Chromogranin A as a valid marker in oncology: Clinical application or false hopes?

Chromogranin A, due to its primary expression throughout the neuroendocrine system, is a widely accepted biomarker for the assessment of neuro-endocrine tumors. It has been traditionally used in the management of patients with tumors of gastro-enteropancreatic origin. Lately, it has also been implicated in various conditions and diseases, both benign and malignant. However, the paucity of data of adequate strength, as well as its relation with common physiologic conditions and its interaction with commonly prescribed medications, limit its clinical use in only a narrow spectrum. Herein, we present a thorough review to the most frequent conditions where its levels are affected, focusing specifically on its potential use as a prognostic and predictive biomarker in oncology.

Expressions of chromogranin A and cathepsin D in human primary hepatocellular carcinoma

AIM To determine the expression and clinicalsignificance of chromogranin A and cathepsin Din hepatocellular carcinoma(HCC).METHODS Double immunofluorescence stain-ing techniques combined with laser confocalscanning microscopy(LSCM)was used toinvestigate chromogranin A and cathepsin Dexpressions in 85 HCC patients.RESULTS Cathepsin D was expressed in :3normal liver tissues,while in HCC the stainingshowed regional variation and the fraction ofstrongly stained cells increased as the tumorsbecame less differentiated and usually clinicallymore malignant.Cells which showed strongpositivity for cathepsin D were present in 71/85(83.5%)cases.Strong expression of cathepsinD in cancer cells was related tohistopathological features.They were morecommon in grade 3-4(26/28,92.9%)and grade2(46/53,86.8%)tumors than in grade 1 tumors(1/4,25.0%)(P【0.01).No significantcorrelation was found between age andcathepsin D expression.In patients with positivecathepsin D reaction,the mean age was 52.1±2.8 years(range 32-68 years)and in the groupwith negative reaction,the mean age was 51.3±4.5 years(range 28-71 years).No obvious relationship was observed between CgAexpression in cancer cells and thehistopathological features.The CgA positiverate was 75.0%(3/4)in grade 1,71.7%(38/53)in grade 2,and 71.4%(20/28)in grade 3-4(P】0.05)tumors.The coexpression of CgA andcathepsin D was found by double labeledimmunofluorescence staining techniques.Theprocessing of cathepsin D was disturbed in HCCcells and accumulated in the cells.Cathepsin Dhad proteolytic activity and autocrine mitogeniceffect,suggesting their functions in invasion.These findings demonstrated that the expressionof cathepsin D in HCC had prognostic value.CONCLUSION Chromogranin A and cathepsin Dare expressed in a high proportion of HCC andthe existence of cathepsin D in HCC might berelated to processing of CgA.This is clearly asubject for further studies because of itspotential clinical applications.

Salivary levels of cortisol and chromogranin A in patients with burning mouth syndrome: A case-control study

Burning mouth syndrome (BMS) is a poorly understood oral pain disorder characterized by a painful burning sensation in the oral cavity without any mucosal abnormalities. In this study, we evaluated the salivary cortisol and chromogranin A (CgA) levels of patients with BMS in comparison with age-matched controls. Subjects (n = 114) included 81 BMS patients and 33 controls. Patients with BMS were further classified into a subgroup of subjects who occasionally feel a burning sensation (BMS 1), and a subgroup of subjects who always feel a burning sensation (BMS 2). Salivary cortisol and CgA levels were measured using ELISA kits. All individuals with BMS had significantly higher cortisol and CgA levels than the controls did. Furthermore, when comparing the controls with each BMS subgroup, salivary levels of cortisol were significantly higher in both subgroups than controls. In contrast, the level of CgA was significantly higher in the BMS 2 subgroup only. Multiple regression analysis revealed a significant independent association between salivary levels of cortisol and BMS even after adjustment for gender, antidepressant or antianxiety drug use and hypertension (drug-treated). The study revealed that a significant association was observed between salivary cortisol levels and BMS.

Qinghua decoction(清化饮)improves chronic nonbacterial prostatitis possibly via regulating the chromogranin A/nerve growth factor/tyrosine kinase A signaling pathway mediated by inflammatory factors

OBJECTIVE:To explore the mechanism by which Qinghua decoction(清化饮)regulates neuroendocrine inflammation in chronic nonbacterial prostatitis(CNP)model rats and provide an experimental basis for clinical treatment.METHODS:The rats were randomly divided into six groups:normal control,model,Qianlie Tongyu capsule,low-dose Qinghua decoction,medium-dose Qinghua decoction,and high-dose Qinghua decoction group with six rats in each group.Rats in each group were sacrificed on the 29th day of treatment,and blood and prostate tissues were collected.Serum levels of tumor necrosis factor-alpha and interleukins 1-beta,6,8,and 10(TNF-αand IL-1β,-6,-8,and-10,respectively)were measured using enzyme-linked immunosorbent assay.The pathological changes in the rat prostate tissue in each group were observed under a light microscope.The expression levels of chromogranin A(CgA),nerve growth factor(NGF),and tyrosine kinase A(TrkA)were detected using reverse transcription quantitative polymerase chain reaction.Western blotting was used to detect protein expression of CgA,NGF,and TrkA.RESULTS:In the model group,the prostate capsule membrane and stroma were significantly dilated with more inflammatory cells infiltrating the stroma and perivessels.TNF-α,IL-1β,-6,and-8,CgA,NGF,and TrkA levels increased,whereas the content of IL-10 decreased,which was statistically significant compared to that in the normal control group(P<0.05).Prostate tissue cells in the high-dose group were neatly arranged with no obvious inflammatory cell infiltration.When compared with the model group,the high-dose Qinghua decoction group showed a significant improvement in these indices(P<0.05).CONCLUSION:Qinghua decoction led to inhibition of pathological changes in the prostate tissue of rats with CNP,regulation of inflammatory cytokine expression,and inhibition in the expression of CgA,NGF,and TrkA.This mechanism may be primarily related to regulation of the CgA/NGF/TrkA signaling pathway mediated by various inflammatory factors.

Prognostic role of chromogranin A in ：astration-resistant prostate cancer： a meta-analysis

We aimed to investigate the prognostic value of chromogranin A （CgA） in castration-resistant prostate cancer （CRPC）. We conducted a systematic literature search of PubMed, Web of Science, and EMBASE for citations published prior to September 2017 that described CgA and CRPC and performed a standard meta-analysis on survival outcomes. Our meta-analysis included eight eligible studies with 686 patients. The results were as follows： progression-free survival （PFS） was associated with CgA level （hazard ratio [HR] = 2.47, 95% confidence interval [CI]： 1.47-4.14, P = 0.0006）; PFS was relative to CgA change （HR = 9.22, 95% Ch 3.03-28.05, P〈 0.0001）; and overall survival （OS） was relative to CgA level （HR = 1.47, 95% Ch 1.15-1.87, P= 0.002）. When we divided the patients into two groups according to therapy status, the result for OS relative to CgA level was an HR of 1.26 （95% CI： 1.09-1.45, P = 0.001） in the first-line hormonal therapy group, and an HR of 2.33 （95% Ch 1.40-3.89, P = 0.001） in the second-line hormonal therapy or chemotherapy group. This meta-analysis indicated that a high CgA level had a negative influence on OS and PFS in CRPC patients. In addition, CRPC patients with a rising CgA had a shorter PFS. Further studies are needed to verify the prognostic value of CgA in CRPC.

Combination of insulin-like growth factor-1, IGF binding protein-3, chromogranin A and prostate specific antigen can improve the detection of prostate cancer

Aim:Prostate cancer(PCa)is the second most prevalent male cancer worldwide and designated the sixth most frequent male cancer in Arab countries.Although prostate specific antigen(PSA)has become the best and most valuable biomarker for screening of PCa,elevated levels of PSA can reflect the presence of malignant cells but can overlap with benign prostatic diseases.There is a necessity to develop and improve current tools for early detection and diagnosis of PCa.This study was done to evaluate the validation of serum insulin-like growth factor-1(IGF-1),IGF binding protein-3(IGFBP-3),chromogranin A(CgA)and combination with PSA in treatment of benign prostatic hyperplasia(BPH)and PCa patients.Methods:The study included 72 patients with PCa,70 BPH patients and 56 healthy male subjects of matched age.Full history and clinical data were recorded for all subjects.Results:Serum PSA attained sensitivity of 84%at 82%specificity with an accuracy of 83%,although IGF-1,IGFBP-3 and CgA did not recognize PCa patients.Conclusion:Combinations of IGF-1 and IGFBP-3 biomarkers with PSA were effectively differentiated between PCa and control groups as well as improving the overall value of sensitivity,specificity and diagnostic accuracy of PCa to 85%and 86%for IGF-1/PSA and IGFP-3/PSA respectively.

Investigation of possible relationship between atopic dermatitis and salivary biomarkers,stress,and sleep disorders

Atopic dermatitis(AD)is a chronic,relapsing,multifactorial inflammatory disease with genetic,environmental,and immunological characteristics.The quality of life and sleep of patients and their families are affected by AD,which triggers stress,described as one of the factors that worsens AD.Salivary biomarkers such as cortisol,alpha-amylase,chromogranin A,and melatonin have been associated with stress and sleep disturbances.Therefore,the evaluation of stress and sleep disorders using salivary biomarkers in AD patients is important.This review aims to describe the possible relationship between atopic dermatitis and stress,sleep disorders,and salivary biomarkers,seeking to contribute to better understanding and clinical management of AD.This descriptive study is characterized as a narrative literature review.A literature search was conducted of studies published in English and Portuguese between January 2012 and October 2022 that are available in electronic media from various databases,such as Scientific Electronic Library Online,Latin American and Caribbean Literature on Health Sciences,and PubMed.AD is associated with different degrees of impact on the lives of individuals who present with the disease.Psychological stress may induce changes in saliva composition and worsen AD;at the same time,the severity of the disease may be associated with emotional impact.Further studies are needed to assess and correlate AD severity,stress,and sleep disturbances with salivary biomarkers in order to better understand this association.

Duodenal neuroendocrine tumor-tertiary care centre experience:A case report

BACKGROUND Neuroendocrine neoplasms(NENs)are a heterogeneous group of neoplasms arising from neuroendocrine cells,which contribute a small fraction of gastrointestinal malignancies.Duodenal neuroendocrine tumors(dNETs)represent 2%of all gastroenteropancreatic NENs.NENs are heterogeneous in terms of clinical symptoms,location,and prognosis.Non-functional NETs are mostly asymptomatic and need a high degree of clinical suspicion.Diagnosis of NETs is by endoscopic,endosonographic biopsy,and histopathological examination with immunohistochemistry staining for synaptophysin and chromogranin A.CASE SUMMARY We present case reports of 5 patients obtained over a period of 10 years in our center with dNETs.One patient had moderately differentiated NET and the remaining four had well-differentiated NET.Surveillance endoscopy was recommended in all the patients and is kept under regular follow-up after performing endoscopic therapy using endoscopic mucosal resection in 4 of them and one patient was advised to undergo a Whipple procedure.CONCLUSION Recently,the number of reported cases of NETs has increased due to advancements in diagnostic modalities and prevalence because of longer survival duration.The management differs based on the site,size,proliferation grade,and locally invasive pattern.They are slow-growing tumors with a good overall prognosis.The prognosis correlates with local lymph node status and metastasis.

Mutual relationships between contents of chromogranin A, cholecys-tokinin octapeptide and serotonin in individual EC cells

Chromogranin A (CgA) is a kind of acidic protein originally isolated from the chromaffin cells of the ox adrenal gland medulla. It was found that the CgA was also widely distributed in the neuroendocrine cells besides the adrenal medulla. The physiological function of the CgA is not yet elucidated, but it was presumed to be involved in organizing the granule matrix and regulating the processing of the prohormones. Besides, CgA is also the precursor of some peptide hormones such

CGA 衍生多肽 CHR 抑制 TNF -α引起的血管内皮细胞高通透性的研究

目的：观察嗜铬粒蛋白 A （ chromogranin A ， CGA ）的衍生多肽 CGA47-66（chromogranin， CHR）对TNF-α引起血管内皮细胞（EA．hy926）高通透性的影响和初步机制。方法分别用 CHR、TNF -α作用人血管内皮细胞系 EA．hy926，应用 Transwell 小室法、PCR、Western-blot检测单层内皮细胞通透性的改变，血管内皮钙黏蛋白VE-cadherin mRNA和蛋白的表达，以及磷酸化p38丝裂素活化蛋白激酶（ p38 mitogen activated protien kinase ， p38 MAPK）和总p38 MAPK等渗透性相关蛋白的表达。结果与空白对照组比较，TNF-α组EA．hy926细胞的通透性显著增高（2．479±0．117比1．769±0．554，t＝3．543，P＝0．008），VE-cadherin mRNA的表达显著降低（1．145±0．035比1．593±0．161， t＝-4．707， P＝0．035），而CHR （1 nM、10 nM、100 nM）组中EA．hy926细胞的VE-cadherin mRNA的表达较空白对照组有显著增加（1．512±0．04、1.615±0．170、1．918±0．355比1．162±0．189，P＜0．05），同时CHR（1 nM、10 nM、100 nM、1000 nM）能够缓解TNF-α组引起的高渗透性改变（1．954±0．379、1．835±0．090、1．430±0．349、1.559±0．447比2．479±0．117，P＜0．05）和 VE -cadherin mRNA 的低表达（1．541±0．149、1．529±0．098、2．087±0．437、1．640±0．160比1．145±0．035，P＜0．05），并且在1～100 nM范围内，上述作用呈剂量依赖性；Western-blot检测到TNF-α组EA．hy926细胞的VE-cadherin蛋白表达明显低于空白对照组，磷酸化p38 MAPK蛋白表达明显高于空白对照组；TNF-α组＋CHR组与TNF-α组相比，TNF-α组＋CHR组中VE -cadherin 蛋白的表达明显增加，磷酸化p38 MAPK蛋白明显降低。结论 CGA衍生多肽CHR能改善TNF-α引起的血管内皮细胞高通透性，这一作用在一定剂量范围内呈剂量依赖性，并且可能与p38 MAPK信号通路相关。

Role and function of granin proteins in diabetes mellitus

The granin glycoprotein family consists of nine acidic proteins;chromogranin A(CgA),chromogranin B(CgB),and secretogranin II–VIII.They are produced by a wide range of neuronal,neuroendocrine,and endocrine cells throughout the human body.Their major intracellular function is to sort peptides and proteins into secretory granules,but their cleavage products also take part in the extracellular regulation of diverse biological processes.The contribution of granins to carbohydrate metabolism and diabetes mellitus is a recent research area.CgA is associated with glucose homeostasis and the progression of type 1 diabetes.WE-14,CgA10-19,and CgA43-52 are peptide derivates of CgA,and act as CD4+or CD8+autoantigens in type 1 diabetes,whereas pancreastatin(PST)and catestatin have regulatory effects in carbohydrate metabolism.Furthermore,PST is related to gestational and type 2 diabetes.CgB has a crucial role in physiological insulin secretion.Secretogranins II and III have angiogenic activity in diabetic retinopathy(DR),and are novel targets in recent DR studies.Ongoing studies are beginning to investigate the potential use of granin derivatives as drugs to treat diabetes based on the divergent relationships between granins and different types of diabetes.

GENE EXPRESSION OF GROWTH FACTOR RECEPTORS AND NEURONAL MARKERS IN NEURO BLASTOMA CELL LINES

Gene expression of nerve growth factor receptor (NGFR), epidermal growth factor receptor (EGFR), chromogranin A (CGA) and neuropetide Y (NPY)in 4 aeuroblsstoma cell lines without N-myc amplification was studied by wins Northern blot technique, N type cells expressed more NGFR mRNA than S type cells and have only little or no EGFR expression. S type cells had stronger expression of EGFR mRNA than that of N type cells accompanying with only less or even no NGFR expression. The results Indicated that difference of gene expression of theae growth factor receptors might be due to the various of tumor cell differetiation. Celli differentiating toward neurons gave more NGFR expression and cells prepared to be differentiating toward other direction might give more EGFR gene expression.Various gene expression of CGA and NPY In neuroblsstoma cell lines might be due to the presence of different stages of tumor cell differentiation and NGF only Induced differentiation of those neuroblastoma cells ready to be differentiation to neurons afterwards.

Validation of diagnostic strategies of autoimmune atrophic gastritis:A case report

BACKGROUND Autoimmune atrophic gastritis(AAG)is a type of chronic gastritis that mainly affects the gastric corpus.Due to the lack of standard diagnostic criteria and overlaps with the courses of Helicobacter pylori-related atrophic gastritis,reports on the diagnostic strategy of AAG at an early stage are limited.CASE SUMMARY A 71-year-old woman with severe anemia was diagnosed with AAG.Endoscopic views and pathological findings showed the coexistence of normal mucosa in the gastric antrum and atrophic mucosa in the gastric fundus.Serological tests showed that anti-parietal cell antibodies and anti-intrinsic factor antibodies were both positive.Immunohistochemical results,which showed negative H^(+)-K^(+)ATPase antibody staining and positive chromogranin A(CgA)staining,confirmed the mechanism of this disease.After vitamin B12 and folic acid supplementation,the patient recovered well.CONCLUSION Successful diagnosis of AAG includes serological tests,endoscopic characteristics,and immunohistochemistry for H^(+)-K^(+)ATPase and CgA antibodies.

Markers of bile duct tumors

Biliary tract carcinomas are relatively rare,representing less than 1%of cancers.However,their incidence has increased in Japan and in industrialized countries like the USA.Biliary tract tumors have a poor prognosis and a high mortality rate because they are usually detected late in the course of the disease;therapeutic treatment options are often limited and of minimal utility.Recent studies have shown the importance of serum and molecularmarkers in the diagnosis and follow up of biliary tract tumors.This review aims to introduce the main features of the most important serum and molecular markers of biliary tree tumors.Some considerable tumor markers are cancer antigen 125,carbohydrate antigen 19-9,carcinoembryonic antigen,chromogranin A,mucin 1,mucin 5,alpha-fetoprotein,claudins and cytokeratins.

New therapeutic approaches to metastatic gastroenteropancreatic neuroendocrine tumors:A glimpse into the future

Neuroendocrine(NE) gastroenteropancreatic tumors are a heterogeneous group of neoplasias arising from neuroendocrine cells of the embryological gut. Their incidence have increased significantly over the past 3 decades probably due to the improvements in imaging and diagnosis. The recent advances in molecular biology have translated into an expansion of therapeutic approaches to these patients. Somatostatin analogs, which initially were approved for control of hormonal syndromes, have recently been proven to inhibit tumor growth. Several new drugs such as antiangiogenics and others targeting mammalian target of rapamycin pathways have been approved to treat progressive pancreatic neuroendocrine tumors(NETs) although their role in nonpancreatic is still controversial. The treatment of NETs requires a coordinated multidisciplinary approach. The management of localized NETs primarily involves surgical resection followed by surveillance. However, the treatment of unresectable and/or metastatic disease may involve a combination of surgical resection, systemic therapy, and liver-directed therapies with the goal of alleviating symptoms of peptide release and controlling tumor growth. This article will review the current therapeutic strategies for metastatic gastroenteropancreatic NETs and will take a glimpse into the future approaches.

Immunohistochemical study on endocrine-like tumor cells in colorectal carcinomas

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The Influence of a Posture on the Autonomic Nervous System and Stress Hormones in Saliva

Humans and animals give several impressions to their recipients with their postures. In this study, the influence of postures on a body was examined through the perspective of the endocrine system and the autonomic nervous system. The subjects were 18 healthy adults (7 males and 11 females). A slouching posture like arching back was defined as a low power pose (LP), and a posture straightening back and throwing out chest is defined as a high power pose (HP). Starting at rest, the subjects took LP posture and changed to HP posture, and their autonomic nervous functions were measured and their saliva was collected before and after taking each posture. In taking LP posture, the decrease of the parasympathetic nervous activity, the increase of the pathetic nervous activity and the increase of chromogranin A in saliva were observed. The increase of the autonomic nervous activity, and the decrease of chromogranin A which had been increased by taking LP posture were observed by taking HP posture. There was no influence on cortisol by taking either of the postures. This study suggested that bad postures such as curving back affected stress reactions through the perspective of the endocrine system and the automatic nervous system.

Maternal Depression and Mother-to-Infant Bonding: The Association of Delivery Mode, General Health and Stress Markers

Aim: The aim of the present study was to examine associations among maternal stress level, general health, mother to infant bonding, maternal depression level, and mode of delivery. Methods: Mothers who delivered a single baby at term were recruited with a total 435 mothers participating in the study. Outcome measures: Data were collected 6 months after delivery using General Health Questionnaire (GHQ-28), Mother-to-Infant Bonding Scale (MIBS), Edinburgh Postnatal Depression Scale (EPDS) as well as socio-demographic and medical information at 6 months. Additionally, salivary cortisol and chromogranin levels were determined. Results: The proportion of breast-feeding mothers in the vaginal delivery group (51.4%) was significantly higher than that of the cesarean section group (24%). GHQ-28 scores were significantly related to EPDS scores and MIBS scores (P Conclusion: Maternal general health is associated with maternal psychological health. These results suggest that the support of maternal health is important to maintain maternal psychological status and bonding to infants. Because EPDS scores were significantly worse in the planned cesarean section group (4.2 ± 3.3), careful management is needed of mothers who deliver by planned cesarean section.

Neuroendocrine Differentiation in the Progression of Prostate Cancer: An Update on Recent Developments

Neuroendocrine (NE) differentiation, either benign or malignant, is the hallmark of prostate cancer (PCa). Clusters of malignant NE cells are found in most prostate cancer cases. NE differentiation is among the non-mutually exclusive theories proposed to explain the progression to androgen independence of PCa. NE differentiation is usually associated with an increased aggressivity and invasiveness of prostate tumors and a poor prognosis. This review aims to present an overview of current knowledge on neuroendocrine differentiation in PCa to improve our understanding of tumour progression and androgen independence. The NE component represents an important therapeutic axis. Development of new generation of drugs that selectively target NE-like cells may lead to the development of new therapeutic modalities for advanced and hormone-refractory PCa.

Tumor-Associated Lymphatic and Venous Vessels in Medullary Thyroid Carcinomas

Objective: Medullary thyroid carcinomas (MTCs) invade local lymph node through lymphatic vessels and metastasize to distant organs hematogenously and account for a significant mortality. There are possibly increased lymphatic and venous vessels, through which the tumor spreads to lymph nodes and distant organs. Materials and Methods: By immunocytochemical staining for lymphatic and venous vessels, MTC lesions with adjacent normal thyroid and both normal and metastatic lymph nodes were studied for the peritumoral lymphatic and venous vessels, which were morphometrically compared with those of normal thyroid and lymph nodes. Sixteen cases of MTC cases with adjacent thyroid tissues and attached lymph nodes were immunocytochemically stained for lymphatic vessels using lymphatic vessel hyaluronan receptor (LYVE-1) and venous vessels for factor VIII (F-8). The immunostained sections of MTC lesions and metastatic lymph nodes were morphometrically compared for the number and sizes of the vessels with those of normal thyroid tissues and lymph nodes. Results: Significantly increased lymphatic vessels and markedly increased blood vessels were identified in many MTC cases at the peritumoral tissues and metastatic lymph nodes whereas a few lymphatic vessels and no venous vessels were identified in midst of MTCs. The irregular peritumoral lymphatic vessels resembled that of immature lymphatic vessels observed in papillary thyroid carcinomas and increased irregularly, entrapped venous vessels in peritumoral tissues resembled those observed in follicular thyroid carcinomas. Conclusion: The significantly increased lymphatic vessels and markedly increased venous vessels in the peritumoral thyroid tissue support a propensity of MTCs for providing an easy access of tumor cells to both lymphatic spread to the regional lymph nodes and venous spread to distant organs with further tumor spread through metastatic lymph nodes by moderately increased lymphatic and venous vessels.