Xianda Zhao

Caveolin-1 expression level in cancer associated fibroblasts predicts outcome in gastric cancer.

Aims Altered expression of epithelial or stromal caveolin-1 (Cav-1) is observed in various types of human cancers. However, the clinical significance of Cav-1 expression in gastric cancer (GC) remains largely unknown. The present study aims to explore the clinicopathological significance and prognostic value of both tumor cells and cancer associated fibroblasts (CAFs) Cav-1 in GC. Methods and Results Quantum dots immunofluorescence histochemistry was performed to examine the expression of Cav-1 in 20 cases of gastritis without intestinal metaplasia (IM), 20 cases of gastritis with IM and 286 cases of GC. Positive rates of epithelial Cav-1 in gastritis without IM, gastritis with IM and GC showed a decreasing trend (P = 0.012). Low expression of Cav-1 in CAFs but not in tumor cells was an independent predictor of poor prognosis in GC patients (P = 0.034 and 0.005 respectively in disease free survival and overall survival). Cav-1 level in tumor cells and CAFs showed no significant correlation with classic clinicopathological features. Conclusions Loss of epithelial Cav-1 may promote malignant progression and low CAFs Cav-1 level herald worse outcome of GC patient, suggesting CAFs Cav-1 may be a candidate therapeutic target and a useful prognostic marker of GC.

Autophagic tumor stroma: Mechanisms and roles in tumor growth and progression

Macroautophagy (hereafter autophagy) is a cellular homeostatic mechanism that involves protein and organelle degradation, and has a number of connections to human physiology and diseases. Autophagy in tumor parenchyma acts as either a tumor‐promoting role or a tumor‐inhibiting role depending on the types and stages of tumors. In recent years, attention to autophagy in tumor stroma that is referred as “autophagic tumor stroma” has created a new paradigm to understand the role of autophagy in cancer. Here we propose that the autophagic tumor stroma is a phenomenon of adaptation at a certain stage of tumor development, and has a prominent role in tumor growth, progression and spread of tumors. This idea is supported by recent studies: (i) Autophagic tumor stroma is activated by hypoxia and cancer cells induced oxidative stress, when tumors grow to a certain stage; (ii) Autophagic tumor stroma aids in providing essential nutrients to malignant cells, remodeling the tumor microenvironment, increasing DNA damage, genetic instability and stemness in cancer cells, and decreasing the apoptotic sensitivity of cancer cells. The autophagic tumor stroma is therefore a significant determinant in tumor growth and progression and implicates an important target for cancer therapies.

Quantum Dots-Based Immunofluorescent Imaging of Stromal Fibroblasts Caveolin-1 and Light Chain 3B Expression and Identification of Their Clinical Significance in Human Gastric Cancer

Caveolin-1 (Cav-1) expression deficiency and autophagy in tumor stromal fibroblasts (hereafter fibroblasts) are involved in tumor proliferation and progression, particularly in breast and prostate cancer. The aim of this study was to detect the expression of fibroblastic Cav-1 and LC3B, markers of autophagy, in gastric cancer (GC) and to analyze their clinical significances. Furthermore, because Epstein-Barr virus (EBV)-associated GC (EBVaGC) is a unique subtype of GC; we compared the differential expression of fibroblastic Cav-1 and LC3B in EBVaGC and non-EBVaGC. Quantum dots (QDs)-based immunofluorescence histochemistry was used to examine the expression of fibroblastic Cav-1 and LC3B in 118 cases of GC with adequate stroma. QDs-based double immunofluorescence labeling was performed to detect the coexpression of Cav-1 and LC3B proteins. EBV-encoded small RNA was detected by QDs-based fluorescence in situ hybridization to identify EBVaGC. Multivariate analysis indicated that low fibroblastic Cav-1 level was an independent prognosticator (p = 0.029) that predicted poorer survival of GC patients. Positive fibroblastic LC3B was correlated with lower invasion (p = 0.032) and was positively associated with Cav-1 expression (r = 0.432, p < 0.001). EBV infection did not affect fibroblastic Cav-1 and LC3B expression. In conclusion, positive fibroblastic LC3B correlates with lower invasion, and low expression of fibroblastic Cav-1 is a novel predictor of poor GC prognosis.

The different functions and clinical significances of caveolin-1 in human adenocarcinoma and squamous cell carcinoma

Caveolin-1 (Cav-1), a major structural protein of caveolae, is an integral membrane protein which plays an important role in the progression of carcinoma. However, whether Cav-1 acts as a tumor promoter or a tumor suppressor still remains controversial. For example, the tumor-promoting function of Cav-1 has been found in renal cancer, prostate cancer, tongue squamous cell carcinoma (SCC), lung SCC and bladder SCC. In contrast, Cav-1 also plays an inhibitory role in esophagus adenocarcinoma, lung adenocarcinoma and cutaneous SCC. The role of Cav-1 is still controversial in thyroid cancer, hepatocellular carcinoma, gastric adenocarcinoma, colon adenocarcinoma, breast cancer, pancreas cancer, oral SCC, laryngeal SCC, head and neck SCC, esophageal SCC and cervical SCC. Besides, it has been reported that the loss of stromal Cav-1 might predict poor prognosis in breast cancer, gastric cancer, pancreas cancer, prostate cancer, oral SCC and esophageal SCC. However, the accumulation of stromal Cav-1 has been found to be promoted by the progression of tongue SCC. Taken together, Cav-1 seems playing a different role in different cancer subtypes even of the same organ, as well as acting differently in the same cancer subtype of different organs. Thus, we hereby explore the functions of Cav-1 in human adenocarcinoma and SCC from the perspective of clinical significances and pathogenesis. We envision that novel targets may come with the further investigation of Cav-1 in carcinogenesis.

High Expression of Bcl-2 Protein Predicts Favorable Outcome in Non-small Cell Lung Cancer: Evidence from a Systematic Review and Meta-analysis

BACKGROUND The prognostic value of Bcl-2 protein expression in non-small cell lung cancer (NSCLC) is under debate. We therefore systematically reviewed the evidence for Bcl-2 protein effects on NSCLC survival to elucidate this issue. MATERIALS AND METHODS An electronic search in Pubmed and Embase complemented by manual searches in article references were conducted to identify eligible studies to evaluate the association between Bcl-2 protein expression and overall survival (OS) as well as disease free survival (DFS) of NSCLC patients. Combined hazard ratios (HRs) with corresponding 95% confidence intervals (95%CIs) were pooled using the random-effects model. RESULTS A total of 50 trials (including 52 cohorts) encompassing 7,765 patients were pooled in the meta-analysis regarding Bcl-2 expression and OS of NSCLC patients. High expression of Bcl-2 protein had a favorable impact (HR=0.76, 95%CI=0.67-0.86). In the group of Bcl-2 expression and DFS, 11 studies including 2,634 patients were included. The synthesized result indicated high expression of Bcl-2 protein might predict good DFS (HR=0.85, 95%CI=0.75-0.95). CONCLUSIONS Our present meta-analysis demonstrated favorable prognostic values of Bcl-2 expression in patients with NSCLC. Further prospective trails are welcomed to validate the utility of assessing Bcl-2 in NSCLC patient management.

Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancer death reasons. Anti-tumor necrosis factor-alpha (TNF-α) antibodies have shown promising effects in PDAC pre-clinical models. However, the prognostic values of TNF-α, underlying mechanisms by which anti-TNF-α treatments inhibit PDAC, and potential synergistic effects of anti-TNF-α treatments with chemotherapy are still unclear. Results and Methods To identify the targeting values of TNF-α in PDAC, we measured TNF-α expression in different stages of PDAC initiation and evaluated its prognostic significance in a pancreatic cancer cohort. We found that TNF-α expression elevated in PDAC initiation process, and high expression of TNF-α was an independent prognostic marker of poor survival. We further evaluated anti-tumor effects of anti-TNF-α treatments in PDAC. Anti-TNF-α treatments resulted in decreased cell viability in both PDAC tumor cells and pancreatic satellite cells in similar dose in vitro. In vivo, anti-TNF-α treatments showed effects in reducing desmoplasia and the tumor promoting inflammatory microenvironment in PDAC. Combination of anti-TNF-α treatments with chemotherapy partly overcame chemoresistance of PDAC tumor cells and prolonged the survival of PDAC mouse model. Conclusions In conclusion, our findings indicated that TNF-α in PDAC can be a prognostic and therapeutic target. Inhibition of TNF-α synergized with chemotherapy in PDAC resulted in better pre-clinical responses via killing tumor cells as well as diminishing desmoplasia and inflammation in PDAC tumor stroma.

Quantum dots immunofluorescence histochemical detection of EGFR gene mutations in the non-small cell lung cancers using mutation-specific antibodies

Background Epidermal growth factor receptor (EGFR) mutation status plays an important role in therapeutic decision making for non-small cell lung cancer (NSCLC) patients. Since EGFR mutation-specific antibodies (E746-A750del and L858R) have been developed, EGFR mutation detection by immunohistochemistry (IHC) is a suitable screening test. On this basis, we want to establish a new screening test, quantum dots immunofluorescence histochemistry (QDs-IHC), to assess EGFR gene mutation in NSCLC tissues, and we compared it to traditional IHC and amplification refractory mutation system (ARMS). Materials and methods EGFR gene mutations were detected by QDs-IHC, IHC, and ADx-ARMS in 65 cases of NSCLC composed of 55 formalin-fixed, paraffin-embedded specimens and ten pleural effusion cell blocks, including 13 squamous cell carcinomas, two adenosquamous carcinomas, and 50 adenocarcinomas. Results Positive rates of EGFR gene mutations detected by QDs-IHC, IHC, and ADx-ARMS were 40.0%, 36.9%, and 46.2%, respectively, in 65 cases of NSCLC patients. The sensitivity of QDs-IHC when detecting EGFR mutations, as compared to ADx-ARMS, was 86.7% (26/30); the specificity for both antibodies was 100.0% (26/26). IHC sensitivity was 80.0% (24/30) and the specificity was 92.31% (24/26). When detecting EGFR mutations, QDs-IHC and ADx-ARMS had perfect consistency (κ  =0.882; P<0.01). Excellent agreement was observed between IHC and ADx-ARMS when detecting EGFR mutations (κ  =0.826; P<0.01). Conclusion QDs-IHC is a simple and standardized method to detect EGFR mutations with its high sensitivity and specificity, as compared with real-time polymerase chain reaction. In addition, the development of specific antibodies against EGFR mutation proteins might be useful for the diagnosis and treatment of lung cancer.

High expression of synthesis of cytochrome c oxidase 2 and TP53-induced glycolysis and apoptosis regulator can predict poor prognosis in human lung adenocarcinoma

Synthesis of cytochrome c oxidase 2 (SCO2) and TP53-induced glycolysis and apoptosis regulator (TIGAR) are 2 p53-mediated proteins that can play a regulatory role in cancer energy metabolism. However, no study has examined the association of SCO2 and TIGAR with the prognosis of patients with lung adenocarcinoma (AC). In our study, the expression of SCO2 and TIGAR proteins in lung AC was detected, and the potential relation to prognosis was evaluated, aiming to take a further view of lung AC progression. Quantum dots-based immunofluorescence histochemistry staining was performed to observe the expression of p53, SCO2, and TIGAR in 75 specimens of lung AC. Of these, 51 (68.0%) showed high expression of SCO2, and 59 (78.7%) showed high expression of TIGAR. High TIGAR expression was significantly associated with a history of smoking (P = .017) and being male (P = .006). The correlation between high SCO2 expression and age also was significant (P = .042). Moreover, high TIGAR expression was positively correlated with high SCO2 expression (P = .019; rs = 0.271). High expression of the SCO2 and TIGAR proteins predicted poorer survival and a higher mortality rate (P = .024 and .030, respectively). High expression of SCO2 and TIGAR proteins is significantly associated with lung AC progression, suggesting their potential use as prognostic markers and therapeutic targets.

Overexpression of junctional adhesion molecule-A and EphB2 predicts poor survival in lung adenocarcinoma patients

Junctional adhesion molecules are important components of tight junctions, and Eph/ephrin proteins constitute the largest family of receptor tyrosine kinases. Both junctional adhesion molecules and Eph/ephrin are involved in normal tissue development and cancer progression. However, the expression levels and clinical significances of junctional adhesion molecule-A, a member of junctional adhesion molecules, and EphB2, a member of Eph/ephrin family, in lung adenocarcinoma patients are unclear. Therefore, in this study, we aimed to identify the expression and prognostic values of junctional adhesion molecule-A and EphB2 in lung adenocarcinoma patients’ cohort. In our study, 70 (55.6%) showed high expression of junctional adhesion molecule-A protein and 51 (40.5%) showed high expression of EphB2 protein in 126 lung adenocarcinoma tissues. Junctional adhesion molecule-A and EphB2 expressions were both significantly increased in tumor tissues compared with noncancerous lung tissues. Kaplan–Meier analysis and log-rank test indicated that low expression of junctional adhesion molecule-A and EphB2 proteins can predict better survival and low mortality rate of lung adenocarcinomas. In univariate analysis, high expression levels of junctional adhesion molecule-A and EphB2 were both found to be significantly correlated with poor overall survival of lung adenocarcinoma patients (hazard ratio = 1.791, 95% confidence interval = 1.041–3.084, p = 0.035; hazard ratio = 1.762, 95% confidence interval = 1.038–2.992, p = 0.036, respectively). The multivariate Cox proportional hazard model demonstrated that EphB2 expression is an independent prognosis parameter in lung adenocarcinoma patients (hazard ratio = 1.738, 95% confidence interval = 1.023–2.952, p = 0.016). Taken together, high expression of junctional adhesion molecule-A and EphB2 can predict poor overall survival and high mortality rate, and EphB2 is an independent prognostic biomarker in lung adenocarcinoma patients.

Role of Glioma-associated GLI1 Oncogene in Carcinogenesis and Cancertargeted Therapy

Glioma-associated oncogenes (GLIs) are zinc finger protein family members and downstream regulatory factors of the classic Hedgehog (Hh) signaling pathway. GLI proteins influence the growth and development of organisms and aid in tissue repair. However, aberrant expression of the GLI family member GLI1 promotes carcinogenesis by inducing epithelial-mesenchymal transition (EMT), angiogenesis, and other signaling pathways. Overexpression of GLI1 is thought to be an indicator of poor prognosis as well as a potential therapeutic target for cancers. GLI inhibitors such as zerumbone, GANT61, resveratrol, and cyclopamine depress the Hh pathway in vitro and in vivo cancer research, and other non-canonical pathways may also activate expression of GLI1. Here, we summarize GLI function in carcinogenesis and cancer-targeted therapy.