salvatore L, et al.
Neuron-derived orphan receptor 1 promotes proliferation of quiescent hepatocytes.
Gastroenterology. 2013; 144(7):1518-1529.e3 [PubMed] Related Publications
BACKGROUND & AIMS: Studies of the transcriptional networks that regulate nuclear receptor-mediated proliferation of quiescent hepatocytes could lead to new information about liver growth and hepatoprotective strategies.
METHODS: We used quantitative real-time PCR to analyze expression of neuron-derived orphan receptor 1 (Nor-1) and its target genes during liver regeneration after hepatectomy in mice, and in hepatocellular carcinoma (HCC) samples from patients. We used adenoviral vectors to express Nor-1 in normal liver (Ad/CMV/V5-Nor-1), or reduce its level with small hairpin RNAs (Ad/BLOCK-iT/Nor-1(small hairpin RNA)) after partial hepatectomy.
RESULTS: Levels of Nor-1 messenger RNA and protein, and transcription of Nor-1 target genes (Ccnd1 and Vcam-1), increased during the late priming and proliferative phases of liver regeneration after partial hepatectomy. Levels of NOR-1 messenger RNA and transcription of its target gene CCND1 and of the NOR-1 subfamily member NUR-77 also increased in human HCC samples compared with paired HCC-free tissue. Ad-Nor-1(small hairpin RNA) reduced the hepatocyte proliferation after hepatectomy. Overexpression of Nor-1 in normal livers of mice induced proliferation of quiescent hepatocytes independently of interleukin-6 and tumor necrosis factor-α signaling. In gene expression profile analysis, Nor-1 altered expression of genes involved in the cell cycle, proliferation, and tumorigenesis.
CONCLUSIONS: In mice, the orphan nuclear receptor Nor-1 activates proliferation of quiescent hepatocytes and is required for hepatocyte proliferation after partial hepatectomy. Nor-1 and its gene targets are also up-regulated in human HCC samples. Nor-1 activates a transcriptional program that induces hepatocyte proliferation independently of inflammatory signaling pathways.

Related: Liver Cancer

Fröhlich C, Klitgaard M, Noer JB, et al.
ADAM12 is expressed in the tumour vasculature and mediates ectodomain shedding of several membrane-anchored endothelial proteins.
Biochem J. 2013; 452(1):97-109 [PubMed] Related Publications
ADAM (a disintegrin and metalloproteinase) 12 is a metalloprotease implicated in cancer progression. ADAM12 can activate membrane-anchored proteins, such as sonic hedgehog, Delta-like 1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding. We screened several membrane-anchored proteins to further dissect the substrate profile of ADAM12-mediated ectodomain shedding, and found shedding of five previously unreported substrates [Kitl1, VE-cadherin (vascular endothelial cadherin), Flk-1 (fetal liver kinase 1), Tie-2, and VCAM-1 (vascular cell adhesion molecule 1)], of which the latter four are specifically expressed by endothelial cells. We also observed that ADAM12 expression was increased in the tumour vasculature of infiltrating ductal carcinoma of the human breast as compared with little to no expression in normal breast tissue vasculature, suggesting a role for ADAM12 in tumour vessels. These results prompted us to further evaluate ADAM12-mediated shedding of two endothelial cell proteins, VE-cadherin and Tie-2. Endogenous ADAM12 expression was very low in cultured endothelial cells, but was significantly increased by cytokine stimulation. In parallel, the shed form of VE-cadherin was elevated in such cytokine-stimulated endothelial cells, and ADAM12 siRNA (small interfering RNA) knockdown reduced cytokine-induced shedding of VE-cadherin. In conclusion, the results of the present study demonstrate a role for ADAM12 in ectodomain shedding of several membrane-anchored endothelial proteins. We speculate that this process may have importance in tumour neovascularization or/and tumour cell extravasation.

Related: Breast Cancer Angiogenesis and Cancer

Liu SQ, Su YJ, Qin MB, et al.
Sphingosine kinase 1 promotes tumor progression and confers malignancy phenotypes of colon cancer by regulating the focal adhesion kinase pathway and adhesion molecules.
Int J Oncol. 2013; 42(2):617-26 [PubMed] Related Publications
Studies suggest a tumor-promoting function of sphingosine kinase 1 (SphK1) in some types of human tumors, however, its effect on colon cancer is still unclear. The aims of this study were to investigate the roles of SphK1 in the progression and tumor cell phenotypic changes in colon cancer. Moreover, the focal adhesion kinase (FAK) pathway and the expression of intercellular adhesion molecule‑1 (ICAM‑1) and vascular cell adhesion molecule‑1 (VCAM‑1) were detected to explore the mechanisms of SphK1 action. In this study, the expression of SphK1, FAK and phospho-FAK (p-FAK) was analyzed in 66 surgical specimens of primary colon cancer and matched adjacent normal tissues by immunohistochemistry and western blotting. In addition, N,N-dimethylsphingosine (DMS), SphK1 DNA and shRNA transfection were used to regulate the expression and activity of SphK1 in the LOVO colon cancer cell line. Tumor cell phenotypic changes were analyzed by cell viability, invasion and apoptosis assays. Results showed that the expression of SphK1, FAK and p-FAK in colon cancer tissues were significantly stronger compared to those in matched normal tissues. There was a close correlation between the expression of SphK1 and FAK or p-FAK and the co-expression of SphK1, FAK and p-FAK significantly associated with histological grade, Dukes' stage, lymph node metastasis and distant metastasis. Overexpression of SphK1 after DNA transfection enhanced tumor cell viability and invasiveness, but suppressed cell apoptosis. In contrast, suppression of SphK1 by DMS and shRNA reduced tumor cell viability and invasiveness, but promoted cell apoptosis. The expression of FAK, p-FAK, ICAM-1 and VCAM-1 in LOVO cells were increased with the overexpression of SphK1 but decreased with the suppression of SphK1. These findings indicate that SphK1 regulates tumor cell proliferation, apoptosis and invasion, which ultimately contributes to tumor progression and malignancy phenotype in colon cancer. FAK pathway, ICAM-1 and VCAM-1 may play critical roles in this SphK1‑mediated effect.

Related: Apoptosis

Sulicka J, Surdacki A, Mikołajczyk T, et al.
Elevated markers of inflammation and endothelial activation and increased counts of intermediate monocytes in adult survivors of childhood acute lymphoblastic leukemia.
Immunobiology. 2013; 218(5):810-6 [PubMed] Related Publications
BACKGROUND: Adult survivors of childhood malignancy are prone to accelerated atherogenesis and late cardiovascular complications. Plaque formation is initiated by recruitment of monocytes and T-cells into the intima, mediated by adhesion molecules and chemokines expressed by activated endothelial cells.
AIM: To assess markers of inflammatory activity, endothelial activation as well as monocyte heterogeneity in adult survivors of childhood acute lymphoblastic leukemia (ALL) who had been treated with chemotherapy without cranial irradiation.
METHODS AND RESULTS: We studied 27 (age: 18-28 years) healthy survivors of childhood ALL and 20 controls (age: 20-31 years). Flow cytometry was used to identify monocyte subsets: classical CD14(++)CD16(-), intermediate CD14(++)CD16(+) and nonclassical CD14(+)CD16(++) monocytes which were further characterized by their expression of HLA-DR and β2-integrins CD11b/CD18 and CD11c/CD18. In ALL survivors we found increased levels of pentraxin-3 (median [interquartile range]: 0.63 [0.36-0.94] vs. 0.40 [0.32-0.57] ng/ml; p = 0.03), soluble vascular cell adhesion molecule-1 (687 [597-761] vs. 558 [534-702]ng/ml; p = 0.02), osteoprotegerin (mean ± SD: 5.24 ± 1.00 vs. 4.42 ± 1.34 pmol/l; p = 0.02) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (107.0 ± 23.6 vs. 89.5 ± 18.9 pg/ml; p = 0.01), whereas C-reactive protein, interleukin 6 and 18, TNF-α, monocyte chemotactic protein-1 and soluble intercellular adhesion molecule-1 were unchanged. Former ALL patients exhibited elevated counts of intermediate monocytes (6.3 ± 4.0 vs. 4.3 ± 1.5% of blood monocytes; p = 0.03). CD11b/CD18 and CD11c/CD18 expression on intermediate monocytes tended to be higher in ALL survivors (1917 ± 993 vs. 1396 ± 673 MFI [median fluorescence intensity]; p = 0.06 and 3883 ± 1445 vs. 3185 ± 645 MFI; p = 0.05, respectively).
CONCLUSION: Our findings suggest chronic inflammatory activation and immune dysregulation in adult survivors of childhood ALL, which can translate into late cardiovascular morbidity.

Related: Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology

Xishan Z, Xinna Z, Baoxin H, Jun R
Impaired immunomodulatory function of chronic myeloid leukemia cancer stem cells and the possible mechanism involved in it.
Cancer Immunol Immunother. 2013; 62(4):689-703 [PubMed] Related Publications
BACKGROUND: Cancer stem cells (CSCs) are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Development of specific therapies targeted at CSCs holds hope for the improvement of survival and quality of life of cancer patients, especially for sufferers of metastatic disease. This is particularly true in chronic myeloid leukemia (CML).
METHODS: In this study, we isolated fetal liver kinase-1-positive (Flk1(+)) cells carrying the BCR/ABL fusion gene from the bone marrow of Philadelphia chromosome-positive (Ph(+)) patients with stem cells property. We examined their biological characteristics as well as immunological function and further detected the possible molecular mechanism involved in the leukemia genesis.
RESULTS: We showed that CML patient-derived Flk1(+)CD31(-)CD34(-) MSCs had normal morphology, phenotype and karyotype but appeared impaired immunomodulatory function. The capacity of Flk1(+)CD31(-)CD34(-) MSCs from CML patients to inhibit T lymphocyte activation and proliferation was impaired in vitro. CML patient-derived MSCs have dampening immunomodulatory functions, suggesting that the dysregulation of hematopoiesis and immune response might originate from MSCs rather than HSCs. These Ph(+) putative CML hemangioblast upregulated TGF-β1 and resultantly activated matrix metalloproteinase-9 (MMP-9) to enhance s-KitL and s-ICAM-1 secretion, which activated c-kit(+) HSCs from the quiescent state to proliferative state. Further studies showed that phosphatidylinositol-3 kinase (PI3K)/Akt/nuclear factor (NF)-κB signaling pathway was involved in CML pathogenesis.
CONCLUSIONS: Flk1(+)CD31(-)CD34(-) MSCs that express BCR/ABL leukemia oncogene are CSCs of CML and they play a critical role in the progression of CML through PI3K/Akt/NF-κB/MMP-9/s-ICAM-1/s-KitL signaling pathway beyond HSCs.

Related: Apoptosis ABL1 Chronic Myeloid Leukemia (CML) CML - Molecular Biology MMP9: matrix metallopeptidase 9 AKT1 Signal Transduction TGFB1

Uchibori R, Tsukahara T, Mizuguchi H, et al.
NF-κB activity regulates mesenchymal stem cell accumulation at tumor sites.
Cancer Res. 2013; 73(1):364-72 [PubMed] Related Publications
Mesenchymal stem cells (MSC) accumulate at tumor sites when injected into tumor-bearing mice, perhaps offering cellular vectors for cancer-targeted gene therapy. However, the molecular mechanisms involved in MSC targeting the tumors are presently little understood. We focused on MSC-endothelial cell (EC) adhesion following TNF-α stimulation in an attempt to elucidate these mechanisms. Interestingly, stimulation of MSCs with TNF-α enhanced the adhesion of MSCs to endothelial cells in vitro. This adhesion was partially inhibited by blocking antibodies against vascular cell adhesion molecule-1 (VCAM-1) and very late antigen-4 (VLA-4). It is well known that TNF-α induces VCAM-1 expression via the NF-κB signaling pathway. Parthenolide has an anti-inflammatory activity and suppressed NF-κB activity by inhibition of IκBα phosphorylation after TNF-α stimulation and strongly inhibited TNF-α-induced VCAM-1 expression on MSCs. In vivo imaging using luciferase-expressing MSCs revealed that the bioluminescent signal gradually increased at tumor sites in mice injected with untreated MSCs. In contrast, we observed very weak signals at tumor sites in mice injected with parthenolide-treated MSCs. Our results suggest that NF-κB activity regulates MSC accumulation at tumors, by inducing VCAM-1 and thereby its interaction with tumor vessel endothelial cells. These findings have implications for the ongoing development of efficient MSC-based gene therapies for cancer treatment.

Huang J, Deng Q, Wang Q, et al.
Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma.
Nat Genet. 2012; 44(10):1117-21 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and shows a propensity to metastasize and infiltrate adjacent and more distant tissues. HCC is associated with multiple risk factors, including hepatitis B virus (HBV) infection, which is especially prevalent in China. Here, we used exome sequencing to identify somatic mutations in ten HBV-positive individuals with HCC with portal vein tumor thromboses (PVTTs), intrahepatic metastases. Both C:G>A:T and T:A>A:T transversions were frequently found among the 331 non-silent mutations. Notably, ARID1A, which encodes a component of the SWI/SNF chromatin remodeling complex, was mutated in 14 of 110 (13%) HBV-associated HCC specimens. We used RNA interference to assess the roles of 91 of the confirmed mutated genes in cellular survival. The results suggest that seven of these genes, including VCAM1 and CDK14, may confer growth and infiltration capacity to HCC cells. This study provides a view of the landscape of somatic mutations that may be implicated in advanced HCC.

Related: Chromosome X Liver Cancer ARID1A gene

Jeong JJ, Lee JH, Chang KC, Kim HJ
Honokiol exerts an anticancer effect in T98G human glioblastoma cells through the induction of apoptosis and the regulation of adhesion molecules.
Int J Oncol. 2012; 41(4):1358-64 [PubMed] Related Publications
Glioblastoma is one of the most lethal and common malignant human brain tumors, with aggressive proliferation and highly invasive properties. Honokiol derived from Magnolia officinalis is able to cross the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), suggesting a strong possibility that it could be an effective drug for the treatment of brain tumors, including glioblastoma. Thus, we investigated the effects of honokiol on the expression of adhesion molecules in TNF-α-stimulated endothelial cells, and cancer growth and invasion were determined in T98G human glioblastoma cells. Honokiol dose-dependently inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) stimulated with TNF-α for 6 h. Pretreatment with honokiol significantly reduced the adhesion of T98G cells to HUVECs. Moreover, honokiol inhibited the invasion of T98G cells, suggesting that honokiol has an anti-metastatic effect. In addition, honokiol increased the cytotoxicity of T98G cells in a dose- and time-dependent manner as assayed by MTT. TUNEL assay showed that honokiol significantly induced apoptosis in T98G cells at doses of 10 µM or more. The induction of apoptotic cell death was mediated by the downregulation of the anti-apoptotic protein Bcl-2 and the upregulation of the pro-apoptotic protein Bax. Taken together, the results of this study suggest that honokiol exerts an anticancer effect by preventing metastasis and inducing apoptotic cell death of brain tumor cells.

Related: Apoptosis TNF

Astarci E, Sade A, Cimen I, et al.
The NF-κB target genes ICAM-1 and VCAM-1 are differentially regulated during spontaneous differentiation of Caco-2 cells.
FEBS J. 2012; 279(16):2966-86 [PubMed] Related Publications
Intestinal epithelial differentiation entails the formation of highly specialized cells with specific absorptive, secretory, digestive and immune functions. Cell-cell and cell-microenvironment interactions appear to be crucial in determining the outcome of the differentiation process. Using the Caco-2 cell line, which undergoes spontaneous re-differentiation when grown past confluency, we observed a loss of VCAM-1 (vascular cell adhesion molecule 1) mRNA expression, while ICAM-1 (intercellular cell adhesion molecule 1) mRNA expression was seen to increase over the course of differentiation. Protein kinase Cθ (PKCθ) acted downstream of protein kinase Cα (PKCα) to inactivate inhibitor of κB (IκB) and activate nuclear factor κB (NF-κB) in undifferentiated cells, and this pathway was inhibited in the differentiated cells. The increase in ICAM-1 mRNA expression in the differentiated cells was due to increased promoter recruitment of C/EBPβ, which transcriptionally up-regulated ICAM-1 mRNA. However, protein expression of ICAM-1 was found to decrease over the course of differentiation due to degradation in the proteasome and lysosome. Immunohistochemistry using tumor samples from colon cancer patients indicated that non-transformed matched normal cells (well-differentiatied) showed no ICAM-1 expression, but the poorly differentiated tumor cells showed higher expression. Functionally, a decrease in adhesion to human umbilical vein endothelial cells was observed in the differentiated Caco-2 cells. Thus, regulation of ICAM-1 and VCAM-1, although both NF-κB target genes, appears to be different over the course of epithelial differentiation in Caco-2 cells.

Nakahata S, Morishita K
CADM1/TSLC1 is a novel cell surface marker for adult T-cell leukemia/lymphoma.
J Clin Exp Hematop. 2012; 52(1):17-22 [PubMed] Related Publications
CADM1/TSLC1 (Cell adhesion molecule 1/Tumor suppressor in lung cancer 1) is a cell adhesion molecule that was originally identified as a tumor suppressor in lung cancer. CADM1/TSLC1 expression is reduced in a variety of cancers via promoter methylation, and this reduction is associated with poor prognosis and enhanced metastatic potential. In contrast, we observed that CADM1/TSLC1 is highly and ectopically expressed in all primary adult T-cell leukemia/lymphoma (ATLL) cells and in most human T-cell leukemia virus type (HTLV)-1-infected T-cell and ATLL cell lines. No expression, however, was detected in CD4+ T cells or in several other non-HTLV-1-infected leukemia cells. Moreover, we identified that high CADM1/TSLC1 expression plays an important role in enhanced cell-cell adhesion to the vascular endothelium, tumor growth and the ability of ATLL cells to infiltrate organs. We developed various antibodies as diagnostic tools to identify CADM1+ ATLL cells. Using flow cytometry, we determined that CADM1/TSLC1 is present on the surface of ATLL cells. The percentage of CD4+CADM1+ cells in the peripheral blood of HTLV-1 carriers and ATLL patients was highly correlated with the DNA copy number of HTLV-1 in lymphocytes. In particular, we identified the soluble form of CADM1/TSLC1 in the peripheral blood of HTLV-1 carriers and ATLL patients. Therefore, measurements of soluble CADM1/TSLC1 serum levels and the detection of CD4+CADM1+ cells in the blood, when combined with standard diagnostic methods, would be useful for identifying and monitoring disease progression in HTLV-1 carriers. Such tests would provide increased accuracy and may aid in early diagnosis and in determining the effects of ATLL treatments.

Related: CADM1

Chaves KC, Peron JP, Chammas R, et al.
Endostatin gene therapy stimulates upregulation of ICAM-1 and VCAM-1 in a metastatic renal cell carcinoma model.
Cancer Gene Ther. 2012; 19(8):558-65 [PubMed] Related Publications
One of the greatest challenges in urological oncology is renal cell carcinoma (RCC), which is the third leading cause of death in genitourinary cancers. RCCs are highly vascularized and respond positively to antiangiogenic therapy. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we examined the potential of ES-based antiangiogenic therapy to activate tumor-associated endothelial cells in metastatic RCC (mRCC). Balb/c-bearing Renca cells were treated with NIH/3T3-LendSN or, as a control, with NIH/3T3-LXSN cells. The T-cell subsets and lymphocyte populations of tumors, mediastinal lymph nodes and the spleen were assessed by flow cytometry. The expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was assessed by real-time PCR, flow cytometry and immunohistochemistry analysis. ES gene therapy led to an increase in the percentage of infiltrating CD4-interferon (IFN)-γ cells (P<0.05), CD8-IFN-γ cells (P<0.01) and CD49b-tumor necrosis factor-α cells (P<0.01). In addition, ES therapy caused an increase at the mRNA level of ICAM-1 (1.4-fold; P<0.01) and VCAM-1 (1.5-fold) (control vs treated group; P<0.001). Through flow cytometry, we found a significant increase in the CD34/ICAM-1 cells (8.1-fold; P<0.001) and CD34/VCAM-1 cells (1.6-fold; P<0.05). ES gene therapy induced a significant increase in both T CD4 and CD8 cells in the lymph nodes and the spleen, suggesting that ES therapy may facilitate cell survival or clonal expansion. CD49b cells were also present in increased quantities in all of these organs. In this study, we demonstrate an antitumor inflammatory effect of ES in an mRCC model, and this effect is mediated by an increase in ICAM-1 and VCAM-1 expression in tumor-associated endothelial cells.

Related: Angiogenesis and Cancer

Berindan-Neagoe I, Chiorean R, Braicu C, et al.
Quantitative mRNA expression of genes involved in angiogenesis, coagulation and inflammation in multiforme glioblastoma tumoral tissue versus peritumoral brain tissue: lack of correlation with clinical data.
Eur Cytokine Netw. 2012; 23(2):45-55 [PubMed] Related Publications
Glioblastoma multiforme is a very aggressive brain tumor. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a process that plays an essential role in cancer development. The evolution of this process depends upon several proangiogenic factors as well as inhibitors of angiogenesis. Coagulation and inflammation also play an important role in tumorigenesis. Their expression is controlled by over- or under-expression of certain genes. The objective of our study was to evaluate the expression, in tissue samples, of a set of six genes involved in tumoral angiogenesis. The study concerned a group of 14 patients with pathologically-confirmed glioblastoma multiforme. Samples of tumoral and peritumoral brain tissue were taken during surgery. We used RT-PCR to evaluate the expression of six genes involved in angiogenesis: VEGF, PDGF, EPCR, TNF, ICAM-1 and CTGF. Gene expression was calculated by comparing the values obtained for the tumoral tissue with those obtained for the peritumoral tissue. Increased transcription of VEGF, PDGF and ICAM-1 genes were observed in glioblastoma tumoral tissues compared with peritumoral brain tissues. Correlations were observed between transcription of the CTGF and TNF genes (rho = 0.54, p-value = 0.05) and PDGF and ICAM-1 genes (rho = 0.54, p-value = 0.05). Under-expression of CTGF, EPCR and TNF genes was observed in glioblastoma tumoral tissue in comparison with peritumoral brain tissue. The association between gene expression and histopathological results (endothelial hyperplasia, coagulation necrosis and ischemic necrosis) was evaluated. No statistically significant associations were observed between gene expression and survival rates.

Related: Angiogenesis and Cancer Tumor Necrosis Factors VEGFA

Alevizos L, Gomatos IP, Smparounis S, et al.
Review of the molecular profile and modern prognostic markers for gastric lymphoma: how do they affect clinical practice?
Can J Surg. 2012; 55(2):117-24 [PubMed] Free Access to Full Article Related Publications
Primary gastric lymphoma is a rare cancer of the stomach with an indeterminate prognosis. Recently, a series of molecular prognostic markers has been introduced to better describe this clinical entity. This review describes the clinical importance of several oncogenes, apoptotic genes and chromosomal mutations in the initiation and progress of primary non-Hodgkin gastric lymphoma and their effect on patient survival. We also outline the prognostic clinical importance of certain cellular adhesion molecules, such as ICAM and PECAM-1, in patients with gastric lymphoma, and we analyze the correlation of these molecules with apoptosis, angiogenesis, tumour growth and metastatic potential. We also focus on the host-immune response and the impact of Helicobacter pylori infection on gastric lymphoma development and progression. Finally, we explore the therapeutic methods currently available for gastric lymphoma, comparing the traditional invasive approach with more recent conservative options, and we stress the importance of the application of novel molecular markers in clinical practice.

Related: CDKN2A Non Hodgkin's Lymphoma Stomach Cancer Gastric Cancer

Sun DZ, Jiao JP, Ju DW, et al.
Tumor interstitial fluid and gastric cancer metastasis: an experimental study to verify the hypothesis of "tumor-phlegm microenvironment".
Chin J Integr Med. 2012; 18(5):350-8 [PubMed] Related Publications
OBJECTIVE: To extract tumor interstitial fluid (TIF) from MKN-45 gastric cancer which is similar to "muddy phlegm" in Chinese medicine and observe influences of MKN-45 tumor interstitial fluid (MKN-45 TIF) intervention on metastasis of gastric cancer and on the expressions of vascular endothelial growth factor (VEGF), kinase insert domain containing receptor (KDR), epithelial-cadherin (E-cad), cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1) and telomerase genes and proteins in primary tumor tissue.
METHODS: An MKN-45 tumor-bearing model was established in 50 nude mice. The modeled animals were equally randomized to 5 groups: the simple tumor-bearing group (model group), the normal saline (NS) via tail vein injection (i.v.) group (NS i.v. group), MKN-45 TIF i.v. group (TIF i.v. group), NS intraperitoneal injection (i.p.) group (NS i.p. group), and MKN-45 TIF i.p. group (TIF i.p. group). The TIF and NS intervention groups received injection (i.p. or i.v.) of MKN-45 TIF or NS twice a week, 0.2 mL at a time. After 8 weeks, the primary tumors were removed, weighed and HE stained to observe tumor metastasis. The primary tumor tissues were analyzed by immunohistochemistry and real-time quantitative PCR to detect expressions of VEGF, KDR, E-cad, COX-2, ICAM-1, and telomerase genes and proteins in different groups.
RESULTS: There were significant differences in tumor weight between TIF intervention groups and the model and NS intervention groups. Tumor metastasis was observed in all 5 groups, but the tumor metastasis rate in TIF intervention groups was significantly higher than those in the model and NS intervention groups. The gene and protein expressions of gastric cancer-related factors VEGF, KDR, COX-2, ICAM-1 and telomerase were unregulated while the gene and protein expressions of E-cad were downregulated in TIF intervention groups.
CONCLUSIONS: TIF promotes tumor growth, invasion and metastasis of gastric cancer. These findings provide preliminary experimental clues for verifying the hypothesis of "tumor-phlegm microenvironment".

Related: COX2 (PTGS2) VEGFA


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Cite this page: Cotterill SJ. VCAM1, Cancer Genetics Web: http://www.cancerindex.org/geneweb/VCAM1.htm Accessed: date

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