br T br Simple Mohantaa b
Simple Mohantaa,b,c, Samanta Sekhar Khorac, Amritha Suresha,b,d,
a Integrated Head and Neck Oncology Program, Mazumdar Shaw Medical Foundation, Mazumdar Shaw Medical Center, Narayana Health City, Bommasandra Industrial Area, Anekal Taluk, Bangalore, 560099, Karnataka, India b Department of Head and Neck Oncology, Mazumdar Shaw Medical Center, Narayana Health City, Bommasandra Industrial Area, Anekal Taluk, Bangalore, 560099, Karnataka, India c School of Bio Sciences & Technology, VIT University, Vellore, 632014, Tamil Nadu, India d Mazumdar Shaw Medical Centre-Roswell Park Collaboration Program, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, 14263, New York, USA
Oral squamous cell carcinoma
Cancer stem cells
Objective: This study aimed to identify the cancer stem cell specific biomarkers that can be effective candidate prognosticators of oral squamous cell carcinoma. Design: Microarray-based meta-analysis derived transcriptional profile of head and neck cancers was compared with the Cancer Stem Cell database to arrive at a subset of markers. This subset was further co-related with clinico-pathological parameters, recurrence and survival of oral cancer patients (n = 313) in The Cancer Genome Atlas database and in oral cancer (n = 28) patients.
Results: Meta-analysis in combination with database comparison identified a panel of 221 genes specific to head and neck cancers. Correlation of expression levels of these markers in the oral cancer cohort of The Cancer Genome Atlas (n = 313) with treatment outcome identified 54 genes (p < 0.05 or fold change > 2) associated with disease recurrence, 8 genes (NQO1, UBE2C, EDNRB, FKBP4, STAT3, HOXA1, RIT1, AURKA) being sig-nificant with high fold change. Assessment of the efficacy of the subset (n = 54) as survival predictors identified an additional 4 genes (CDK1, GINS2, PHF5 A, ERBB2) that co-related with poor disease-free survival (p < 0.05). CDK1 showed a significant association with the clinical stage, margin status and with advanced pathological parameters. Initial patient validation indicated that CDK1 and NQO1 significantly co-related with the poor disease-free and overall survival (p < 0.05).
Conclusion: This panel of oral cancer specific, cancer stem cell associated markers identified in this study, a subset of which was validated, will be of clinical benefit subject to large scale validation studies.
Cancer stem 4μ8C (CSCs), the slow dividing and resistant sub-po-pulation of cells in the tumor are involved in tumor maintenance, in-vasion, metastasis, drug resistance, and recurrence in oral squamous cell carcinoma. (Mitra, Mishra, & Li, 2015; Simple, Suresh, Das, & Kuriakose, 2015). In oral cancer, as in other tumors, the high rate of
mortality (40–50%) is attributed to therapy resistance and the resulting incidences of local recurrence (30%) (Coelho, 2012). Current treatment protocols target the dividing cancer cells, leading to regression of the tumor bulk, but are often unable to eliminate the critical cancer stem cells population, protected by specific resistance mechanisms (Simple et al., 2015) and with potential to give rise to aggressive/highly re-sistant tumors, further deteriorating the prognosis of the patients
Abbreviations: ABCG2, ATP bindingCassette Transporter G2; ALDH1A1, Aldehyde dehydrogenase 1 family, member A1; AURKA, Aurora Kinase1; BMI1, B lym-phoma Mo-MLV insertion region 1 homolog; CDK1, Cyclin-dependent kinase 1; CD44, Cluster of Differentiation 44; CD133, Cluster of Differentiation 133; EDNRB, Endothelin Receptor Type B; ERBB2, Erb-B2 Receptor Tyrosine Kinase 2; FKBP4, FK506-binding protein 4; GINS2, GINS Complex Subunit 2; HOXA1, Homeobox A1; NANOG, homeobox transcription factor NANOG; NOTCH3, Neurogenic Locus Notch homolog protein 3; NQO1, NAD(P)H dehydrogenase [quinone] 1; OCT4, Octamer binding transcription factor 4; PHF5A, PHD Finger Protein 5A; RIT1, RIC-like protein without CAAX motif 1; SOX2, Sex determining region Y-box 2; STAT3, Signal transducer and activator of transcription 3; UBE2C, Ubiquitin Conjugating Enzyme E2 C
Corresponding author at: Integrated Head and Neck, Oncology Program, DSRG-5, Mazumdar Shaw Center for Translational Research, Mazumdar Shaw Medical Foundation, Narayana Health, #258/A, Bommasandra Industrial Area, Anekal Taluk, Bangalore, 560099, Karnataka, India.
E-mail address: [email protected] (A. Suresh).
S. Mohanta et al.
(Abdullah & Chow, 2013). An understanding of markers that specify the cancer stem cells-driven mechanisms of resistance, survival, tumor re-currence could provide new directions for accurate prognostication.
Markers that specify cancer stem cells have been identified through multiple studies and include surface markers, markers defining stem cell maintenance, pluripotency, hypoxia and epithelial-mesenchymal transition. Pluripotent stem cell markers (Oct4, NANOG, ALDH1A1 and BMI1) regulate and maintain the tumorigenic nature of cancer stem cells (Brakenhoff, 2011; Chiou et al., 2008; Neumann et al., 2011; Shi, Liu, Zhou, He, & Jiang, 2010; Y. Wang et al., 2012; Zhou, Huang, & Hu, 2011). Recently Toustrup et al have identified hypoxia related gene finger prints, which modulate cancer stem cell population and can be classifiers of responders and non-responders to radiotherapy in head and neck cancer (Perez-Sayans et al., 2011; Toustrup et al., 2011). Epithelial Mesenchymal Transition is a major process in cancer pro-gression, linked to tumor invasion, metastatic and therapeutic resistant property of cancer stem cells in various human epithelial cancers (H. Li et al., 2017; Noh et al., 2017; Pagaki et al., 2010; Satpute, Hazarey, Ahmed, & Yadav, 2013). Although considered a heterogeneous group of tumors, the known cancer stem cell- identifiers in the various sub sites of head and neck cancer are mainly CD44, CD133 and ALDH1A1 (Satpute et al., 2013). While in laryngeal/pharyngeal cancers, ALDH1A1 positive cells drive the tumorigenesis potential with en-hanced proliferation, CD44 correlated with poor survival rates in both laryngeal and oropharyngeal cancers (J. Chen et al., 2014; Dong et al., 2017; Greco et al., 2016). In oral cancer, cancer stem cells were positive for ALDH1A1, CD133 and CD44, along with other markers (OCT4, SOX2, NANOG). Nevertheless, there is a need for identifying func-tionally relevant, novel and site-specific markers specific to cancer stem cells and/or associated with them.