胃癌中神经内分泌细胞的临床病理学意义

 本文应用铬粒素A（CgA）、胃泌素（GAS）、生长抑素（SS）及5-羟色胺（5-HT）对120例普通型胃癌用免疫组化SP法标记其神经内分泌细胞。结果表明：四种激素抗体检测，以CgA最敏感、阳性率最高为31.7%;高分化腺癌CgA阳性率显着高于低分化和未分化癌（P<0.05）,但高分化腺癌CgA阳性病例以（+）为主，未分化癌以（++）为主；而SS.5HT的阳性率，高、低分化腺癌均高于未分化癌（P>0.05）.CgA及5-HT阳性病例淋巴结转移率高于阴性病例（P<0.05）,CgA（++）病例术后生存期明显短于CgA（+）及CgA（-）者（P<0.05）,GAS、5-HT及SS阳性与阴性病例术后生存期无显着差异。     

Prognostic implications of P-glycoprotein, epidermal growth factor receptor and transforming growth factor alpha

The prognostic value of clinical and pathological factors in 97 patients (pts) with non-small cell lung cancer (NSCLC), were analyzed through immunohistochemical methods. The impact on response rate and survival of age, Karnofsky performance status (PS), sex, NSCLC subtype and grade, extent of disease, objective chemotherapy response, LDH values, metastatic sites involved and immunohistochemical study of epidermal growth factor receptor (EGF-r), transforming growth factor alpha (TGF-alpha) and P-glycoprotein (Pgp) employing two monoclonal antibodies: C-219 and JSB-1, were analyzed. Median age was 61 years, seven pts were women. Histologically, 58 had squamous cell carcinoma, 28 adenocarcinoma and 11 large cell undifferentiated carcinoma. One patient had stage II, 35 stage IIIA, 19 stage IIIB and 42 stage IV. Six pts achieved complete response, 18 partial response, 34 stable disease and 39 progressive disease. EGF-r was positive in 30 cases, TGF-alpha in 51, C-219 Pgp in 13 and JSB-1 Pgp in 35 cases. The univariate analysis showed that 4 parameters had significant adverse effect on survival: non-responders, poor PS, abnormal LDH value and absence of EGF-r expression. On the other hand, we found no correlation between TOP-alpha and EGF-r immunostaining. But 22 pts expressed both autocrine markers and these pts had a worse median survival time. Multivariate analysis showed that the only independent prognostic factor in predicting survival was Karnofsky performance status.     

Interrelationship between transforming growth factor-alpha and epidermal growth factor receptor in advanced gastric cancer.

An immunohistochemical study for transforming growth factor-alpha (TGF alpha) and epidermal growth factor receptor (EGFR) was made with 167 primary tumors of advanced gastric cancer to demonstrate the potential existence of autocrine mechanism. TGF alpha stained positively in 87 (52%), and EGFR in 68 (41%) of the tumors. The authors classified the tumors into the following three groups: group 1 with neither TGF alpha nor EGFR staining positively (63 tumors); group 2 with either TGF alpha or EGFR staining positively (53 tumors); group 3 with both TGF alpha and EGFR staining positively (51 tumors). The incidence rates of macroscopically infiltrative tumors and large tumor measuring 6 cm or more in diameter were significantly higher for group 3 than for groups 1 and 2. The patients of group 3 had the poorest prognosis, with a 5-year survival rate of only 12%, while the 5-year survival rates were 45 and 36% for groups 1 and 2. There was a significant difference in survival between the patients of group 1 and those of group 3. Bromodeoxyuridine labeling indices were significantly higher in the tumors belonging to group 3 (median 15.8%) than in those of group 1 (median 10.8%). The results suggest that the autocrine mechanism between TGF alpha and EGFR may play an important role in the progression of gastric cancer, and that when such a mechanism becomes operative, prognosis may be poor.     

G protein pathway suppressor 2 suppresses gastric cancer by destabilizing epidermal growth factor receptor

G protein pathway suppressor 2 (GPS2) is expressed in most human tissues, including the stomach. However, the biological functions of GPS2 in cancer, as well as the underlying molecular mechanisms, remain poorly understood. Here, we report that GPS2 expression was aberrantly downregulated in gastric cancer (GC) tissues compared with control tissues. Clinicopathologic analysis showed that low GPS2 expression was significantly correlated with pathological grade, lymph node stage, and invasive depth. Kaplan-Meier analysis indicated that patients with low GPS2 expression showed poorer overall survival rates than those with high GPS2 expression. Moreover, GPS2 overexpression decreased GC cell proliferation, colony formation, tumorigenesis, and invasion. Overexpression of GPS2 reduced the protein expression of epidermal growth factor receptor (EGFR) and inhibited its downstream signaling in GC cells. Interestingly, GPS2 decreased EGFR protein expression, which was reversed by a lysosome inhibitor. Furthermore, GPS2 reduced EGFR protein stability by enhancing the binding of EGFR and an E3 ligase, c-Cbl, which promoted the ubiquitination of EGFR, ultimately leading to its degradation through the lysosomal pathway. Further analysis indicated that GPS2 activated autophagy and promoted the autophagic flux by destabilizing EGFR. Taken together, these results suggest that low GPS2 expression is associated with GC progression and provide insights into the applicability of the GPS2-EGFR axis as a potential therapeutic target in GC.     

Prognostic value of epidermal growth factor receptor mutations in resected lung adenocarcinomas

In this study, we investigated the associations of polymorphisms in glutathione-S-transferases (GSTs) genes that are GSTM1, GSTT1, and GSTP1, with sporadic colorectal cancer (CRC). Hundred and fifty patients with CRC and 128 healthy controls were genotyped. DNA was isolated from blood samples. Polymorphisms were assessed by polymerase chain reaction–restriction fragment length polymorphism-based methods and polymerase chain reaction multiplex. Logistic regression analyses showed significant risk for CRC associated with GSTP1 homozygotes for Val-105 (OR 4.82; 95 % CI 1.97–11.80) or for individuals who possessed at least one Val-105 allele (OR 2.54; 95 % CI 1.751–3.703). There were no statistically significant differences in the frequency of GSTM1- and GSTT1-null genotypes (p > 0.05). The GSTM1-null was found in 70.47 % of all cases and 70.07 % of controls (OR 0.61; 95 % CI 0.33–1.12). The GSTT1-null genotype was found in 38.77 % of cases and 49.22 % of controls (OR 1.53; 95 % CI 0.94–2.47). No effect of any genotype for GSTM1 and GSTT1 on CRC was detected. But then an association between the polymorphism of the GSTP1 and the CRC susceptibility was detected.     

Inhibition of PC-3 prostate cancer cell growth in vitro using both antisense oligonucleotides and taxol

Antisense oligonucleotides (oligos) directed against mRNA-encoding transforming growth factor-α (TGF-α) and the epidermal growth factor receptor (EGFR) have demonstrated in vitro and in vivo efficacy against prostate cancer tumor models. However, many therapeutic agents have increased effectiveness when given in combination with other more established agents. We evaluated the effectiveness of two oligos (3.32 and 6.64 μM/L) known to have significant activity against the PC-3 prostate cell line in combination therapy with the chemotherapeutic agent paclitaxel (Taxol) (2.5 and 5.0 nm). Therapy was evaluated when oligos and Taxol were administered either as (1) single agents, (2) simultaneously in a combined therapy, or (3) sequentially, a form of combination therapy with both agents being administered in a series. We found that when either of the two oligos were given simultaneously with Taxol, no synergistic activity was noted. However, when sequentially administered in a series 1 d apart, a pretreatment with the antisense directed against TGF-α (6.64 μM/L) followed by Taxol (5 nm) had significantly greater activity than these agents similarly administered in the reverse order or simultaneously.     

Expression of transforming growth factor alpha, epidermal growth factor receptor and epidermal growth factor in precursor lesions to gastric carcinoma.

Epidermal growth factor (EGF), its related peptide transforming growth factor (TGF-alpha) and their common receptor (EGFR) have been implicated in the control of cell proliferation and differentiation in the gastrointestinal epithelium and may play an important role in gastric carcinogenesis. We compared the immunohistochemical expression and topographic distribution of these peptides using Western blot analysis in gastric carcinoma precursor lesions and in non-cancer tissue. We observed: (i) increased and extended expression of TGF-alpha in normal mucosa and hyperplasia in carcinoma fields compared with non-cancer controls; (ii) increased expression of EGFR in intestinal metaplasia (IM) from carcinoma fields compared with controls; (iii) EGF expression was not detected in normal mucosa and only weakly in IM; (iv) coexpression of TGF-alpha/EGFR and EGF/EGFR was higher in intestinal metaplasia in carcinoma fields than in non-cancer controls. We conclude that altered expression of TGF-alpha/EGFR is associated with morphological changes during gastric carcinogenesis. In this regard increased expression of TGF-alpha is a very early event which is subsequently followed by up-regulation of EGFR and this has important biological and clinical implications.     

辅助化疗对胃神经内分泌癌患者预后的意义

背景与目的:胃神经内分泌肿瘤(neuroendocrine neoplasm,NEN)是胃恶性肿瘤中一种较为罕见的类别,根据2019年世界卫生组织(World Health Organization,WHO)消化系统NEN的分类标准,分为分化好的神经内分泌瘤(neuroendocrine tumor,NET)和分化差的神经内分泌癌(neuroendocrine carcinoma,NEC)。目前,关于胃NEC(gastric NEC,GNEC)辅助化疗预后的研究匮乏,本研究旨在探讨辅助化疗能否使GNEC患者获益,以期为临床决策提供参考依据。方法:回顾性分析中山大学肿瘤防治中心、中山大学附属第一医院和复旦大学附属肿瘤医院2008年7月—2019年6月收治的184例GNEC患者的临床病理学资料,随访截至2022年5月31日。利用Kaplan-Meier法绘制生存曲线,根据单因素COX回归分析和多因素COX回归分析筛选出影响GNEC患者生存的独立预后因素,并进一步分析化疗、手术等因素对患者预后的影响。检验水准为α=0.05,所有统计学分析均使用SPSS 25.0软件。结果:单因素分析显示,手...     

Heparin-binding epidermal growth factor-like growth factor isoforms and epidermal growth factor receptor/ErbB1 expression in bladder cancer and their relation to clinical outcome

BACKGROUND: Cleavage of membrane-anchored heparin-binding epidermal growth factor-like growth factor (proHB-EGF) yields a soluble HB-EGF isoform (sHB-EGF), which is an activating epidermal growth factor receptor (EGFR) ligand and a C-terminal fragment HB-EGF-C acting directly in the nucleus. In bladder cancer, overexpression of both HB-EGF and EGFR have been observed, but to the authors' knowledge the prognostic significance of different modes of HB-EGF signaling have remained unclear. METHODS: Expression and intracellular localization of HB-EGF and EGFR were examined by immunohistochemistry in paraffin-embedded specimens from 121 patients who underwent cystectomy for bladder cancer. Tumor stage was pTis/pT1 in 7 patients, pT2 in 41 patients, pT3 in 55 patients, and pT4 in 18 patients. Lymph node metastases were present in 32 patients. RESULTS: Using an antibody directed against the C-terminal domain, HB-EGF expression was detected in the cytoplasm or in the nucleus of tumor cells. EGFR staining was uniform at the plasma membrane. The actuarial 5-year cancer-specific survival of patients with tumors with predominant nuclear HB-EGF staining was 28% compared with 57% if HB-EGF staining was predominantly cytoplasmic (P = .027). Disease outcome of patients with a 'mixed' HB-EGF staining pattern was found to be between that of the 2 former groups. In agreement with previous studies, strong EGFR expression was associated with poor prognosis. Despite strong EGFR expression, predominant cytoplasmic HB-EGF staining was associated with a more favorable outcome, whereas a predominant nuclear pattern defined a subgroup with extremely poor prognosis (5-year tumor-specific survival of 55% vs 13%, respectively; P = .026). CONCLUSIONS: The current study results confirm that EGFR expression is significantly correlated with disease-specific mortality but that the outcome is also influenced by the mode of HB-EGF signaling. Additional nuclear HB-EGF signaling, indicative of increased cleavage of proHB-EGF, appears to enhance the adverse activities. Cytoplasmic HB-EGF staining likely reflects proHB-EGF, which may also exert antiproliferative effects.     

Expression of epidermal growth factor, transforming growth factor-alpha and their receptor genes in human gastric carcinomas; implication for autocrine growth

The expressions of mRNA for epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) and EGF receptor (EGFR) genes were examined in 7 human gastric carcinoma cell lines and 15 gastric carcinoma tissues and the corresponding normal mucosas. All of the gastric carcinoma cell lines expressed mRNA for EGFR and TGF-alpha genes. TMK-1 and MKN-28 cells also expressed EGF mRNA. Production of EGF, TGF-alpha and EGFR protein by gastric carcinoma cell lines was also confirmed by EGF and TGF-alpha specific monoclonal antibody binding. As for surgical specimens, EGFR and TGF-alpha mRNA were detected at high levels in all the tumor tissues. Interestingly, EGF mRNA was detected in 5 (33.3%) of the 15 gastric carcinomas but it was not detected in normal tissues. Moreover, anti-EGF and anti-TGF-alpha monoclonal antibodies inhibited the spontaneous 3H-TdR uptake by gastric carcinoma cells. These results suggest that EGF and/or TGF-alpha produced by tumor cells act as autocrine growth factors for gastric carcinomas.     

Co-expression of epidermal growth factor receptor and transforming growth factor-alpha predicts worse prognosis in breast-cancer patients

Epidermal growth factor receptor (EGF-R) and its ligand, transforming growth factor-alpha (TGF-alpha), play an important role through the autocrine growth-regulation system in several human cancers, including breast cancer. However, the clinical significance of co-expression of EGF-R and TGF-alpha has not been elucidated. One hundred seventy-three female patients diagnosed as invasive ductal carcinoma who had undergone a mastectomy (159 patients) or breast-conserving surgery (14 patients) were followed up for 81 to 119 months (median 94 months) post-operatively. Immunoreactivity for EGF-R, TGF-alpha, p53 and c-erbB-2 with paraffin-embedded carcinoma tissue was investigated using labeled streptavidin-biotin methods. Positive rates of carcinoma cells were 27%, 33%, 32% and 26% for EGF-R, TGF-alpha, p53 and c-erbB-2, respectively. Expression of EGF-R only was observed in 16% (28/173), of TGF-alpha only in 22% (38/173), of both EGF-R and TGF-alpha in 11% (19/173) and of neither in 51% (88/173). By univariate analysis, significant differences in overall survival and disease-free survival were noted according to the co-expression of EGF-R and TGF-alpha (p< 0.0001, p<0.0001), co-expression of EGF-R and c-erbB-2 (p = 0.0029, p = 0.0028), nodal status (p = 0.0028, p = 0.0001), tumor size (p = 0.0001, p<0.0001) and c-erbB-2 expression (p = 0.0034, p = 0.018), respectively. The status of p53 expression (p = 0.01), estrogen receptor (p = 0.042) and progesterone receptor (p = 0.046) showed significant differences in overall survival. According to Cox's multivariate analysis, co-expression of EGF-R and TGF-alpha had the most significant effect on disease-free survival (p<0.0001) and overall survival (p<0.0001), followed by nodal status. Co-expression of EGF-R and TGF-alpha by immunohistochemical detection is an independent prognostic indicator, and it may be helpful for determining the group of breast-cancer patients with an aggressive phenotype.     

EGFR在结直肠癌组织中的表达及其临床意义

目的：检测表皮生长因子受体（epidermal growth factor receptor,EGFR）在结直肠癌组织中的表达情况,分析其表达水平与各种主要临床病理学预后因子及长期生存的关系。方法：选取解放军307医院和301医院第二附属医院64例结直肠癌患者的石腊包埋肿瘤标本,以免疫组化方法检测结直肠癌肿瘤标本中EGFR的表达。通过单因素分析和多因素分析判断EGFR表达与临床病理学指标之间的关系;通过多因素分析（COX模型）判断EGFR表达水平与患者总生存期的关系。结果：所有患者肿瘤组织EGFR的阳性表达率为69%。T3期肿瘤EGFR阳性表达明显多于T1和T2期（P〈0.05）,淋巴结转移阳性者EGFR阳性表达明显多于无转移者（P〈0.05）,有远处转移者EGFR阳性表达明显多于无远处转移者（P〈0.05）;EGFR表达与患者性别、年龄、肿瘤原发部位、肿瘤大小、肿瘤分化程度等均无明显相关性。EGFR表达水平与患者总生存期无明显相关。结论：结直肠癌组织EGFR的表达与肿瘤TNM分期相关,与患者总生存期无明显相关。     

湖南地区肺腺癌EGFR基因突变及突变位点的临床病理特点

目的:研究湖南地区肺腺癌EGFR基因突变及突变位点的临床病理特点。方法:收集中南大学湘雅医院胸外科肺腺癌患者组织标本134例,采用扩增阻滞突变系统(ARMS)检测EGFR外显子18、19、20、21号突变状态。结果:134例肺腺癌患者中EGFR突变68例,突变率50.7%。其中男、女突变率分别为40.7%、58.7%（P=0.039）,吸烟、不吸烟患者突变率分别为30.6%、62.4%（P=0.000）。外显子18、19、20、21号突变分别为2例（2.9%）、32例（47.1%）、3例（4.4%）、31例（45.6%）。19、21号外显子突变在肺癌TNM分期中I-II期与III-IV期比较有差异,21号外显子突变在I-II期多见,P=0.048。结论:湖南地区肺腺癌中女性、不吸烟患者EGFR突变率高,EGFR突变以19、21号外显子为主,19与21号外显子突变相比较,21号外显子突变在肺癌TNM分期中I-II期多见。     

Co-expression of epidermal growth factor receptor and transforming growth factor-alpha is independent of ras mutations in lung adenocarcinoma

The interaction of epidermal growth factor receptor (EGFR) and its ligand transforming growth factor-alpha (TGF-alpha) leads to an autocrine activation of the ras signaling pathway and putatively its oncogenic activity. It is thus hypothesized that the co-overexpression of EGFR-TGFalpha will be redundant hence rare in tumors with oncogenic ras mutations. To test this hypothesis, we studied by immunohistochemistry the expression of EGFR and TGF-alpha in primary non small cell lung cancers. Such putative EGFR autocrine loop activation was found in 73% of squamous cell carcinomas that rarely develop ras mutations. In contrast, EGFR-TGFalpha co-expression occurred with equal frequency in adenocarcinomas irrespective of their ras genotype. The results indicate that EGFR autocrine loop activity in adenocarcinoma may have alternative signaling activities aside from the activation of ras-MAP kinase pathway.     

Growth control by epidermal growth factor and transforming growth factor-alpha in human lung squamous carcinoma cells.

Although EGF receptor expression is generally elevated in human lung squamous carcinoma, the biological significance of this phenomenon and the role of EGF and TGF-alpha in this disease are poorly understood. We have investigated three human lung squamous carcinoma cell lines (NX002, CX140 and CX143) and have shown, using an antibody (EGFR1) directed against the EGF receptor, that the majority of cells in all three lines express the EGF receptor. Using a ligand binding assay, Scatchard analysis indicated high concentrations (1,300-2,700 fmol mg-1 protein) of a single low affinity binding site (Kd = 3-5 nM) within these lines. Addition of EGF or TGF-alpha at concentrations greater than 0.1 nM resulted in growth inhibition of all three lines and this was associated with an accumulation of cells in the G2/M phase of the cell cycle. Growth inhibitory effects were not explained by an enhancement of cellular differentiation as monitored by involucrin expression and the ability to form cornified envelopes. While the presence of EGF could not be detected in medium conditioned by the NX002 cell line, mRNA for TGF-alpha was detected in all three lines suggesting the possibility of an autocrine loop. These results together with reports of growth inhibition by EGF and TGF-alpha in other systems suggest that EGF and similar molecules might have a growth regulatory role in lung cancer cells and modulation of such may have therapeutic potential.     

胃癌患者血清表皮生长因子测定的临床评价

目的　探讨胃癌患者血清表皮生长因子 (EGF)水平变化的临床价值。方法　采用放射免疫分析 (RIA)对46例胃癌患者进行测定EGF的含量。结果　胃癌患者血清EGF水平显著高于正常对照组 (P <0 .0 1)且中晚期胃癌组亦显著高于早期胃癌组 (P <0 .0 5 )。结论　胃癌患者检测EGF水平有助于判断胃癌的恶性程度及预后评价。