CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer / 医学前沿

The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of "eat me" signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.

Cigarette Smoke Induces Gefitinib Resistance in NSCLC Cells via ROS/Sirt3/SOD2 Pathway / 中国肺癌杂志

BACKGROUND@#Epidermal growth factor receptor (EGFR) gene mutations are the most common driver mutations in non-small cell lung cancer (NSCLC). To prolong the survival of the patients, EGFR tyrosine kinase inhibitors (TKIs) resistance in NSCLC is a major challenge that needs to be addressed urgently, and this study focuses on investigating the mechanism of cigarette smoke (CS) induced Gefitinib resistance in NSCLC.@*METHODS@#PC-9 and A549 cells were cultured in vitro and treated with 1 µmol/L Gefitinib for 4 h and 10% cigarette smoke extract (CSE) for 48 h. Western blot was used to detect Sirtuin 3 (Sirt3) and superoxide dismutase 2 (SOD2) protein expressions; DCFH-DA probe was used to detect intracellular reactive oxygen species (ROS); CCK-8 kit was used to detect cell activity, and EdU was used to detect cell proliferation ability. Sirt3 overexpression plasmid (OV-Sirt3) was transfected in PC-9 and A549 cells and treated with 1 µmol/L Gefitinib for 4 h and 10% CSE for 48 h after N-acetylcysteine (NAC) action. The expressions of Sirt3 and SOD2 were detected by Western blot; the ROS level in the cells was detected by DCFH-DA probe, and the cell activity was detected by CCK-8.@*RESULTS@#CSE induced an increase in the 50% inhibitory concentration (IC50) of both PC-9 and A549 cells to Gefitinib (P<0.01) and enhanced the proliferation of PC-9 and A549 cells, suggesting that CS induced Gefitinib resistance in NSCLC. ROS was involved in CSE-induced Gefitinib resistance (P<0.05). CSE induced low expressions of Sirt3 and SOD2 (P<0.01), and Sirt3/SOD2 was associated with poor prognosis in lung cancer patients (P<0.05). OV-Sirt3 in PC-9 and A549 cells reversed CSE-induced Gefitinib resistance (P<0.05) and significantly reduced ROS production. NAC reversed CSE-induced Gefitinib resistance in PC-9 and A549 cells (P<0.05).@*CONCLUSIONS@#The ROS/Sirt3/SOD2 pathway is involved in CS-induced Gefitinib resistance in NSCLC.

Relationship between Preoperative 18F-Fluorodeoxyglucose Uptake and Epidermal Growth Factor Receptor Status in Primary Colorectal Cancer

PURPOSE: Both 18F-fluorodeoxyglucose (18F-FDG) uptake and epidermal growth factor receptor (EGFR) status are prognostic variables of colorectal cancer (CRC). The aim of this study was to investigate a possible association between 18F-FDG uptake on preoperative positron emission tomography/computed tomography (PET/CT) and EGFR status in primary CRC. MATERIALS AND METHODS: Records of 132 patients (66 men and 66 women; mean age=67.1+/-11.1 years) who underwent 18F-FDG PET/CT for CRC staging and subsequent bowel resection were reviewed. In primary lesions, 18F-FDG uptake was semiquantitatively evaluated in terms of maximum standardized uptake value (SUVmax), and EGFR status was determined by immunohistochemistry. Associations of clinicopathological parameters and EGFR status were analyzed by Pearson's chi-square test, multiple logistic regression, and receiver operating characteristic curves. RESULTS: Eighty-six patients (65.2%) showed EGFR expression. SUVmax was significantly lower in EGFR-negative tumors than in EGFR-expressing tumors (10.0+/-4.2 vs. 12.1+/-2.1; p=0.012). It was the only significant parameter correlated with EGFR expression (odds ratio=2.457; relative risk=2.013; p=0.038). At the SUVmax threshold of 7.5, the sensitivity and specificity for predicting EGFR expression were 84.9% and 40.4%, respectively (area under the curve=0.624; p=0.019). CONCLUSION: Preoperative 18F-FDG uptake is slightly correlated with EGFR status in primary CRC. Preoperative SUVmax of 18F-FDG may have a limited role in predicting EGFR expression in such tumors because of its poor specificity.

Acarbose versus trans-chalcone: comparing the effect of two glycosidase inhibitors on obese mice

Objective Acarbose and trans-chalcone are glucosidase inhibitors whose beneficial effects have been demonstrated in diabetes. The present study aimed at investigating their potential effects in obesity.Materials and methods NMRI male mice (n = 48) were subjected to a high fat diet for four weeks, which induced an initial state of obesity. One control group was given normal rodent diet. Obese animals were then switched to normal rodent diet, and divided to four groups (n = 12 in each): untreated, sham (receiving grape seed oil), and experimental groups receiving acarbose and trans-chalcone (12 mg/kg) during eight weeks. Body weight, blood glucose and other biochemical parameters including triglycerides (TG), cholesterol, HDL, AST, and ALT were measured, as well as leptin, adiponectin, TNF-α, and total antioxidant capacity (TAC). Histological studies were performed on adipose cells and liver tissue samples.Results All factors were affected in a positive manner by acarbose, save for body weight, blood sugar and leptin levels, on which acarbose effects, although observable, were not statistically significant. Grape seed oil, used as a solvent for trans-chalcone was found to possess significant effect on TG and TAC, and had beneficial effects on other factors including liver enzymes and cholesterol. Trans-chalcone effects were significant on HDL, leptin and ALT. All compounds seemed to be able to affect fat deposition in liver tissue, and decrease the size of adipose tissue cells to some extent.Conclusion In conclusion, the tested compounds were able to affect lipid accumulation in tissues and influence adipokines, which may result in an enhanced state with regard to inflammation and oxidative stress. Arch Endocrinol Metab. 2015;59(3):202-9.

Inflammation and Cancer Development in Pancreatic and Biliary Tract Cancer / 대한소화기학회지

Chronic inflammation has been known to be a risk for many kinds of cancers, including pancreatic and biliary tract cancer. Recently, inflammatory process has emerged as a key mediator of cancer development and progression. Many efforts with experimental results have been given to identify the underlying mechanisms that contribute to inflammation-induced tumorigenesis. Diverse inflammatory pathways have been investigated and inhibitors for inflammation-related signaling pathways have been developed for cancer treatment. This review will summarize recent outcomes about this distinctive process in pancreatic and biliary tract cancer. Taking this evidence into consideration, modulation of inflammatory process will provide useful options for pancreatic and biliary tract cancer treatment.

The pleckstrin homology domain of phospholipase D1 accelerates EGFR endocytosis by increasing the expression of the Rab5 effector, rabaptin-5

Endocytosis is differentially regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) and phospholipase D (PLD). However, the relationship between HIF-1alpha and PLD in endocytosis is unknown. HIF-1alpha is degraded through the prolyl hydroxylase (PHD)/von Hippel-Lindau (VHL) ubiquitination pathway in an oxygen-dependent manner. Here, we show that PLD1 recovers the decrease in epidermal growth factor receptor (EGFR) endocytosis induced by HIF-1alpha independent of lipase activity via the Rab5-mediated endosome fusion pathway. EGF-induced interaction of PLD1 with HIF-1alpha, PHD and VHL may contribute to EGFR endocytosis. The pleckstrin homology domain (PH) of PLD1 itself promotes degradation of HIF-1alpha, then accelerates EGFR endocytosis via upregulation of rabaptin-5 and suppresses tumor progression. These findings reveal a novel role of the PLD1-PH domain as a positive regulator of endocytosis and provide a link between PLD1 and HIF-1alpha in the EGFR endocytosis pathway.

Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells

BACKGROUND/AIMS: Silibinin, the main component of silymarin, is used as a hepatoprotectant and exhibits anticancer effects against various cancer cells. This study evaluated the effects of a combination of silibinin with either gefitinib or sorafenib on hepatocellular carcinoma (HCC) cells. METHODS: Several different human HCC cell lines were used to test the growth-inhibiting effects and cell toxicity of silibinin both alone and in combination with either gefitinib or sorafenib. The cell viability and growth inhibition were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and a colony-forming assay. Furthermore, changes in epidermal growth factor receptor (EGFR)-related signals were evaluated by Western blot analysis. RESULTS: Gefitinib, sorafenib, and silibinin individually exhibited dose-dependent antiproliferative effects on HCC cells. Combined treatment with silibinin enhanced the gefitinib-induced growth-inhibiting effects in some HCC cell lines. The combination effect of gefitinib and silibinin was synergistic in the SNU761 cell line, but was only additive in the Huh-BAT cell line. The combination effect may be attributable to inhibition of EGFR-dependent Akt signaling. Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin. CONCLUSIONS: Combined treatment with silibinin enhanced the growth-inhibiting effects of both gefitinib and sorafenib. Therefore, the combination of silibinin with either sorafenib or gefitinib could be a useful treatment approach for HCC in the future.

Comparison of proliferative activity of epithelial cells between the follicles of impacted teeth / Comparación de la actividad proliferativa de las células epiteliales entre los folículos de dientes impactados

The aim of this comparative observational study was to compare the proliferative activity of dental follicles surrounding impacted maxillary canines and mandibular third molars. Following extraction, forty follicles of the impacted mandibular third molars and 40 follicles of the impacted maxillary canines were removed. Epithelial cell proliferative activity of these samples was assessed using immunohistochemical labeling for Ki-67, minichromosome maintenance 2 (MCM-2) protein and epithelial growth factor receptor (EGFR). Intensity and extent of Ki-67, MCM-2 and EGFR expressions were evaluated by a scoring formula. The lining epithelium of the maxillary canine follicles had mean scores of 4.65±0.27 for Ki-67, 1.25±0.33 for MCM-2 and 7.30±0.23 for EGFR which were not significantly different than those expressed in the mandibular third molar follicles (4.46±0.26 for Ki-67, 1.39±0.33 for MCM-2 and 7.21±0.20 for EGFR). The expression of Ki-67 and MCM-2 could not be detected in the epithelial remnants within the connective tissue in both groups. EGFR expression, detected in the epithelial remnants in both groups, was not significantly different (7.28±0.14 in the canine group as opposed to 7.21±0.16 in the third molar group). Based on these findings, it can be deduced that impacted mandibular third molars and maxillary canines carry similar risk of pathology development.

El objetivo fue comparar la actividad proliferativa de los folículos dentarios que rodean a dientes caninos maxilares y terceros molares mandibulares impactados. Luego de realizada la extracción dentaria, se removieron 40 folículos dentarios de los terceros molares mandibulares impactados y 40 de caninos maxilares impactados. Se evaluó la actividad proliferativa de las células epiteliales de estas muestras mediante marcaje inmunohistoquímico para Ki-67, para la proteína de mantenimiento minicromosoma 2 (MCM-2) y para el receptor del factor de crecimiento epitelial (EGFR). Se evaluó la intensidad y extensión de Ki-67, MCM-2 y las expresiones de EGFR mediante una fórmula de puntuación. El epitelio de revestimiento de los folículos correspondientes a los caninos maxilares presentaron valores promedios de 4,65±0,27 para Ki-67, 1,25±0,33 para MCM-2 y 7,30±0,23 para EGFR, que no fueron significativamente diferentes de los expresados en los folículos de terceros molares mandibulares (4,46±0,26 para Ki-67, 1,39±0,33 para MCM-2 y 7,21±0,20 para EGFR). La expresión de Ki-67 y MCM-2 no pudo ser detectada en los restos epiteliales dentro del tejido conectivo en ambos grupos. La expresión de EGFR, detectada en los restos epiteliales en ambos grupos, no fue significativamente diferente (7,28±0,14 en el grupo de los caninos, y 7,21±0,16 en el grupo de los terceros molares). Sobre la base de estos resultados, se puede deducir que la retención de terceros molares y caninos maxilares conlleva un riesgo similar para el desarrollo de patología.

Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.

Immunohistochemical profile of high-grade ductal carcinoma in situ of the breast

OBJECTIVE: To determine the frequency of the immunohistochemical profiles of a series of high-grade ductal carcinoma in situ of the breast. METHODS: One hundred and twenty-one cases of high-grade ductal carcinoma in situ, pure or associated with invasive mammary carcinoma, were identified from 2003 to 2008 and examined with immunohistochemistry for estrogen receptor, human epidermal growth factor receptor 2, cytokeratin 5, and epidermal growth factor receptor. The tumors were placed into five subgroups: luminal A, luminal B, HER2, basal-like, and “not classified”. RESULTS: The frequencies of the immunophenotypes of pure ductal carcinoma in situ were the following: luminal A (24/42 cases; 57.1%), luminal B (05/42 cases; 11.9%), HER2 (07/42 cases; 16.7%), basal-like phenotype (00/42 cases; 0%), and “not classified” (06/42 cases; 14.3%). The immunophenotypes of ductal carcinoma in situ associated with invasive carcinoma were the following: luminal A (46/79 cases; 58.2%), luminal B (10/79 cases; 12.7%), HER2 (06/79 cases; 7.6%), basal-like (06/79 cases; 7.6%), and “not classified” (11/79 cases; 13.9%). There was no significant difference in the immunophenotype frequencies between pure ductal carcinoma in situ and ductal carcinoma in situ associated with invasive carcinoma (p>0.05). High agreement was observed in immunophenotypes between both components (kappa=0.867). CONCLUSION: The most common immunophenotype of pure ductal carcinoma in situ was luminal A, followed by HER2. The basal-like phenotype was observed only in ductal carcinoma in situ associated with invasive carcinoma, which had a similar phenotype. .

Increasing the alpha 2, 6 Sialylation of Glycoproteins May Contribute to Metastatic Spread and Therapeutic Resistance in Colorectal Cancer

Abnormal glycosylation due to dysregulated glycosyltransferases and glycosidases is a key phenomenon of many malignancies, including colorectal cancer (CRC). In particular, increased ST6 Gal I (beta-galactoside alpha 2, 6 sialyltransferase) and subsequently elevated levels of cell-surface alpha 2, 6-linked sialic acids have been associated with metastasis and therapeutic failure in CRC. As many CRC patients experience metastasis to the liver or lung and fail to respond to curative therapies, intensive research efforts have sought to identify the molecular changes underlying CRC metastasis. ST6 Gal I has been shown to facilitate CRC metastasis, and we believe that additional investigations into the involvement of ST6 Gal I in CRC could facilitate the development of new diagnostic and therapeutic targets. This review summarizes how ST6 Gal I has been implicated in the altered expression of sialylated glycoproteins, which have been linked to CRC metastasis, radioresistance, and chemoresistance.

Imaging Characteristics of Stage I Non-Small Cell Lung Cancer on CT and FDG-PET: Relationship with Epidermal Growth Factor Receptor Protein Expression Status and Survival

OBJECTIVE: To identify CT and FDG-PET features associated with epidermal growth factor receptor (EGFR) protein overexpression, and to evaluate whether imaging features and EGFR-overexpression can help predict clinical outcome. MATERIALS AND METHODS: In 214 patients (M : F = 129 : 85; mean age, 63.2) who underwent curative resection of stage I non-small cell lung cancer, EGFR protein expression status was determined through immunohistochemical analysis. Imaging characteristics on CT and FDG-PET was assessed in relation to EGFR-overexpression. Imaging features and EGFR-overexpression were also evaluated for clinical outcome by using the Cox proportional hazards model. RESULTS: EGFR-overexpression was found in 51 patients (23.8%). It was significantly more frequent in tumors with an SUVmax > 5.0 (p 2.43 cm (p 5.0 (OR, 3.113; 95% CI, 1.375-7.049; p = 0.006) and diameter > 2.43 cm (OR, 2.799; 95% CI, 1.285-6.095; p = 0.010) were independent predictors of EGFR overexpression. Multivariate analysis showed that SUVmax > 4.0 (hazard ratio, 10.660; 95% CI, 1.370-82.966; p = 0.024), and the presence of cavitation within a tumor (hazard ratio, 3.122; 95% CI, 1.143-8.532; p = 0.026) were factors associated with poor prognosis. CONCLUSION: EGFR-overexpression is associated with high SUVmax, large tumor diameter, and small GGO proportion. CT and FDG-PET findings, which are closely related to EGFR overexpression, can be valuable in the prediction of clinical outcome.

Epidermal Growth Factor Receptor Is Related to Poor Survival in Glioblastomas: Single-Institution Experience

PURPOSE: There are conflicting results surrounding the prognostic significance of epidermal growth factor receptor (EGFR) status in glioblastoma (GBM) patients. Accordingly, we attempted to assess the influence of EGFR expression on the survival of GBM patients receiving postoperative radiotherapy. MATERIALS AND METHODS: Thirty three GBM patients who had received surgery and postoperative radiotherapy at our institute, between March 1997 and February 2006, were included. The evaluation of EGFR expression with immunohistochemistry was available for 30 patients. Kaplan-Meier survival analysis and Cox regression were used for statistical analysis. RESULTS: EGFR was expressed in 23 patients (76.7%), and not expressed in seven (23.3%). Survival in EGFR expressing GBM patients was significantly less than that in non-expressing patients (median survival: 12.5 versus 17.5 months, p=0.013). Patients who received more than 60 Gy showed improved survival over those who received up to 60 Gy (median survival: 17.0 versus 9.0 months, p=0.000). Negative EGFR expression and a higher radiation dose were significantly correlated with improved survival on multivariate analysis. Survival rates showed no differences according to age, sex, and surgical extent. CONCLUSION: The expression of EGFR demonstrated a significantly deleterious effect on the survival of GBM patients. Therefore, approaches targeting EGFR should be considered in potential treatment methods for GBM patients, in addition to current management strategies.

Immunophenotypes of Glycogen Rich Clear Cell Carcinoma

PURPOSE: Glycogen rich clear cell carcinoma (GRCC) of the breast is a rare subtype of invasive ductal carcinoma and involves a poor prognosis. In the literature, less than 150 cases have been reported. Many researchers have attempted to characterize GRCC according to electron microscope, flow cytometry, or clinical data. However, an organized study of the immunophenotype of GRCC has yet to be reported. MATERIALS AND METHODS: Here, we present three cases of GRCC and their immunohistochemical profiles. RESULTS: Histologically, all three cases contained periodic acid stain (PAS) positive and d-PAS labile granules in their clear cytoplasm. Case I showed positivity for only estrogen receptor (ER) and c-erbB2. Case II exhibited positivity for progesterone receptor and negativity for ER and c-erbB2. Case III presented with triple negative invasive carcinoma. The expression pattern of E-cadherin was concordant with epidermal growth factor receptor and c-kit, but discordant with ki-67. Among these three cases, p53-positive cases exhibited a low proliferative index (ki-67: 15%), while p53-negative cases showed a high proliferative index (ki-67: 50-60%). CONCLUSION: In conclusion, the immunophenotype of GRCC is not uniform, but is similar to that of conventional ductal carcinoma.

Clinicopathologic and Molecular Characteristics of Lung Adenocarcinoma Arising in Young Patients

Lung cancer rarely occurs in young patients. Recent studies have demonstrated that epidemiologic data are closely correlated to some molecular characteristics. We investigated the clinicopathologic characteristics of lung adenocarcinoma in young patients and evaluated immunohistochemically detected epidermal growth factor receptor (EGFR) mutation status and anaplastic lymphoma kinase (ALK) positivity. Among lung adenocarcinoma patients, 31 cases were of the 50 yr-old group. Young patients were more likely to be females (67.7% vs 40.2%), and nonsmokers (58.1% vs 45.2%) and more often had high TNM stage (stage IV was 80.6% vs 52.1%) and had a high rate of distant metastasis (51.6% vs 28.0%) compared with older patients. The signet ring cell feature was more common (25.8% vs 11.5%) and lepidic growth pattern was rarely present (3.2% vs 16.5%) in the adenocarcinoma of young patients. There was no significant survival difference between the two age groups. The rate of EGFR mutation status and ALK positivity did not show a statistical difference between two groups. In conclusion, lung adenocarcinoma of young patients demonstrates distinct pathologic features with frequent presence of a signet ring cell feature and rare occurrence of lepidic growth pattern. Further investigation for other genetic abnormalities would be needed.

The effect of combining interferon-α and gefitinib in human colon cancer cell lines / El efecto de combinar el interferón α y el gefitinib en las líneas celulares del cáncer de colon humano

BACKGROUND AND AIMS: Interferon-α (IFN-α) treatment is associated with up-regulation of epidermal growth factor receptor (EGFR) expression and marked growth inhibition of colon cancer cell lines. We aimed to determine the effect of combining IFN-α and gefitinib in the growth of human colon cancer cell lines. METHODS: Two human colon cancer cell lines SW480 and LOVO were treated with IFN-α alone or gefitinib alone or IFN-α plus gefitinib. Proliferation of colon cancer cells was measured by methyl thiazolyl tetrazolium (MTT) assay; the apoptosis rate was analysed by flow cytometry (FCM). The expression of XIAP, XAF1 mRNA was detected by RT-PCR and the expression of XIAP, XAF1 protein was detected by western blotting. RESULTS: Methyl thiazolyl tetrazolium showed that IFN-α, gefitinib and IFN-α plus gefitinib significantly inhibited SW480 and LOVO cells in a dose-dependent manner (p < 0.05). The FCM revealed that IFN α, gefitinib and IFN-α plus gefitinib could markedly upgrade the apoptosis rate (p < 0.05). The expression of XIAP mRNA down-regulated markedly (p < 0.05) while the expression of XAF1 mRNA up-regulated significantly (p < 0.05). The expression of XIAP protein was down-regulated markedly (p < 0.05) while the expression of XAF1 protein was up-regulated significantly (p < 0.05). CONCLUSION: IFN-α promotes the antiproliferaative effect of gefitinib on human colon cancer cell lines and the mechanism may be related to up-regulation expression of EGFR by IFN-α.

ANTECEDENTES Y OBJETIVOS: El tratamiento con interferón α (IFN-α) se halla asociado con la regulación por incremento de la expresión del receptor del factor de crecimiento epidérmico y la acentuada inhibición del crecimiento de las líneas celulares del cáncer colorrectal. El presente trabajo tuvo por objetivo determinar el efecto que se produce al combinar el IFN-α y el gefitinib en el crecimiento de las líneas celulares del cáncer de colon. MÉTODOS: Dos líneas celulares de cáncer del colon en humanos - SW480 y LOVO - fueron tratadas con IFN-α solamente, gefitinib solamente, o IFN-α más gefitinib. La proliferación de las células cancerosas del colon se midió mediante ensayo de metil tiazolil tetrazolio (MTT); la tasa de apoptosis se analizó mediante citometría de flujo (CMF); la expresión de XIAP/XAF1 mRNA fue detectada mediante RT-PCR y la expresión de la proteína XIAP/XAF1 fue detectada mediante inmunoblot (western blot). RESULTADOS: El MTT mostró que el IFN-α, el gefitinib, y el IFN-α más gefitinib inhibían de forma significativa las células SW480 y LOVO en dependencia de la dosis (p < 0.05). La CMF reveló que el IFN-α, el gefitinib, y el IFN-α más gefitinib podían aumentar notablemente la tasa de apoptosis (p < 0.05). La expresión de XIAP mRNA tuvo una marcada regulación por decremento (p < 0.05) mientras que la expresión de XAF1 mRNA tuvo una significativa regulación por incremento (p < 0.05); la expresión de la proteína XIAP fue notablemente regulada por decremento (p < 0.05) mientras que la expresión de la proteína XAF1 fue regulada por incremento de manera significativa (p < 0.05). CONCLUSIÓN: El IFN-α promueve el efecto antiproliferativo del gefitinib sobre las líneas celulares del cáncer colorrectal, y el mecanismo puede hallarse relacionado con la expresión de la regulación por incremento del EGFR mediante el IFN-α.

VEGF as a Predictor for Response to Definitive Chemoradiotherapy and COX-2 as a Prognosticator for Survival in Esophageal Squamous Cell Carcinoma

We investigated the patterns of pretreatment expression of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) by immunohistochemical staining and determined their correlation with treatment response and survival in 44 patients with esophageal squamous cell carcinoma (ESCC) treated with definitive concurrent chemoradiotherapy (CCRT). The definitive CCRT consisted of a median dose of 54 Gy (range: 40.0-68.4 Gy) and two cycles of concurrent administration of mostly 5-fluorouracil + cisplatinum. High expression of EGFR, VEGF, and COX-2 was found in 79.5%, 31.8%, and 38.6%, respectively. The Cox regression analysis for overall survival (OS) showed that both the treatment response and COX-2 expression were significant. The 3-yr OS rates of patients that achieved a complete response and those that did not were 46.7% and 5.3%, respectively (P = 0.006). The logistic regression analysis for treatment response with various parameters showed that only a high expression of VEGF was significantly associated with a complete response. Unlike other well-known studies, higher expression of VEGF was significantly correlated with a complete response to CCRT in this study. However, higher expression of COX-2 was significantly associated with shorter survival. These results suggest that VEGF might be a predictive factor for treatment response and COX-2 a prognostic factor for OS in patients with ESCC after definitive CCRT.

Clinicopathlogic and Immunohistochemical Characteristics of Triple Negative Invasive Lobular Carcinoma

PURPOSE: Our study is performed to find out clinicopathlogic and immunohistochemical (IHC) characteristics of triple negative invasive lobular carcinoma (ILC), as has been demonstrated in their invasive ductal counterparts. MATERIALS AND METHODS: Retrospective analysis of variable clinicopathlogic parameters and IHC stains for androgen receptor, estrogen receptor, progesterone receptor, p53, c-kit, galectin-3, cytokeratin 5 (CK5), CK5/6, vimentin, E-cadherin, epidermal growth factor receptor, and HER2 were performed in 117 cases of ILC. RESULTS: Eight cases (6.8%) were triple negative carcinoma (TNC), which showed higher incidence of high histologic grade than non-TNC (p = 0.019). Galectin-3 was expressed with higher incidence in tumor cells of TNC (62.5%) than those of non-TNC (7.3%) (p = 0.000). In contrast, galectin-3 was expressed with higher incidence in stromal cells of non-TNC (53.2%) than those of TNC (12.5%) (p = 0.029). CK5 and CK5/6 were not expressed in all ILCs. CONCLUSION: TNC in ILC showed distinct clinicopathologic and IHC characteristics such as higher histologic grade and increased expression of galectin-3, compared to non-TNC in ILC. TNC in ILC was less frequent and did not show CK5 and CK5/6 expression when compared to TNC in invasive ductal carcinoma.

Cobalt chloride stimulates phosphoinositide 3-kinase/Akt signaling through the epidermal growth factor receptor in oral squamous cell carcinoma

Tumor cells are often found under hypoxic conditions due to the rapid outgrowth of their vascular supply, and, in order to survive hypoxia, these cells induce numerous signaling factors. Akt is an important kinase in cell survival, and its activity is regulated by the upstream phosphoinositide 3-kinase (PI3K) and receptor tyrosine kinases (RTKs). In this study, we examined Akt activation and RTKs/PI3K/Akt signaling using the hypoxia-mimetic cobalt chloride in oral squamous carcinoma cells. Cobalt chloride increases Akt phosphorylation in both a dose- and time-dependent manner. Blocking the activation of the PI3K/Akt pathway using LY294002 abolished Akt activation in response to cobalt chloride, suggesting that Akt phosphorylation by cobalt chloride is dependent on PI3K. In addition, activation of the PI3K/Akt path way seems to rely on the epidermal growth factor receptor (EGFR), since the inhibition of EGFR attenuated cobalt chloride-induced Akt activation. The results in this study also demonstrate that cobalt chloride increases EGFR protein levels and induces oral squamous cell carcinoma cells to enter S phase.

HER2 over expression in malignant palpable breast lumps of pre and postmenopausal women attending RICK

Human Epidermal growth factor Receptor 2 [HER-2/neu] over expression in breast cancer is associated with poor outcome and decrease disease free survival [DFS]. The aim of this study was to evaluate the over expression of HER2/neu among premenopausal and postmenopausal females presented with malignant palpable breast lumps to Radio Isotope Center Khartoum [RICK]. The study was a case-control conducted among patients attending Radiation Isotopes Centre Khartoum [RICK]. A total of 328 women were randomly selected. Data were collected by a pre coded, pre tested questionnaire. Tissue biopsies of breast lumps had been analyzed using immunohistochemical techniques for HERR-2/neu over expression and its relation to other prognostic factors was evaluated. HER-2/neu + vein first pregnancy at 23 years, were 32 [41%] in the cases, 6 [35%] in the controls of premenopausal women, and 21[44%] in the cases, 5 [38%] in the controls of postmenopausal women. HER-2/neu + veexpression in relation to age at menarche 12 years was 39 [51%] in the cases, 7[39%] in the controls of premenopausal women, and 36 [56%] in the cases, 7 [45%] in the controls of postmenopausal women. HER-2/neu+ vein relation to Body Mass Index > 29 kg/m2 showed 7 [37%] in the cases, 2 [33%] in the controls of premenopausal women [x2=0.024], and 8[38%] in the cases, 2[40%] in the controls of postmenopausal women [x2= 0.006]. HER-2/neu+ veexpression in relation to history of abortion or miscarriage [ever] was found to be 21 [39%] in the cases, 4 [33%] in the controls of premenopausal women, and 18 [44%] in the cases, 3 [33%] in the controls among postmenopausal women. HER-2/neu+ veexpression in relation to the history of breast cancer in a first degree relatives was 3 [25%] in the cases, 1[50%] in the controls of premenopausal women, and 4 [22%] in the cases, 2 [28%] in the controls of postmenopausal women. HER-2/neu+ veexpression in relation to the use of oral contraceptives was 3 [37%] in the cases, 1[50%] in the controls among premenopausal women, and 3 [27%] in the cases, 1 [50%] in the controls of postmenopausal women. The study confirmed an etiological association between HER2/neu+ve and HER2/neu - ve and age at first pregnancy >/= 23 years, age of menarche at