Signaling pathways and their potential therapeutic utility in esophageal squamous cell carcinoma

Esophageal cancer is a complex gastrointestinal malignancy with an extremely poor outcome. Approximately 80% of cases of this malignancy in Asian countries including India are of squamous cell origin, termed Esophageal Squamous Cell Carcinoma (ESCC).The five-year survival rate in ESCC patients is less than 20%. Neo-adjuvant chemo-radiotherapy (NACRT) followed by surgical resection remains the major therapeutic strategy for patients with operable ESCC. However, resistance to NACRT and local recurrence after initial treatment are the leading cause of dismal outcomes in these patients. Therefore, an alternative strategy to promote response to the therapy and reduce the post-operative disease recurrence is highly needed. At the molecular level, wide variations have been observed in tumor characteristics among different populations, nevertheless, several common molecular features have been identified which orchestrate disease progression and clinical outcome in the malignancy. Therefore, determination of candidate molecular pathways for targeted therapy remains the mainstream idea of focus in ESCC research. In this review, we have discussed the key signaling pathways associated with ESCC, i.e., Notch, Wnt, and Nrf2 pathways, and their crosstalk during disease progression. We further discuss the recent developments of novel agents to target these pathways in the context of targeted cancer therapy. In-depth research of the signaling pathways, gene signatures, and a combinatorial approach may help in discovering targeted therapy for ESCC.

Signaling pathways and their potential therapeutic utility in esophageal squamous cell carcinoma.

Esophageal cancer is a complex gastrointestinal malignancy with an extremely poor outcome. Approximately 80% of cases of this malignancy in Asian countries including India are of squamous cell origin, termed Esophageal Squamous Cell Carcinoma (ESCC).The five-year survival rate in ESCC patients is less than 20%. Neo-adjuvant chemo-radiotherapy (NACRT) followed by surgical resection remains the major therapeutic strategy for patients with operable ESCC. However, resistance to NACRT and local recurrence after initial treatment are the leading cause of dismal outcomes in these patients. Therefore, an alternative strategy to promote response to the therapy and reduce the post-operative disease recurrence is highly needed. At the molecular level, wide variations have been observed in tumor characteristics among different populations, nevertheless, several common molecular features have been identified which orchestrate disease progression and clinical outcome in the malignancy. Therefore, determination of candidate molecular pathways for targeted therapy remains the mainstream idea of focus in ESCC research. In this review, we have discussed the key signaling pathways associated with ESCC, i.e., Notch, Wnt, and Nrf2 pathways, and their crosstalk during disease progression. We further discuss the recent developments of novel agents to target these pathways in the context of targeted cancer therapy. In-depth research of the signaling pathways, gene signatures, and a combinatorial approach may help in discovering targeted therapy for ESCC.

Microarray based gene expression profiling of advanced gall bladder cancer.

BACKGROUND: Gall bladder cancer (GBC) is an aggressive cancer with specific predilection like female gender and specific geographical areas, however the molecular mechanisms and factors contributing to the clinical or biological behavior are not understood. AIM: The aim of this study was to perform a comprehensive analysis of differentially expressed genes in advanced GBC and chronic cholecystitis (CC) cases. MATERIALS AND METHODS: Microarray was planned on fresh specimens of advanced GBC and CC cases using single color cRNA based microarray technique (8X60K format; Agilent Technologies, USA). Twelve advanced GBC and four CC patients were included in the study. RESULTS: Of the total of 1307 differentially expressed genes, 535 genes were significantly upregulated, while 772 genes were significantly downregulated in advanced GBC vs CC samples. Differentially expressed genes were associated with biological processes (55.03%), cellular components (31.48%), and molecular functions (13.49%) respectively. The important pathways or key processes affected were cell cycle, DNA replication, oxidative stress, gastric cancer pathway. Using in silico analysis tools, three differentially expressed genes i.e. TPX2, Cdc45 and MCM4 were selected (for their significant role in DNA replication and microtubule function) and were further validated in 20 advanced GBC cohort by immunohistochemistry. Significant positive association of Cdc45 and MCM4 proteins was found in advanced GBC cases (p = 0.043), suggesting the probable oncogenic role of Cdc45 and MCM4 proteins in advanced GBC. CONCLUSION: Our data demonstrate the potential regulation of Cdc45-MCM4 axis in advanced GBC tumors. Additionally, our study also revealed a range of differentially expressed genes (e.g. TPX2, AKURA etc.) between GBC and CC, and further validation of these genes might provide a potential diagnostic or therapeutic target in future.

Bcl-2 and p53 expressions in Indian women with complete hydatidiform mole.

INTRODUCTION: Hydatidiform moles have a high incidence rate in Asian countries like India. The molecular pathway leading to the pathogenesis and progression of hydatidiform moles is not yet understood. This study aimed to investigate the biological significance of Bcl-2 and p53 in complete hydatidiform moles (CHMs) as well as their influence on disease progression in the Indian population. METHODS: Archival tissues from 35 patients with CHMs and 35 age-matched controls were examined for Bcl-2 and p53 expressions by immunohistochemistry. RESULTS: Bcl-2 was found to be immunolocalised in the cytoplasm of the syncytiotrophoblast, whereas p53 was observed in both the nucleus and cytoplasm of the syncytiotrophoblast and cytotrophoblasts. In CHMs, Bcl-2 was detected in 23 percent of patients and p53 nuclear expression, in 66 percent. A significant decrease in Bcl-2 expression was observed in CHMs (p-value is 0.015), and the down-regulation of Bcl-2 significantly correlated with higher nuclear expression of p53 (p-value is 0.002), indicating an inverse association between the two proteins (p-value is 0.0001). However, no correlation was found between the clinical progress of patients with CHMs and p53 and those with Bcl-2 protein expression. CONCLUSION: The current study demonstrated the significance of Bcl-2 and p53 in the pathogenesis of CHMs but did not reveal any association with disease progression.

Apoptosis and Bcl-2 protein expression in human placenta over the course of normal pregnancy.

Apoptosis plays a central role in organ development, homeostasis and immune defence in multicellular organisms and is strictly controlled in part by members of Bcl-2 family. The Bcl-2 is a pro-survival molecule identified through its involvement in B-cell lymphomas. The aim of the study was to evaluate the incidence of apoptosis in the human placenta at different stages of pregnancy and to correlate it further with Bcl-2 expression. A total of 96 placental samples from first trimester, mid-trimester and uncomplicated term pregnancies were collected (n = 32 + 32 + 32). M30 cyto death monoclonal antibody was used to identify apoptotic cells. The apoptosis index of first trimester placentae was 2.33 ± 1.70, mid- trimester was 1.77 ± 1.36 and term placenta was 1.15 ± 0.21. Bcl-2 protein was found immunolocalized in the cytoplasm of syncytiotrophoblast. Apoptosis index was significantly reduced in term cases as compared with first trimester (P < 0.002) and mid-trimester placentae (P = 0.01). On the contrary, Bcl-2 expression was significantly higher at term cases than in first trimester (P < 0.0001) and mid-trimester cases (P < 0.001). The present study divulges the importance of apoptosis in permitting normal physiological turnover of villous trophoblast and also exhibits the contribution of bcl-2 in maintaining syncytial integrity throughout normal pregnancy.