Insulin-like growth factor (IGF) binding protein 2 (IGFBP2) was discovered and identified as an IGF system regulator, controlling the distribution, function, and activity of IGFs in the pericellular space. IGFBP2 is a developmentally regulated gene that is highly expressed in embryonic and fetal tissues and markedly decreases after birth. Studies over the last decades have shown that in solid tumors, IGFBP2 is upregulated and promotes several key oncogenic processes, such as epithelial-to-mesenchymal transition, cellular migration, invasion, angiogenesis, stemness, transcriptional activation, and epigenetic programming via signaling that is often independent of IGFs. Growing evidence indicates that aberrant expression of IGFBP2 in cancer acts as a hub of an oncogenic network, integrating multiple cancer signaling pathways and serving as a potential therapeutic target for cancer treatment.

IGFBP2: integrative hub of developmental and oncogenic signaling network.

Background: The aim of this study is to identify serum biomarkers with classification and prognosis utility for astrocytoma, in particular glioblastoma (GBM) Methods: Our previous glioma microarray database was mined to identify genes that encode secreted or membrane-localized proteins Subsequent analysis was done using significant analysis of microarrays, followed by reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemical validation in tumor tissues, ELISA and Western blot validation in sera, and correlation with survival of GBM patients Results: Significant analysis of microarrays identified 31 upregulated and 3 downregulated genes specifically in GBMs RT-qPCR validation on an independent set of samples confirmed the GBM-specific differential expression of several genes, including three upregulated (CALU, CXCL9, and TIMP1) and two downregulated (GPX3 and TIMP3) novel genes With respect to osteopontin (OPN), we show the GBM-specific upregulation by RT-qPCR and immunohistochemical staining of tumor tissues Elevated serum OPN levels in GBM patients were also shown by ELISA and Western blot GBM patients with high serum OPN levels had poorer survival than those with low serum OPN levels (median survival 9 versus 22 months respectively; P = 00001) Further, we also show high serum TIMP1 levels in GBM patients compared with grade II/III patients by ELISA and downregulation of serum GPX3 and TIMP3 proteins in GBMs compared with normal control by Western blot analysis Conclusions: Several novel potential serum biomarkers of GBM are identified and validated High serum OPN level is found as a poor prognostic indicator in GBMs Impact: Identified serum biomarkers may have potential utility in astrocytoma classification and GBM prognosis

https://cebp.aacrjournals.org/content/cebp/19/6/1409.full.pdf

Identification of potential serum biomarkers of glioblastoma: serum osteopontin levels correlate with poor prognosis.

Validated biomarkers for patients suffering from gliomas are urgently needed for standardizing measurements of the effects of treatment in daily clinical practice and trials. Circulating body fluids offer easily accessible sources for such markers. This review highlights various categories of tumor-associated circulating biomarkers identified in blood and cerebrospinal fluid of glioma patients, including circulating tumor cells, exosomes, nucleic acids, proteins, and oncometabolites. The validation and potential clinical utility of these biomarkers is briefly discussed. Although many candidate circulating protein biomarkers were reported, none of these have reached the required validation to be introduced for clinical practice. Recent developments in tracing circulating tumor cells and their derivatives as exosomes and circulating nuclear acids may become more successful in providing useful biomarkers. It is to be expected that current technical developments will contribute to the finding and validation of circulating biomarkers.

/pdf/circulating-glioma-biomarkers-jjocwqw57y.pdf

Circulating glioma biomarkers

Lung cancer is the most frequently occurring cancer in the world and continually leads in mortality among cancers. The overall 5-year survival rate for lung cancer has risen only 4% (from 12% to 16%) over the past 4 decades, and late diagnosis is a major obstacle in improving lung cancer prognosis. Survival of patients undergoing lung resection is greater than 80%, suggesting that early detection and diagnosis of cancers before they become inoperable and lethal will greatly improve mortality. Lung cancer biomarkers can be used for screening, detection, diagnosis, prognosis, prediction, stratification, therapy response monitoring, and so on. This review focuses on noninvasive diagnostic and prognostic biomarkers. For that purpose, our discussion in this review will focus on biological fluid-based biomarkers. The body fluids include blood (serum or plasma), sputum, saliva, BAL, pleural effusion, and VOC. Since it is rich in different cellular and molecular elements and is one of the most convenient and routine clinical procedures, serum or plasma is the main source for the development and validation of many noninvasive biomarkers. In terms of molecular aspects, the most widely validated ones are proteins, some of which are used in the clinical sector, though in limited accessory purposes. We will also discuss the lung cancer (protein) biomarkers in clinical trials and currently in the validation phase with hundreds of samples. After proteins, we will discuss microRNAs, methylated DNA, and circulating tumor cells, which are being vigorously developed and validated as potential lung cancer biomarkers. The main aim of this review is to provide researchers and clinicians with an understanding of the potential noninvasive lung cancer biomarkers in biological fluids that have recently been discovered.

Lung Cancer Biomarkers.

Insulin-like growth factor binding protein-2 (IGFBP-2) is significantly increased in the serum of patients with malignant gliomas. High plasma IGFBP-2 levels are correlated with poor prognosis in glioma patients. However, the exact role of exogenous IGFBP-2 in gliomas is unclear. Using the MTT cell viability assay, cell cycle analysis, and the transwell migration assay, it was demonstrated that IGFBP-2 treatment stimulated proliferation and invasion in U87 and U251 cell lines and primary SU3 glioma cells. Western blot analysis and immunofluorescence staining revealed that IGFBP-2 promoted ERK phosphorylation and nuclear translocation. Moreover, blocking ERK activation using the inhibitor PD98059 markedly reduced the effects of IGFBP-2 in glioma cells. As IGFBP-2 has an integrin-binding domain, the contribution of integrin β1 to these IGFBP-2-mediated processes was examined. Neutralisation or knockdown of the expression of integrin β1 inhibited IGFBP-2-induced ERK activation, cell proliferation, and cell invasion. Significantly, IGFBP-2 induced temozolomide resistance in glioma cells in an integrin β1/ERK-dependent manner. Exogenous IGFBP-2 induces proliferation, invasion, and chemoresistance in glioma cells via integrin β1/ERK signaling, suggesting that targeting this pathway could represent a potential therapeutic strategy for the treatment of gliomas. The identification of this pathway in glioma progression provides insight into the mechanism by which serum IGFBP-2 levels can predict the prognosis of glioma patients.

/pdf/exogenous-igfbp-2-promotes-proliferation-invasion-and-2dqt6gxned.pdf

Exogenous IGFBP-2 promotes proliferation, invasion, and chemoresistance to temozolomide in glioma cells via the integrin β1-ERK pathway.

Insulin-like growth factor binding protein 2 (IGFBP-2) is a malignancy-associated protein measurable in tumors and blood. Increased IGFBP-2 is associated with shortened survival of advanced glioma patients. Thus, we examined plasma IGFBP-2 levels in glioma patients and healthy controls to evaluate its value as a plasma biomarker for glioma. Plasma IGFBP-2 levels in 196 patients with newly diagnosed glioma and 55 healthy controls were analyzed using an IGFBP-2 ELISA kit. Blood was collected before surgery, after two-cycle adjuvant chemotherapy, and at recurrence. Plasma IGFBP-2 levels were correlated with disease-free survival DFS) using Cox regression analyses. We found that preoperative plasma IGFBP-2 levels were significantly higher in high-grade glioma patients n = 43 for grade III glioma; n = 72 for glioblastoma multiforme [GBM]) than in healthy controls n = 55; p < 0.001) and low-grade (grade II) glioma patients n 5 81; p, 0.001). No significant differences in preoperative plasma IGFBP-2 levels were observed between grade III glioma and GBM patients or between grade II glioma patients and healthy controls. After recurrence, plasma IGFBP-2 levels were significantly increased in GBM patients (n = 26; p < 0.001). Preoperative plasma IGFBP-2 levels were significantly correlated with DFS in GBM patients ( hazard ratio, 1.404; 95% confidence interval, 1.078-1.828; p = 0.012). We conclude that preoperative plasma IGFBP-2 levels are significantly higher in high-grade glioma patients than in low-grade glioma patients and healthy subjects, and are significantly correlated with recurrence and DFS in patients with GBM. Longitudinal studies with a larger study population are needed to confirm these findings. Neuro-Oncology 11, 468-476, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00199, January 22, 2009. URL http://neuro-oncology. dukejournals. org; DOI: 10.1215/15228517-2008-114)

/pdf/plasma-igfbp-2-levels-predict-clinical-outcomes-of-patients-1r3rhw0sr1.pdf

Plasma IGFBP-2 levels predict clinical outcomes of patients with high-grade gliomas.

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Plasma IGFBP-2 levels predict clinical outcomes of patients with high-grade gliomas.