Basal Epidermal Growth Factor Research Articles

Identifying predictive biomarkers of CIMAvaxEGF success in non\u2013small cell lung cancer patients

BackgroundImmunosenescence biomarkers and peripheral blood parameters are evaluated separately as possible predictive markers of immunotherapy. Here, we illustrate the use of a causal inference model to identify predictive biomarkers of CIMAvaxEGF success in the treatment of Non–Small Cell Lung Cancer Patients.MethodsData from a controlled clinical trial evaluating the effect of CIMAvax-EGF were analyzed retrospectively, following a causal inference approach. Pre-treatment potential predictive biomarkers included basal serum EGF concentration, peripheral blood parameters and immunosenescence biomarkers. The proportion of CD8 + CD28- T cells, CD4+ and CD8+ T cells, CD4/CD8 ratio and CD19+ B cells. The 33 patients with complete information were included. The predictive causal information (PCI) was calculated for all possible models. The model with a minimum number of predictors, but with high prediction accuracy (PCI > 0.7) was selected. Good, rare and poor responder patients were identified using the predictive probability of treatment success.ResultsThe mean of PCI increased from 0.486, when only one predictor is considered, to 0.98 using the multivariate approach with all predictors. The model considering the proportion of CD4+ T cell, basal Epidermal Growth Factor (EGF) concentration, neutrophil to lymphocyte ratio, Monocytes, and Neutrophils as predictors were selected (PCI > 0.74). Patients predicted as good responders according to the pre-treatment biomarkers values treated with CIMAvax-EGF had a significant higher observed survival compared with the control group (p = 0.03). No difference was observed for bad responders.ConclusionsPeripheral blood parameters and immunosenescence biomarkers together with basal EGF concentration in serum resulted in good predictors of the CIMAvax-EGF success in advanced NSCLC. Future research should explore molecular and genetic profile as biomarkers for CIMAvax-EGF and it combination with immune-checkpoint inhibitors. The study illustrates the application of a new methodology, based on causal inference, to evaluate multivariate pre-treatment predictors. The multivariate approach allows realistic predictions of the clinical benefit of patients and should be introduced in daily clinical practice.

Serum Epidermal Growth Factor is Low in Schizophrenia and Not Affected by Antipsychotics Alone or Combined With Electroconvulsive Therapy.

BackgroundEpidermal growth factor (EGF) is implicated in the pathogenesis of schizophrenia, suggesting possible value as a biomarker for disease severity or treatment response. However, basal EGF levels and changes during treatment are inconsistent across studies. The goal of this study is to compare serum EGF in schizophrenia patients before and after treatment with antipsychotics alone or combined with electroconvulsive therapy (ECT).MethodPatients meeting DSM-IV diagnostic criteria for schizophrenia were recruited from June 2013 to December 2015 (n = 186) and followed up after 8 weeks of treatment with antipsychotics alone (n = 119, drug group) or combined with ECT (n = 67, ECT group). Serum EGF levels were measured by ELISA and compared among patients and 74 healthy control subjects. Psychopathology and clinical effects were assessed using the Positive and Negative Syndrome Scale (PANSS).ResultsBasal serum EGF was significantly lower in the entire patient cohort compared to healthy controls (P < 0.05). Repeated-measures ANOVA showed no main effect of time (F = 1.273; P = 0.261), time × group interaction (F = 1.228; P = 0.270), main effect of clinical response (F = 0.191; P = 0.663), or group × clinical interaction (F = 1.765; P = 0.186) on serum EGF. Serum EGF levels did not change significantly following antipsychotic drug or combined therapy (P > 0.05). Additionally, neither basal EGF nor EGF change was associated with the clinical response to drug or combined treatment (P > 0.05). However, baseline serum EGF was weakly associated with PANSS positive score (pretreatment: r = 0.206, posttreatment: r = 0.201) and general symptom score (pretreatment: r = −0.244). Serum EGF was also associated with duration of illness (pretreatment: r = 0.285, posttreatment: r = −0.231).ConclusionsSerum EGF concentration is low in schizophrenia but is unchanged following treatment with antipsychotics alone or combined with ECT, regardless of clinical response. Thus, serum EGF is not a surrogate biomarker for treatment response and is unlikely to be involved in the therapeutic mechanisms of antipsychotics or ECT.

The protein tyrosine phosphatase DEP-1/PTPRJ promotes breast cancer cell invasion and metastasis.

DEP-1/PTPRJ is a receptor-like protein tyrosine phosphatase mainly known for its antiproliferative and tumor-suppressive functions. Many identified substrates are growth factor receptors, and DEP-1 is deleted and/or mutated in human cancers including that of the breast. However, DEP-1 was also identified as a promoter of Src activation and proinvasive functions in the endothelium, suggesting it could perhaps mediate breast cancer invasiveness that is likewise driven by Src family kinases. We show here that DEP-1 expression was greater in highly invasive breast cancer cells (MDA-MB-231, Hs578T, BT-549) than in the less invasive or untransformed cell lines tested (MCF-7, T47D, SK-BR3 and MCF10A). DEP-1 silencing experiments in invasive cells demonstrated that moderately expressed and catalytically active DEP-1 was required, in collaboration with basal epidermal growth factor receptor activity, for Src activation and the phosphorylation of its substrate Cortactin, and for their colocalization at the cell's leading edge. This correlated with an increased number of cell protrusions, and an enhanced capacity of the cells to migrate and invade. Similarly, moderate overexpression of DEP-1 in the low-invasive cells resulted in the promotion of their invasiveness in an Src-dependent manner. Consistent with these data, the expression of endogenous DEP-1 was elevated in a bone metastatic cell line derived from MDA-MB-231 cells, and promoted increased Src Y418 and Cortactin Y421 phosphorylation, as well as pro-MMP9 secretion and Matrigel invasion. Importantly, the silencing of DEP-1 in MDA-MB-231 cells greatly decreased their ability to metastasize, despite having no effect on tumor growth or angiogenesis. Hence, we found that moderate expression of DEP-1 was associated with the increased relapse and decreased survival of breast cancer patients. These results therefore identify a new and unsuspected role for DEP-1 as a mediator of an invasive cell program implicating Src activation and the promotion of breast cancer progression.

Mechanisms of Resistance to Structurally Diverse Antiestrogens Differ under Premenopausal and Postmenopausal Conditions: Evidence from in Vitro Breast Cancer Cell Models

This study questioned whether the mechanisms of resistance to antiestrogens differ when acquired under premenopausal (Pre-M) vs. postmenopausal (PM) conditions and whether structurally diverse antiestrogens induce adaptation of differing signaling pathways. To address this issue, we conducted systematic studies under Pre-M vs. PM culture conditions with long-term exposure to different antiestrogens and examined the resultant "specific biologic signatures" of the various resistant cells. Estradiol stimulated growth and inhibited apoptosis of "pre-menopausal" antiestrogen-resistant cells but exerted opposite effects on their "post-menopausal" counterparts. Under Pre-M conditions, tamoxifen (TAM)-resistant cells exhibited a marked translocation of estrogen receptor alpha from the nucleus into the cytoplasm, whereas this occurred to a lesser extent under PM conditions. MCF-7 cells exposed to PM but not Pre-M conditions exhibited up-regulation of basal epidermal growth factor (EGF) receptor (EGFR) levels, an effect exaggerated in cells exposed to 4-hydroxytamoxifen. Differing effects occurred in response to structurally divergent antiestrogens. Long-term treatment with both 4-hydroxytamoxifen and ICI182,780 increased EGFR levels, but this was not seen in response to TAM. Surprisingly, EGF administration slightly increased cell number in TAM-resistant cells, whereas only increasing cell weight and decreasing cell number in EGFR overexpressing-resistant cells. To assess potential differences among various parental cell lines, we induced resistance in cell lines obtained from other laboratories and confirmed the results from our own parental cells with minor differences. Together, these data demonstrate that culture of breast cancer cells under Pre-M and PM conditions and structurally diverse antiestrogens results in adaptive responses with differing biological signatures.

Active epidermal growth factor (EGFR) level is a predictive factor for response and survival in patients with lung cancer

20058 Background: Over expression of epidermal growth factor receptor (EGFR) has been reported as a poor prognostic factor in patients with cancer. However, active EGFR released from the apoptotic tumor cells could serve as a marker for the prediction of clinical outcome in cancer patients. In this study we aimed to study the role of the level of serum active epidermal growth factor receptor in patients with non-small cell lung cancer as a predictive parameter for response and survival. Methods: Thirty-three consecutive patients with advanced non-small cell lung cancer patients (12 with stage IIIB and 21 stage IV or relapsed disease) were included. The median age was 52 (range: 35–69). The patients were given cisplatinum and docetaxel combination regimen as first line treatment. The serum samples were collected before the first cycle of the chemotherapy and every 2 cycles and kept at -80 C. Response to treatment was evaluated every 2 cycles according to the WHO criteria. Serum active EGFR levels were measured by ELISA (BioSource, Camarillo Ca, USA). Results: Median 4 cycles of chemotherapy (range: 2–6) were administered. Median follow-up time was 11 months. Objective response rate was 18.2%. One-year estimated survival rate was 65.9%. There were no significant differences between the extend of the disease and basal active EGFR levels. Likewise, there was no difference between the basal active EGFR levels of responders and non-responders (0,19 ± 0.09 vs 0.21 ± 0,11 fmol/mL, p = 0.899, respectively). However, the patients responded to the treatment had significantly higher level of active EGFR than the non-responders after 2 cycles (3,74 ± 3,65 vs. 0,174 ± 0,13 fmol/mL, p = 0.028, respectively). While the patients with positive basal EGFR levels (higher than the cutoff level of 0.080 fmol/mL) had lower survival rates than that of negative patients (1 yr survival rate: 62.8% vs. 75%, respectively), active EGFR positive patients after 2 cycles of chemotherapy had longer survival than the negative patients (1 yr survival rate: 70.6% vs. 60%, respectively). Conclusions: Our preliminary results show that serum active EGFR levels could be a predictive marker for response evaluation and survival in patients with non-small cell lung cancer treated with chemotherapy. No significant financial relationships to disclose.

Salivary and gastric epidermal growth factor in patients with Zollinger-Ellison syndrome: its protective potential.

Evidence is accumulating that epidermal growth factor (EGF) is a major molecule contributing to the maintenance of the integrity of the upper alimentary tract mucosa before and after injury by acid and pepsin. Patients with Zollinger-Ellison Syndrome (ZES) typically have hypersecretion of acid and pepsin; however, the concentration and rate of secretion of salivary and gastric EGF that could counteract these potentially aggressive factors are unknown. Accordingly, this study was conducted to determine whether EGF affords mucosal protection in ZES patients. The concentration and output of salivary (sEGF) and gastric epidermal growth factor (gEGF) were measured in eight patients with ZES and the results compared to those in 17 patients with nonulcer dyspepsia (NUD), serving as a control group. All patients had normal esophageal and gastric mucosa as determined by endoscopy. Total saliva was collected during 1-h parafilm- and 1-h pentagastrin/parafilm-stimulated conditions, as well as basal and pentagastrin-stimulated gastric juice. The concentration and output of EGF were determined by radioimmunoassay. The concentration of EGF in saliva collected from ZES patients after parafilm chewing was significantly higher compared to that in NUD patients (4.61 +/- 0.59 vs 2.75 +/- 0.50 ng/ml, p < 0.05). The concentration of EGF in saliva collected after pentagastrin stimulation in ZES patients was also significantly higher than in NUD patients (4.37 +/- 0.73 vs 2.22 +/- 0.37 ng/ml, p < 0.05). Salivary EGF output during parafilm chewing in ZES and NUD were similar (68 +/- 6.4 vs 109 +/- 25.2 ng/h). Salivary EGF output after administration of pentagastrin in ZES and NUD was also similar (66 +/- 6.1 vs 132 +/- 45.4 ng/h). Basal EGF output in the gastric juice of patients with ZES was 3-fold higher than in patients with NUD (801 +/- 73 vs 271 +/- 32 ng/h, p < 0.01). Pentagastrin-stimulated EGF output was similar in both groups (705 +/- 92 vs 675 +/- 168 ng/h). Patients with ZES have a significantly higher EGF concentration in saliva and EGF output in basal gastric juice. This elevated content of salivary and gastric EGF in ZES patients may play a protective role in preventing the development of reflux esophagitis and gastric ulcer under the impact of gastric acid and pepsin hypersecretion.

Salivary and gastric epidermal growth factor in patients with Zollinger-Ellison syndrome: its protective potential

OBJECTIVE: Evidence is accumulating that epidermal growth factor (EGF) is a major molecule contributing to the maintenance of the integrity of the upper alimentary tract mucosa before and after injury by acid and pepsin. Patients with Zollinger-Ellison Syndrome (ZES) typically have hypersecretion of acid and pepsin; however, the concentration and rate of secretion of salivary and gastric EGF that could counteract these potentially aggressive factors are unknown. Accordingly, this study was conducted to determine whether EGF affords mucosal protection in ZES patients. METHODS: The concentration and output of salivary (sEGF) and gastric epidermal growth factor (gEGF) were measured in eight patients with ZES and the results compared to those in 17 patients with nonulcer dyspepsia (NUD), serving as a control group. All patients had normal esophageal and gastric mucosa as determined by endoscopy. Total saliva was collected during 1-h parafilm- and 1-h pentagastrin/parafilm-stimulated conditions, as well as basal and pentagastrin-stimulated gastric juice. The concentration and output of EGF were determined by radioimmunoassay. RESULTS: The concentration of EGF in saliva collected from ZES patients after parafilm chewing was significantly higher compared to that in NUD patients (4.61 ± 0.59 vs 2.75 ± 0.50 ng/ml, p < 0.05). The concentration of EGF in saliva collected after pentagastrin stimulation in ZES patients was also significantly higher than in NUD patients (4.37 ± 0.73 vs 2.22 ± 0.37 ng/ml, p < 0.05). Salivary EGF output during parafilm chewing in ZES and NUD were similar (68 ± 6.4 vs 109 ± 25.2 ng/h). Salivary EGF output after administration of pentagastrin in ZES and NUD was also similar (66 ± 6.1 vs 132 ± 45.4 ng/h). Basal EGF output in the gastric juice of patients with ZES was 3-fold higher than in patients with NUD (801 ± 73 vs 271 ± 32 ng/h, p < 0.01). Pentagastrin-stimulated EGF output was similar in both groups (705 ± 92 vs 675 ± 168 ng/h). CONCLUSIONS: Patients with ZES have a significantly higher EGF concentration in saliva and EGF output in basal gastric juice. This elevated content of salivary and gastric EGF in ZES patients may play a protective role in preventing the development of reflux esophagitis and gastric ulcer under the impact of gastric acid and pepsin hypersecretion.

Activator Protein-1 Mediates Induced but not Basal Epidermal Growth Factor Receptor Gene Expression

The epidermal growth factor receptor (EGFR) is expressed at different levels in many cell types and found overexpressed in many cancers. EGFR expression is increased or decreased in response to extracellular stimuli. We examined the effect of increased c-Jun expression on EGFR promoter activity. We used DNAse I foot-printing analysis to determine the binding of activator protein 1 (AP-1) to the promoter region. We also used cotransfection experiments and western blotting analysis to determine the effect of AP-1 family members on EGFR expression. AP-1 was able to bind to at least seven sites in the EGFR promoter region. Cotransfection of MCF-7 cells with a c-Jun expression vector and the EGFR promoter reporter resulted in a 7-fold increase in promoter activity. JunB, but not c-fos, also enhanced the EGFR promoter activity. An A-Fos-dominant negative shown to inhibit Jun-dependent transactivation was able to prevent c-Jun induction of the promoter activity, but only slightly decreased the basal activity of the promoter. Furthermore, the A-Fos dominant negative was able to inhibit phorbol ester induction of the EGFR promoter. Examination of EGFR expression of MCF-7 stable cell lines that overexpress c-Jun revealed an increase in EGFR expression. Additionally, a cisplatin-resistant cell line, A2780/CP70, which has an increase in AP-1 activity compared with the parental cell line, A2780, was found to have an increase in EGFR level. These results indicate that AP-1 can act to increase the expression of EGFR and may play a role in upregulation of EGFR in cancer cells.