Cancer Research Institute

About: Cancer Research Institute is a nonprofit organization based out in New York, New York, United States. It is known for research contribution in the topics: Cancer & Population. The organization has 1061 authors who have published 754 publications receiving 26712 citations.

Notch pathway activation is essential for maintenance of stem-like cells in early tongue cancer

Abstract: // Pawan Upadhyay 1, * , Sudhir Nair 2, * , Ekjot Kaur 3 , Jyotirmoi Aich 1 , Prachi Dani 1 , Vidyalakshmi Sethunath 1 , Nilesh Gardi 1 , Pratik Chandrani 1 , Mukul Godbole 1 , Kavita Sonawane 2 , Ratnam Prasad 1 , Sadhana Kannan 4 , Beamon Agarwal 5 , Shubhada Kane 6 , Sudeep Gupta 7 , Shilpee Dutt 3 , Amit Dutt 1 1 Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education In Cancer, Tata Memorial Centre, Navi Mumbai- 410210, India 2 Division of Head and Neck Oncology, Department of Surgical Oncology, Tata Memorial Hospital, Tata Memorial Centre,Mumbai- 4100012, India 3 Shilpee Laboratory, Advanced Centre for Treatment, Research and Education In Cancer, Tata Memorial Centre, Navi Mumbai- 410210, India 4 Advanced Centre for Treatment, Research and Education In Cancer, Tata Memorial Centre, Navi Mumbai- 410210, India 5 Department of Pathology, Advanced Centre for Treatment, Research and Education In Cancer, Tata Memorial Centre, Navi Mumbai- 410210, India 6 Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai- 400012, India 7 Department of Medical Oncology, Advanced Centre for Treatment, Research and Education In Cancer, Tata Memorial Centre, Mumbai- 400012, India * These authors have contributed equally to this work Correspondence to: Amit Dutt, email: adutt@actrec.gov.in Keywords: early stage tongue cancer, exome and transcriptome sequencing, IHC based expression analysis, cancer stem cell-like feature, Notch pathway inhibitors Received: January 25, 2016 Accepted: June 07, 2016 Published: July 06, 2016 ABSTRACT Background: Notch pathway plays a complex role depending on cellular contexts: promotes stem cell maintenance or induces terminal differentiation in potential cancer-initiating cells; acts as an oncogene in lymphocytes and mammary tissue or plays a growth-suppressive role in leukemia, liver, skin, and head and neck cancer. Here, we present a novel clinical and functional significance of NOTCH1 alterations in early stage tongue squamous cell carcinoma (TSCC). Patients and Methods: We analyzed the Notch signaling pathway in 68 early stage TSCC primary tumor samples by whole exome and transcriptome sequencing, real-time PCR based copy number, expression, immuno-histochemical, followed by cell based biochemical and functional assays. Results: We show, unlike TCGA HNSCC data set, NOTCH1 harbors significantly lower frequency of inactivating mutations (4%); is somatically amplified; and, overexpressed in 31% and 37% of early stage TSCC patients, respectively. HNSCC cell lines over expressing NOTCH1 , when plated in the absence of attachment, are enriched in stem cell markers and form spheroids. Furthermore, we show that inhibition of NOTCH activation by gamma secretase inhibitor or shRNA mediated knockdown of NOTCH1 inhibits spheroid forming capacity, transformation, survival and migration of the HNSCC cells suggesting an oncogenic role of NOTCH1 in TSCC. Clinically, Notch pathway activation is higher in tumors of non-smokers compared to smokers (50% Vs 18%, respectively, P =0.026) and is also associated with greater nodal positivity compared to its non-activation (93% Vs 64%, respectively, P =0.029). Conclusion: We anticipate that these results could form the basis for therapeutic targeting of NOTCH1 in tongue cancer.

Expression profiling of cervical cancers in Indian women at different stages to identify gene signatures during progression of the disease

Abstract: Cervical cancer is the second most common cancer among women worldwide, with developing countries accounting for >80% of the disease burden. Although in the West, active screening has been instrumental in reducing the incidence of cervical cancer, disease management is hampered due to lack of biomarkers for disease progression and defined therapeutic targets. Here we carried out gene expression profiling of 29 cervical cancer tissues from Indian women, spanning International Federation of Gynaecology and Obstetrics (FIGO) stages of the disease from early lesion (IA and IIA) to progressive stages (IIB and IIIA–B), and identified distinct gene expression signatures. Overall, metabolic pathways, pathways in cancer and signaling pathways were found to be significantly upregulated, while focal adhesion, cytokine–cytokine receptor interaction and WNT signaling were downregulated. Additionally, we identified candidate biomarkers of disease progression such as SPP1, proliferating cell nuclear antigen (PCNA), STK17A, and DUSP1 among others that were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in the samples used for microarray studies as well in an independent set of 34 additional samples. Integrative analysis of our results with other cervical cancer profiling studies could facilitate the development of multiplex diagnostic markers of cervical cancer progression.

Overexpression of Mcl-1L splice variant is associated with poor prognosis and chemoresistance in oral cancers.

Abstract: Background Altered expression of Mcl-1, an anti-apoptotic member of the Bcl-2 family, has been linked to the progression and outcome of a variety of malignancies. We have previously reported the overexpression of Mcl-1 protein in human oral cancers. The present study aimed to evaluate the clinicopathological significance of the expression of three known Mcl-1 isoforms in oral tumors and the effect of targeting Mcl-1L isoform on chemosensitivity of oral cancer cells. Methods The expression of Mcl-1 isoforms- Mcl-1L, Mcl-1S & Mcl-1ES was analyzed in 130 paired oral tumors and 9 oral cell lines using quantitative real-time PCR & protein by western blotting. The Mcl-1 mRNA levels were correlated with clinicopathological parameters and outcome of oral cancer patients. The effect of Mcl-1L shRNA or Obatoclax (a small molecule Mcl-1 inhibitor), in combination with Cisplatin on chemosensitivity of oral cancer cells was also assessed. Results Anti-apoptotic Mcl-1L was predominantly expressed, over low or undetectable pro-apoptotic Mcl-1S and Mcl-1ES isoforms. The Mcl-1L transcripts were significantly overexpressed in all cancer cell lines and in 64% oral tumors versus adjacent normals (P<0.02). In oral cancer patients, high Mcl-1L expression was significantly associated with node positivity (P = 0.021), advanced tumor size (P = 0.013) and poor overall survival (P = 0.002). Multivariate analysis indicated Mcl-1L to be an independent prognostic factor for oral cancers (P = 0.037). Mcl-1L shRNA knockdown or its inhibition by Obatoclax in combination with Cisplatin synergistically reduced viability and growth of oral cancer cells than either treatment alone. Conclusion Our studies suggest that overexpression of Mcl-1L is associated with poor prognosis and chemoresistance in oral cancers. Mcl-1L is an independent prognostic factor and a potential therapeutic target in oral cancers.