ABSTRACT
Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with overall poor prognosis. The Ki67 labeling index (LI) has a major prognostic role in localized ACC after complete resection, but its estimates may suffer from considerable intra- and interobserver variability. VAV2 overexpression induced by increased Steroidogenic Factor-1 dosage is an essential factor driving ACC tumor cell invasion. Objective: To assess the prognostic role of VAV2 expression in ACC by investigation of a large cohort of patients. Design, Setting, and Participants: A total of 171 ACC cases (157 primary tumors, six local recurrences, eight metastases) from seven European Network for the Study of Adrenal Tumors centers were studied. Outcome Measurements: H-scores were generated to quantify VAV2 expression. VAV2 expression was divided into two categories: low (H-score, <2) and high (H-score, ≥2). The Ki67 LI retrieved from patients' pathology records was also categorized into low (<20%) and high (≥20%). Clinical and immunohistochemical markers were correlated with progression-free survival (PFS) and overall survival (OS). Results: VAV2 expression and Ki67 LI were significantly correlated with each other and with PFS and OS. Heterogeneity of VAV2 expression inside the same tumor was very low. Combined assessment of VAV2 expression and Ki67 LI improved patient stratification to low-risk and high-risk groups. Conclusion: Combined assessment of Ki67 LI and VAV2 expression improves prognostic prediction in ACC.
Subject(s)
Adrenal Cortex Neoplasms/blood , Adrenal Cortex Neoplasms/mortality , Adrenocortical Carcinoma/blood , Adrenocortical Carcinoma/mortality , Biomarkers, Tumor/blood , Proto-Oncogene Proteins c-vav/metabolism , Adrenal Cortex Neoplasms/therapy , Adrenocortical Carcinoma/therapy , Adult , Aged , Analysis of Variance , Biopsy, Needle , Cohort Studies , Combined Modality Therapy , Disease-Free Survival , Europe , Female , Humans , Immunohistochemistry , Internationality , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Predictive Value of Tests , Prognosis , Proto-Oncogene Proteins c-vav/blood , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: Overexpression of Vav3, a gene involved in signal transduction, promotes invasion and inhibits apoptosis in several cancers. The clinical value of the protein product of this gene, Vav3, in the peripheral blood of gastric cancer patients is unknown. We hypothesised increased serum Vav3 that related to tissue levels and lymph node metastases. In addition, we further explored its clinical value in respect of linked molecules Rac-1, MMP-7 and ICAM-1 Methods: 120 gastric cancer patients who had radical surgery were enrolled. Immunohistochemistry was used to determine the expressions of Vav3, Rac-1, MMP-7 and ICAM-1 in gastric cancer mucosa and normal mucosa. ELISA was used to detect these proteins in peripheral blood of gastric cancer patients and 100 age- and sex-matched healthy controls. RESULTS: Vav3, Rac-1 and MMP-7 (P < 0.001), but not ICAM-1 (P = 0.303) were more highly expressed by cancer tissues than normal gastric mucosa. Serum levels of all molecules were higher than those in healthy subjects (P < 0.001). Levels of Vav3, Rac-1 and MMP-7 decreased 2 weeks postoperatively (all P < 0.001) but there was no change in ICAM-1 (P = 0.192). Similarly, increased levels of Vav3, Rac-1 and MMP-7 were present in patients with lymphatic metastasis than those without (all P < 0.001) but there was no difference in ICAM-1 levels (P = 0.378). There were positive correlations between Vav3 with Rac-1 and MMP-7 in cancer tissues (P < 0.001), and also between Vav3 and Rac-1 in pre-surgery blood (P = 0.003). CONCLUSIONS: Vav3 in peripheral blood may serve as a biomarker for gastric cancer, and to predict the lymphatic metastasis in gastric cancer.
Subject(s)
Lymphatic Metastasis/pathology , Proto-Oncogene Proteins c-vav/blood , Stomach Neoplasms/blood , Stomach Neoplasms/pathology , Case-Control Studies , Female , Humans , Intercellular Adhesion Molecule-1/metabolism , Male , Matrix Metalloproteinase 7/metabolism , Middle Aged , rac1 GTP-Binding Protein/metabolismABSTRACT
Despite numerous developed drugs based on glucose metabolism interventions for treatment of age-related diseases such as diabetes neuropathies (DNs), DNs are still increasing in patients with type 1 or type 2 diabetes (T1D, T2D). We aimed to identify novel candidates in adipose tissue (AT) and pancreas with T2D for targeting to develop new drugs for DNs therapy. AT-T2D displayed 15 (e.g. SYT4 up-regulated and VGF down-regulated) and pancreas-T2D showed 10 (e.g. BAG3 up-regulated, VAV3 and APOA1 down-regulated) highly differentially expressed genes with neuronal functions as compared to control tissues. ELISA was blindly performed to measure proteins of 5 most differentially expressed genes in 41 human subjects. SYT4 protein was upregulated, VAV3 and APOA1 were down-regulated, and BAG3 remained unchanged in 1- Obese and 2- Obese-T2D without insulin, VGF protein was higher in these two groups as well as in group 3- Obese-T2D receiving insulin than 4-lean subjects. Interaction networks analysis of these 5 genes showed several metabolic pathways (e.g. lipid metabolism and insulin signaling). Pancreas is a novel site for APOA1 synthesis. VGF is synthesized in AT and could be considered as good diagnostic, and even prognostic, marker for age-induced diseases obesity and T2D. This study provides new targets for rational drugs development for the therapy of age-related DNs.
