Significance of pSmad2/3 and Smad4 in hepatitis C virus‐related liver fibrosis and hepatocellular carcinoma

Chronic hepatitis C (CHC) is a major public health problem, especially in Egypt. Risk of hepatocellular carcinoma (HCC) development increases as hepatitis C virus (HCV)‐related liver diseases progress. Smads act as substrates for the transforming growth factor‐beta (TGF‐β) family of receptors. This study aims to assess hepatic expression of pSmad2/3 and Smad4 in CHC with different stages of fibrosis and grades of necro‐inflammation as well as in HCC on top of CHC. This study was done on 33 core liver biopsies from patients with CHC (15 with early fibrosis and 18 with late fibrosis), 15 liver specimens from HCC cases on top of CHC, as well as five normal controls. pSmad2/3 and Smad4 show more immunopositivity, higher percentage of positive hepatocytes and stronger staining intensity in CHC with late fibrosis compared to early fibrosis. pSmad2/3 shows increase of the previous parameters in CHC with high grade activity than those with low activity. Smad4 shows increase of the previous parameters in HCC compared to CHC cases. pSmad2/3 and Smad4 can be used as diagnostic and/or prognostic markers for progression of HCV‐related fibrosis to cirrhosis and further progression to HCC.     

Expression of growth factors,growth inhibiting factors,and their receptors in invasive breast cancer. I: An inventory in search of autocrine and paracrine loops

The aim of the present study was to investigate which growth factors, receptors, and growth inhibiting factors are expressed in invasive breast cancer. Five (angiogenic) growth factors and their receptors: platelet-derived growth factor A chain (PDGF-AA) and PDGF receptor alpha (PDGFαR), PDGF-BB and PDGF beta receptor, transforming growth factor alpha (TGFα) and its receptor epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) and its receptors vascular endothelial growth factor receptor I (Flt-1) and vascular endothelial growth factor receptor II (Flk-1/KDR); two growth inhibiting factors: transforming growth factor beta-1 (TGFβ1) and TGFβ2) and their receptor couple transforming growth factor beta receptor I (TGFβR-I) and TGFβR-II; and basic fibroblast growth factor (bFGF) were stained by standard immunohistochemistry on frozen sections in 45 cases of invasive carcinoma of the breast. Staining was scored as negative or positive in tumour epithelium, stroma, and blood vessels. TGFβ1 and TGFβ2 were expressed in the tumour cells in 67 per cent and 76 per cent of cases, respectively, whereas PDGFβR and TGFβR-II were expressed in 0 per cent and 2 per cent, respectively. The other factors showed variable expression in tumour cells. All factors were expressed in the stroma in most cases, except Flt-1, Flk-1/KDR, TGFβ2, and TGFβR-II, which showed variable expression, and EGFR, which showed no expression. The endothelium was in most cases positive for bFGF, PDGF-AA, PDGF-BB, VEGF, PDGFαR, PDGFβR, and TGFβ1 but TGFβ2 was negative in most cases and TGFα, EGFR, Flt-1, Flk-1/KDR, TGFβR-I, and TGFβR-II were variably expressed. The most interesting possible auto/paracrine loops, as demonstrated on serial sections and by fluorescence double staining, were the TGFα/EGFR, TGFβs/TGFβR, VEGF/Flt-1, and the VEGF/Flk-1 combinations. In conclusion, growth factors, growth inhibiting factors, and their receptors are frequently expressed in invasive breast cancer. Indications for some possible auto-and paracrine loops have been found, which should encourage further study on the role of these factors in breast cancer proliferation and angiogenesis. © 1998 John Wiley & Sons, Ltd.     

Identification of growth differentiation factor 15 as a profibrotic factor in mouse liver fibrosis progression

The aim of this study was elucidate the inhibitory role of growth differentiation factor 15 (GDF15) in liver fibrosis and its possible activation mechanism in hepatic stellate cells (HSCs) of mice. We generated a GDF15neutralizing antibody that can inhibit TGF1induced activation of the TGF/Smad2/3 pathway in LX2 cells. All the mice in this study were induced by carbon tetrachloride and thioacetamide. In addition, primary HSCs from mice were isolated from fresh livers using Nycodenz density gradient separation. The severity and extent of liver fibrosis were evaluated by Sirius Red and Masson staining. The effect of GDF15 on the activation of the TGF pathway was detected using dualluciferase reporter and Western blotting assays. The expression of GDF15 in cirrhotic liver tissue was higher than that in normal liver tissue. Blocking GDF15 with a neutralizing antibody resulted in a delay in primary hepatic stellate cell activation and remission of liver fibrosis induced by carbon tetrachloride or thioacetamide. Meanwhile, TGF pathway activation was partly inhibited by a GDF15neutralizing antibody in primary HSCs. These results indicated that GDF15 plays an important role in regulating HSC activation and liver fibrosis progression. The inhibition of GDF15 attenuates chemicalinducible liver fibrosis and delays hepatic stellate cell activation, and this effect is probably mainly attributed to its regulatory role in TGF signalling.     

The prognostic significance of growth factors and growth factor receptors in gastric adenocarcinoma

We evaluated growth factors/receptors expression in gastric adenocarcinoma. Immunohistochemistry was used to evaluate epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), VEGF‐D, VEGF receptor (VEGFR)‐2, VEGFR‐3, transforming growth factor (TGF)‐α, TGF‐β1, and TGF‐β‐RII in tissue microarrays of adenocarcinoma, dysplasia, metaplasia, and gastritis. In adenocarcinoma, the expression rates of EGFR, VEGF, VEGF‐D, VEGFR‐2, VEGFR‐3, TGF‐α, TGF‐β1, and TGF‐β‐RII were 2.0%, 0%, 10.7%, 4.4%, 11.2%, 26.3%, 9.4%, and 19.5%, respectively. VEGF‐D, TGF‐α, TGF‐β1, and TGF‐β‐RII expression rate were higher in adenocarcinoma than in other groups. TGF‐β‐RII expression was correlated with VEGFR‐3, VEGF‐D, and TGF‐α expression in adenocarcinomas. Tumor location, histologic type, stage, lymphatic invasion, perineural invasion, angioinvasion, VEGF‐D, and VEGFR‐2 expressions were associated with patient survival in a log rank test and advanced stage and positive expression of VEGF‐D were poor prognostic factors using Cox analysis. VEGF‐D expression may be of prognostic value in gastric adenocarcinoma, whereas EGFR and TGF family expression may only have a minor influence.     

Secretion of high amounts of hepatocyte growth factor is a characteristic feature of cancer‐associated fibroblasts with EGFR‐TKI resistance‐promoting phenotype: A study of 18 cases of cancer‐associated fibroblasts

Humoral factors from cancer‐associated fibroblasts (CAFs) reportedly affect epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) resistance in cancer cells with EGFR mutations. The aim of this study was to identify the robust humoral factors secreted from CAFs that induce the primary resistance to EGFR‐TKI. We evaluated the EGFR‐TKI sensitivity of EGFR‐mutant lung adenocarcinoma cell line (PC‐9) treated with condition media (CM) from 18 cases of CAFs and matched non‐cancerous‐tissue‐associated fibroblasts (NCAFs). We measured the expression levels of hepatocyte growth factor (HGF), interleukin‐6, fibroblast growth factor‐2, insulin‐like growth factor‐1, and vascular endothelial growth factor‐A in CAFs and NCAFs. We examined whether HGF neutralizing antibody could annul the EGFR‐TKI resistance induced by CM from CAFs. Compared to CM from NCAFs, CM from CAFs increased the resistance of PC‐9 cells to EGFR‐TKI in five out of 18 cases. Relative expression ratio of HGF messenger RNA was significantly higher in these five CAFs compared to others (P = 0.0013), whereas other cytokines were not. In four of these five cases, the addition of HGF neutralizing antibody significantly decreased the survival ratio of PC‐9 cells. This study suggests that the secretion of higher amounts of HGF is the robust feature of EGFR‐TKI resistance‐promoting CAFs.     

Matrix metalloproteinases,TIMPs and growth factors regulating ameloblastoma behaviour

Siqueira A S, Carvalho M R D, Monteiro A C D, Freitas V M, Jaeger R G & Pinheiro J J V.
(2010) Histopathology 57 , 128–137
Matrix metalloproteinases, TIMPs and growth factors regulating ameloblastoma behaviour Aims: Ameloblastoma is an odontogenic neoplasm with local invasiveness and recurrence. We have previously suggested that growth factors and matrix metalloproteinases (MMPs) influence ameloblastoma invasiveness ¹ . The aim was to study expression of MMPs, tissue inhibitor of metalloproteinases (TIMPs) and growth factors in ameloblastoma. Methods and results: Thirteen cases of solid/multicystic ameloblastoma were examined. As a control, calcifying cystic odontogenic tumour (CCOT), a non‐invasive odontogenic neoplasm with ameloblastomatous epithelium was also studied. Immunohistochemistry detected MMPs, TIMPs and growth factors in ameloblastoma and CCOT. The labelling index (LI) of MMP‐9 and TIMP‐2 was significantly higher in ameloblastoma compared with CCOT. The LI of epidermal growth factor (EGF), transforming growth factor (TGF)‐α and epidermal growth factor receptor (EGFR) was also increased in ameloblastoma. This neoplasm showed greater expression of MMPs, TIMPs and growth factors compared with CCOT. We then analysed these molecules in ameloblastoma cells and stroma. Ameloblastoma cells exhibited increased LI of MMP‐1, ‐2 and EGFR. We found a positive correlation between EGF and TIMP‐1, and between TGF‐α and TIMP‐2. It is known that signals generated by growth factors are transduced by the ERK pathway. Ameloblastoma stroma exhibited the phosphorylated (activated) form of ERK. Conclusions: These results suggest an interplay involving growth factors MMPs and TIMPs that may contribute to ameloblastoma behaviour. Signals generated by this molecular network would be transduced by ERK 1/2 pathway.     

Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen

Background Stimulation of epidermal growth factor receptor (EGFR) induces airway goblet cell hyperplasia, but the role of this molecule in the maintenance of this pathologic change remains uncertain. Objective To determine the mechanisms by which goblet cell hyperplasia is maintained in airway epithelium, we investigated EGFR‐induced signalling pathways that lead to both mucin production and antiapoptosis in vitro. We also tested whether the inhibition of EGFR tyrosine kinase speeds reversal of established goblet cell hyperplasia to normal epithelial phenotype in vivo. Methods MUC5AC production was measured by immunoassay, and antiapoptotic responses were determined by Bcl‐2 expression and terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin Nick End Labelling staining using NCI‐H292 cells. The effect of an inhibitor of EGFR tyrosine kinase (AG1478) on goblet cell hyperplasia was also determined in rats sensitized with ovalbumin (OVA). Results MUC5AC was constitutively expressed and few apoptotic cells were observed in NCI‐H292 cells under non‐stimulated condition. TGF‐α increased MUC5AC and Bcl‐2 expression, an effect that was prevented by inhibitors of EGFR tyrosine kinase (AG1478), MEK (PD98059), and NF‐κB (CAPE). After the addition of TGF‐α, AG1478 and an inhibitor of phosphatidylinositol 3 kinase/Akt (LY294002), but not PD98059, induced a marked apoptotic response, which was prevented by the caspase inhibitor Z‐VAD fmk. Goblet cell hyperplasia and EGFR expression in airway epithelium were noted in the OVA‐sensitized rats. Intratracheal instillation of AG1478 induced apoptosis of goblet cells, reverting the airway epithelium to normal epithelial phenotype. Conclusion These findings indicate that EGFR plays an important role in the maintenance of goblet cell hyperplasia. We speculate that inhibitors of the EGFR cascade might be an effective therapy of airway remodelling.     

Attenuated TGF‐β1 responsiveness of dendritic cells and their precursors in atopic dermatitis

The responsiveness of DCs and their precursors to transforming growth factor beta1 (TGF‐β1) affects the nature of differentiating DC subsets, which are essential for the severity of atopic dermatitis (AD). To evaluate TGF‐β signaling in monocytes and monocyte‐derived DCs of AD patients compared with that of controls, in vitro generated Langerhans cell (LC) like DCs, expression of TGF‐β receptors, phospho‐Smad2/3 and Smad7 were evaluated. Furthermore, TNF‐α expression and synergistic effects of TNF‐α upon TGF‐β signaling and DC generation were evaluated. We found LC‐like DC differentiation of monocytes from AD patients in response to TGF‐β1 was remarkably reduced and TGF‐β1 receptor expression was significantly lower compared with that of healthy controls. Attenuated TGF‐β1 responsiveness mirrored by lower phospho‐Smad2/3 expression after TGF‐β1 stimulation and higher expression of inhibitory Smad7 was observed in monocytes from AD patients. During DC generation, mRNA expression of Smad7 was relatively higher in LC‐like DCs of AD patients. Lower TNF‐α expression of monocytes from AD patients might further contribute to attenuated TGF‐β signaling in the disease since TNF‐α had synergistic effects on TGF‐β1 signaling and LC generation through mediating the degradation of Smad7. Our results demonstrate alleviated TGF‐β1 signaling together with the amount of soluble co‐factors might direct the nature of differentiating DCs.     

EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number

Aims:  Epidermal growth factor receptor (EGFR) expression has been observed in a variety of solid tumours with the potential of new targeted therapeutic agents. The aim was to evaluate the EGFR status of gastric carcinoma (GC) using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).
Methods and results:  The EGFR status was evaluated in GC tissues from 511 patients using IHC and FISH. In addition, the clinicopathological characteristics were examined and the results were compared with the EGFR status. One hundred and forty cases (27.4%) showed EGFR overexpression by IHC. EGFR overexpression was associated with older age ( P  = 0.001), moderately or poorly differentiated histology ( P  = 0.001) and higher stage disease ( P  = 0.046). Sixteen cases (3.1%) showed high polysomy and 12 cases (2.3%) had gene amplification by FISH. The correlation between IHC and FISH results was statistically significant ( P  < 0.001). The patients with GC who had EGFR overexpression had an unfavourable prognosis and multivariate analysis showed that EGFR overexpression was a possible independent unfavourable prognostic factor.
Conclusions:  EGFR overexpression was observed in a subset of cases with GC and was associated with an unfavourable prognosis. It will be important to evaluate EGFR status to interpret future clinical trials properly using EGFR targeted agents.     

Immunohistochemical expression of CD95 (Fas), c-myc and epidermal growth factor receptor in hepatitis C virus infection, cirrhotic liver disease and hepatocellular carcinoma

Gene product expression in normal and chronic hepatitis C virus infection was determined in an attempt to improve our understanding of the molecular events leading to the development of cirrhosis and liver carcinoma. Activation of CD95 (Fas) causes apoptosis of cells and liver failure in mice and has been associated with human liver disorders. c-myc is involved in cell proliferation and EGFR in regeneration of cells. The material of the current study included 50 cases of chronic hepatitis C (CHC) (and negative hepatitis B virus infection), 29 cases of liver cirrhosis and HCV (LC), and 19 cases of hepatocellular carcinoma and HCV (HCC) admitted to the Theodor Bilharz Research Institute (TBRI) during the years 2003-2004. Ten wedge liver biopsies - taken during laparoscopic cholecystectomy - were included in the study as normal controls. Laboratory investigations, including liver function tests, serological markers for viral hepatitis and serum alpha fetoprotein level (alpha-FP), were determined for all cases. Histopathological study and immunohistochemistry using monoclonal antibodies for CD95, c-myc and EGFR were also done. In CHC cases, the histological activity index (HAI) revealed more expression of Fas antigen in liver tissues with active inflammation than in those without active inflammation (p < 0.01). EGFR and c-myc act synergistically in liver tumorigenesis. Upregulation of Fas in chronic hepatitis C infection and of c-myc & EGFR in malignant transformation was concluded from this study. c-myc expression may obstruct the induction of apoptosis of HCC cells and lead to uncontrolled cell growth.     

核表皮生长因子受体在肿瘤发生发展和治疗耐受中的作用

表皮生长因子受体（epidermal growth factor receptor,EGFR）作为膜受体在许多肿瘤组织细胞中具有促进细胞增生、血管生成、侵袭和转移的作用。然而,对核EGFR转导途径及其功能的研究表明：核EGFR作为一个新的转录因子在肿瘤的形成、发展、转移及治疗耐受中发挥着重要的生物学功能,特别是核EGFR能促进细胞生成和促进DNA修复,以及使肿瘤细胞耐受化疗和放疗的作用。因而,针对EGFR的分子靶向治疗具有重要的实际意义。     

Nerve growth factor regulation and production by macrophages in osteoarthritic synovium

Nerve growth factor (NGF) functions to modulate osteoarthritis (OA)‐associated pain. Although recent studies suggest that tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β mediate NGF activity in human synovial fibroblasts, the regulation of NGF expression in human synovial macrophages remains unclear. Here, we examined the role of macrophages in the production and regulation of synovial (SYN) NGF in osteoarthritic knee joints by examining the mRNA expression of TNF‐α and IL‐1β in freshly isolated CD14‐positive (macrophage‐rich fraction) and CD14‐negative cells (fibroblast‐rich fraction) in synovial tissue from OA patients by quantitative polymerase chain reaction. We also examined the effects of IL‐1β and TNF‐α on NGF mRNA expression in cultured CD14‐positive (macrophage‐rich fraction) and CD14‐negative cells (fibroblast‐rich fraction). In addition, to examine the contribution of macrophages to NGF, TNF‐α and IL‐1β expression, we injected clodronate liposomes systemically into STR/Ort mice, an osteoarthritis animal model, to deplete macrophages. TNF‐α and IL‐1β mRNA levels in CD14‐positive cells from the SYN of OA patients was significantly higher than that in CD14‐negative cells, while NGF expression did not differ markedly between the two cell fractions. In addition, treatment of human cultured CD14‐positive and ‐negative cells with IL‐1β and TNF‐α enhanced NGF mRNA and protein levels. Expression of NGF, IL‐1β and TNF‐α was also reduced significantly in STR/Ort mice upon macrophage depletion. These findings suggest that IL‐1β and TNF‐α regulate NGF expression and production in synovial macrophages and fibroblasts in osteoarthritic joints.     

Epidermal growth factor receptor gene amplification and protein overexpression in basal-like carcinoma of the breast

Shao M‐M, Zhang F, Meng G, Wang X‐X, Xu H, Yu X‐W, Chen L‐Y & Tse G M
(2011) Histopathology 59 , 264–273 Epidermal growth factor receptor gene amplification and protein overexpression in basal‐like carcinoma of the breast Aims: Epidermal growth factor receptor (EGFR) is frequently expressed in basal‐like breast cancer (BLBC). The aim of this study was to evaluate their correlation as detected by immunohistochemistry (IHC) or fluorescence in‐situ hybridization (FISH). Methods and results: IHC for oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER) 2, cytokeratin (CK) 5/6 and EGFR, and FISH for EGFR amplification, were performed in 59 cases of BLBC. EGFR IHC results were scored semiquantitatively, and compared with its gene amplification status. ER, PR and HER2 were negative in all cases, whereas 35 and 55 cases were positive for CK5/6 and EGFR. For EGFR IHC, 20, 11, 11 and 17 cases showed a negative, a low, an intermediate or a high staining level, respectively, and seven cases showed gene amplification by FISH, with two, 19, 11 and 20 cases showing balanced monosony, disomy, trisomy, and polysomy respectively. Immunohistochemical expression in gene‐amplified tumours was significantly higher than in those without amplification, including balanced polysomy tumours. EGFR immunohistochemical expression also correlated with the EGFR/chromosome 7 ratio. High sensitivity (86%) and negative predictive value (98%) were achieved with high‐level immunohistochemical expression as a cut‐off to predict gene amplification. Conclusions: High‐level EGFR immunohistochemical expression correlated with and predicted EGFR amplification, and may be used as a screening method to exclude gene amplification.     

A comparison of epidermal growth factor receptor expression in malignant peritoneal and pleural mesothelioma

An evaluation of epidermal growth factor receptor (EGFR) phenotypic expression in malignant pleural and peritoneal mesothelioma was undertaken, using immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) analysis. Thirty-eight malignant mesothelioma (MM) specimens were subjected to IHC staining and FISH to evaluate the expression of EGFR protein and gene status. Overall positive IHC reaction was detected in 20/38 (53%) cases, in 11/22 (50%) pleural MM, and in 9/16 (56%) peritoneal MM. Our study confirmed that EGFR membranous expression is a common feature in MM, but not in benign mesothelial lesion. Thirty-seven cases did not show a gene copy number gain. Only one case showed a copy number gain. The protein overexpression of EGFR was not related to a gene copy number gain.     

Reversible phospho‐Smad3 signalling between tumour suppression and fibrocarcinogenesis in chronic hepatitis B infection

Transforming growth factor (TGF)‐β, type I receptor (TβRI) and c‐Jun N‐terminal kinases (JNK) phosphorylate Smad3 differentially to create 2 isoforms phosphorylated (p) at the COOH‐terminus (C) or at the linker region (L) and regulate hepatocytic fibrocarcinogenesis. This study aimed to compare the differences between how hepatitis B virus (HBV) infection affected hepatocytic Smad3 phosphorylated isoforms before and after anti‐viral therapy. To clarify the relationship between Smad3 phosphorylation and liver disease progression, we studied 10 random patients in each stage of HBV‐related fibrotic liver disease (F1–4) and also 10 patients with HBV‐associated HCC. To examine changes in phosphorylated Smad3 signalling before and after anti‐HBV therapies, we chose 27 patients with chronic hepatitis B who underwent baseline and follow‐up biopsies at 52 weeks from the start of nucleoside analogue treatments (Lamivudine 100 mg daily or Telbivudine 600 mg daily). Fibrosis stage, inflammatory activity and phosphorylated Smad3 positivity in the paired biopsy samples were compared. Hepatocytic pSmad3C signalling shifted to fibrocarcinogenic pSmad3L signalling as the livers progressed from chronic hepatitis B infection to HCC. After nucleoside analogue treatment, serum alanine aminotransferase (ALT) and HBV‐DNA levels in 27 patients with HBV‐related chronic liver diseases were decreased dramatically. Decrease in HBV‐DNA restored pSmad3C signalling in hepatocytes, while eliminating prior fibrocarcinogenic pSmad3L signalling. Oral nucleoside analogue therapies can suppress fibrosis and reduce HCC incidence by successfully reversing phosphorylated Smad3 signalling; even liver disease progressed to cirrhosis in chronic hepatitis B patients.     

c－erbB－2蛋白和表皮生长因子受体在肝脏病变中的表达

对１８４例乙型肝炎、肝硬变和肝细胞癌（ＨＣＣ）及２９例正常肝组织的标本作了ＡＢＣ法染色，观察其ｃ－ｅｒｂＢ－２蛋白和表皮生长因子受体（ＥＧＦＲ）的表达情况。３６％（４８／１３４）的慢性肝炎、肝硬变和ＨＣＣ组织中有ＥＧＦＲ表达，主要定位于血窦内皮。良、恶性病变肝组织之间在ＥＧＦＲ表达强度上无显著差别，提示ＥＧＦＲ可能与慢性肝脏病变中血窦内皮的增生有关。在正常肝，仅少数标本（５／２９）中见到ｃ－ｅｒｂＢ－２微弱表达；在ＨＢＶ相关的慢性肝脏病变，所有标本中均检测到ｃ－ｅｒｂＢ－２蛋白，主要定位于肝小多角细胞（ＳＰＬＣ）、小细胞性不典型增生（ＳＣＤ）及小管状化生（ＤＭ）的肝细胞；ＨＣＣ细胞中ｃ－ｅｒｂＢ－２蛋白阳性较弱。这提示ｃ－ｅｒｂＢ－２基因的活化与人ＨＣＣ发生有关。其作用机制可能是促进ＳＰＬＣ向ＳＣＤ的转化及促进ＳＣＤ的进展。ｃ－ｅｒｂＢ－２与ＨＢｘＡｇ表达的密切关联提示这种原癌基因的活化可能也与ＨＢＶＸ基因有关。     

结缔组织生长因子在慢性肝病诊断中的应用研究

探讨结缔组织生长因子(CTGF)在慢性肝病诊断中的应用价值。运用ELISA方法检测198例研究对象,观察血清CTGF水平的变化,分析CTGF水平与临床特征及实验室指标的相关性;运用实时荧光定量RT-PCR方法检测组织中CT-GF mRNA的表达量,比较各组间表达量的变化。乙肝后重度肝纤维化组、肝硬化组、原发性肝细胞癌(HCC)组的血清CTGF水平均显著高于正常对照组,且具有统计学意义(P<0.05);血清CTGF水平与部分临床实验室特征存在相关性,在区分早晚期肝纤维化上具有诊断提示作用;癌旁组织的CTGF mRNA相对表达量显著高于正常对照和癌组织的表达量且具有统计学差异(P<0.05)。血清CTGF水平与肝纤维化、肝硬化及肝癌的发生发展关系密切,有望成为一个新的无创性肝纤维化检测诊断指标,为临床诊断提供依据。     

Epidermal growth factor receptor signalling contributes to osteoblastic stromal cell proliferation, osteoclastogenesis and disease progression in giant cell tumour of bone

Balla P, Moskovszky L, Sapi Z, Forsyth R, Knowles H, Athanasou N A, Szendroi M, Kopper L, Rajnai H, Pinter F, Petak I, Benassi M S, Picci P, Conti A & Krenacs T
(2011) Histopathology 59 , 376–389 Epidermal growth factor receptor signalling contributes to osteoblastic stromal cell proliferation, osteoclastogenesis and disease progression in giant cell tumour of bone Aims: Epidermal growth factor receptor (EGFR) is implicated in bone remodelling. The aim was to determine whether EGFR protein expression contributes to the aggressiveness and recurrence potential of giant cell tumour of bone (GCTB), an osteolytic primary bone tumour that can exhibit markedly variable clinical behaviour. Methods and results: Immunohistochemical analysis on tissue microarrays (TMA) of 231 primary, 97 recurrent, 17 metastatic and 26 malignant GCTBs was performed using TMA analysis software and whole digital slides allowing validated scoring. EGFR expression was restricted to neoplastic stromal cells and was significantly more frequent in recurrent (71 of 92; 77%) than in non‐recurrent GCTBs (86 of 162; 53%) (P = 0.002); and in clinicoradiologically aggressive (31 of 43; 72%) than latent (27 of 54; 50%) cases (P = 0.034). Detecting phosphotyrosine epitopes pY1068 and ‐pY1173 indicated active EGFR signalling, and finding EGFR ligands EGF and transforming growth factor‐α restricted to cells of the monocytic lineage suggested paracrine EGFR activation in stromal cells. In functional studies EGF supported proliferation of GCTB stromal cells, and the addition of EGF and macrophage‐colony stimulating factor promoted osteoclastogenesis. Conclusion: In GCTB, EGFR signalling in neoplastic stromal cells may contribute to disease progression through promoting stromal cell proliferation and osteoclastogenesis.     

Pathological significance of epidermal growth factor receptor expression and amplification in human gliomas

Zhao L‐l, Xu K‐l, Wang S‐w, Hu B‐l & Chen L‐r
(2012) Histopathology  61, 726–736 Pathological significance of epidermal growth factor receptor expression and amplification in human gliomas Aims: To investigate epidermal growth factor receptor (EGFR) expression and amplification in gliomas and to assess their association with survival. Methods and results: Immunohistochemistry and fluorescence in‐situ hybridization were performed to analyse EGFR status in 158 cases of primary glioma. Kaplan–Meier survival and Cox regression analyses were performed to analyse the prognosis of patients. Overexpression of EGFR and expression of EGFR variant III (EGFRvIII) were found in 102 cases (64.6%) and 47 cases (29.7%), respectively. Overexpression of EGFR was significantly correlated with World Health Organization (WHO) grade and Karnofsky performance score (KPS) (both P < 0.05). Expression of EGFRvIII was significantly correlated with WHO grade, gender, age, and KPS (all P < 0.05). EGFR amplification was found in 46 cases (29.1%), and was significantly correlated with WHO grade, age, KPS and EGFR overexpression (all P < 0.05). Cox multifactor analysis showed that EGFR amplification was an independent unfavourable prognostic factor for human gliomas at all ages, and EGFRvIII was an independent prognostic factor in patients older than 60 years. Conclusions: EGFR amplification and EGFRvIII expression were associated with an unfavourable prognosis for patients of all ages, and for those older than 60 years, respectively. The differing significance of EGFR status in young and old glioma patients and its impact on prognosis needs further study.