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Mesothelium expression of vascular cell adhesion molecule-1 (VCAM-1) is associated with an unfavorable prognosis in epithelial ovarian cancer (EOC).

ABSTRACT: BACKGROUND:Mesothelium vascular cell adhesion molecule-1 (VCAM-1) expression in the metastatic epithelial ovarian cancer (EOC) microenvironment is induced by tumor and mediates tumor cell invasion. VCAM-1 imaging suggests expression during treatment is an indicator of platinum resistance. Here, we assess the potential prognostic significance of mesothelium VCAM-1 expression and prospectively evaluate whether soluble VCAM-1 (sVCAM-1) is a surrogate for mesothelium expression. METHODS:A retrospective review of EOC patients was performed to evaluate outcomes with mesothelium VCAM-1 expression determined by immunohistochemistry of peritoneum or omentum specimens. A prospective cohort of EOC patients was identified and followed through primary treatment. Serum for sVCAM-1 evaluation, which was performed via enzyme-linked immunosorbent assay, was collected before surgery or neoadjuvant chemotherapy and at each treatment cycle. Peritoneal specimens were obtained during debulking to assess mesothelial VCAM-1 expression. RESULTS:A retrospective review identified 54 advanced-stage EOC patients. Patients expressing mesothelium VCAM-1 had shortened overall survival (44 vs 79 months, P?=?0.035) and progression-free survival (18 vs 67 months, P?=?0.010); the median time to platinum resistance was 36 months for VCAM-1-expressing patients and not yet determined for the VCAM-1-negative group. In our prospective observational cohort, 18 EOC patients completed primary treatment; 3 were negative for mesothelium VCAM-1 expression, and sVCAM-1 did not vary between groups. CONCLUSIONS:Mesothelium VCAM-1 expression is negatively associated with progression-free and overall survival in EOC. This is especially compelling in light of previous data suggesting that persistent VCAM-1 expression during treatment is an indicator of platinum resistance. Our pilot study had insufficient cases to determine whether sVCAM-1 would substitute for mesothelium expression. Cancer 2017;123:977-84. © 2016 American Cancer Society.

SUBMITTER: Scalici JM

PROVIDER: S-EPMC5341143 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Mesothelium expression of vascular cell adhesion molecule-1 (VCAM-1) is associated with an unfavorable prognosis in epithelial ovarian cancer (EOC).

Scalici Jennifer M JM Arapovic Sanja S Saks Erin J EJ Atkins Kristen A KA Petroni Gina G Duska Linda R LR Slack-Davis Jill K JK

Cancer 20161107 6

<h4>Background</h4>Mesothelium vascular cell adhesion molecule-1 (VCAM-1) expression in the metastatic epithelial ovarian cancer (EOC) microenvironment is induced by tumor and mediates tumor cell invasion. VCAM-1 imaging suggests expression during treatment is an indicator of platinum resistance. Here, we assess the potential prognostic significance of mesothelium VCAM-1 expression and prospectively evaluate whether soluble VCAM-1 (sVCAM-1) is a surrogate for mesothelium expression.<h4>Methods</ ...[more]

PMID: 28263384

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Project description:Background Ovarian cancer is the most lethal tumor of the female reproductive system. Establishing a methodology to screen and diagnose ovarian cancer in the early stage is important. Exosomes have been shown to be loaded with tumor-associated molecules. In this study, we compared the proteins loaded in exosomes from the peripheral circulation of epithelial ovarian carcinoma (EOC) patients and controls. Methods Exosomes were purified via ultracentrifugation plus 0.22 µm filtration from the blood of EOC patients and patients with pelvic floor dysfunction (PFD). Tumor tissues and normal ovarian tissues were also obtained. Proteomic analyses of exosomes and tumor/normal ovarian tissues were performed with isobaric tags for relative and absolute quantitation (iTRAQ) and high-performance liquid chromatography/mass spectrometry (HPLC/MS) analyses. The LocDB (http://www.rostlab.org/services/locDB), PANTHER (http://www.pantherdb.org/) and Vesiclepedia databases were used for biological information analysis. Results We identified 408 differentially expressed proteins in exosomes from EOC patients and noncancer controls. Furthermore, we identified 954 differentially expressed proteins from ovarian cancer tissues and normal ovarian tissues. Thirty-five proteins exhibited upregulation in both cancer patient exosomes and cancer tissues. Among these 35 proteins, eight proteins (chloride intracellular channel protein 4, serine/threonine-protein kinase 1, aminoacyl tRNA synthetase complex-interacting multifunctional protein 1, sorting nexin-3, protein FAM49B, fermitin family homolog 3, tubulin beta-3 chain and lactotransferrin) were confirmed in both exosome databases and other studies. Conclusions We isolated exosomes from the peripheral blood of EOC patients and noncancer controls and identified 35 proteins that were upregulated in both EOC patient exosomes and ovarian cancer tissues. Comparisons with the exosome molecular databases and other studies identified eight proteins as potential tumor markers, which might offer new tools for the early diagnosis of ovarian cancer.

Project description:Circulating triglyceride-rich lipoproteins (TGRL) from hypertriglyceridemic subjects exacerbate endothelial inflammation and promote monocyte infiltration into the arterial wall. We have recently reported that TGRL isolated from human blood after a high-fat meal can elicit a pro- or anti-atherogenic state in human aortic endothelial cells (HAEC), defined as up- or down-regulation of VCAM-1 expression in response to tumor necrosis factor alpha (TNF?) stimulation, respectively. A direct correlation was found between subjects categorized at higher risk for cardiovascular disease based upon serum triglycerides and postprandial production of TGRL particles that increased VCAM-1-dependent monocyte adhesion to inflamed endothelium. To establish how TGRL metabolism is linked to VCAM-1 regulation, we examined endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) pathways. Regardless of its atherogenicity, the rate and extent of TGRL internalization and lipid droplet formation by HAEC were uniform. However, pro-atherogenic TGRL exacerbated ER membrane expansion and stress following TNF? stimulation, whereas anti-atherogenic TGRL ameliorated such effects. Inhibition of ER stress with a chemical chaperone 4-phenylbutyric acid decreased TNF?-induced VCAM-1 expression and abrogated TGRL's atherogenic effect. Activation of ER stress sensors PKR-like ER-regulated kinase (PERK) and inositol requiring protein 1? (IRE1?), and downstream effectors including eukaryotic initiation factor-2? (eIF2?), spliced X-box-binding protein 1 (sXBP1) and C/EBP homologous protein (CHOP), directly correlated with the atherogenic activity of an individual's TGRL. Modulation of ER stress sensors also correlated with changes in expression of interferon regulatory factor 1 (IRF-1), a transcription factor of Vcam-1 responsible for regulation of its expression. Moreover, knockdown studies using siRNA defined a causal relationship between the PERK/eIF2?/CHOP pathway and IRF-1-mediated VCAM-1 expression. We conclude that ER stress and the UPR contribute to the regulation of Vcam-1 transcription as a function of the atherogenic nature of TGRL.

Dataset Information

Mesothelium expression of vascular cell adhesion molecule-1 (VCAM-1) is associated with an unfavorable prognosis in epithelial ovarian cancer (EOC).

Publications

Mesothelium expression of vascular cell adhesion molecule-1 (VCAM-1) is associated with an unfavorable prognosis in epithelial ovarian cancer (EOC).

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