Oncology and Radiotherapy © 1 (51) 2020: 001-00 • REVIEW ARTICLE - Hallmarks of cancer stem cells in men associated cancers: a review Sreedhar Surampudi 1 , Satyanarayana Swamy 1 , Satyanarayana Rentala 2 , Sivarama Prasad Darsi 1 1 Department of Biotechnology, GITAM Institute of Science, GITAM University, Gandhi Nagar, RushiKonda, Visakhapatnam, 530045, Andhra Pradesh, India 2 Department of Health Informatics and Analytics, The Apollo University, Chittoor, 517 127, Andhra Pradesh, India Received: - 03 March, 2020 Accepted: - 16 March, 2020 Published: - 26 March, 2020 Word count: 5481 Tables: 00 Figures: 02 References: 62 Address for correspondence: Sreedhar Surampudi, Department of Biotechnology, GITAM Institute of Science, GITAM University, Gandhi Nagar, RushiKonda, Visakhapatnam, 530045, Andhra Pradesh, India, email: satyamswami@gmail.com SUMMARY Failure of conventional therapies is the root cause for the progression of cancer. Intrinsic revelation states that Cancer metastasis is due to subclonal diversification of normal cells into subsets of stem-like cells. These cells can be termed as stem cells of cancer or cells that initiate cancer. These diversified cells can differentially activate and escape from the resistant mechanisms causes tumor heterogeneity. Because of these metastatic fuelling which is malignant, it expresses its persistence towards treatment and provokes drug- resistant recurrence. Annihilation of these subsets of stem-like cells in cancer tissues has now become a prime objective to develop and design novel classes of anti-cancer therapeutics to improve clinical efficacy. In this review, the properties and hallmarks of different cancer stem cells that are responsible for disease recurrence and metastases which are elusive targets for present oncotherapies were presented. Key words: cancer stem cells, tumor heterogeneity, malignancy, clinical efficacy, oncotherapies Abbreviations: ABCG: ATP Binding Casette Transporter; ADC: Adenocarcinoma; AFP: Alpha Feto Protein; AKT: AKT8 Virus Oncogene Cellular Homolog, Serine/Threoning Kinase; ALDH: Aldehyde Dehydrogenase; ALK: Anaplastic Lymphoma Kinase; APC: Adenomatous Polyposis Coli; Atg: Autophagy Related Proteins; BCSC: Breast Cancer Stem Cells; Bmi: B-cell specifc Moloney Murine Leukemia Virus Integration Site; BMI: Body Mass Index; BRAF: Rapidly Accelerated Fibrosarcoma of Murine Associated Viral Onocgene Homolog B; CD: Cluster of Diferentiation; CET: Clonal Evolution Theory; CRC: Colorectal Cancer; CSC: Cancer Stem Cells; EGFR: Epidermal Growth Factor; EMT: Epithelial Mesenchymal Transition; EpCAM: Epithelial Cell Adhesion Molecule; ERB: Pan Eryhthroblastic Leukemia Viral Oncogene Homolog; GB’s: Glio Blastaoma; HIF: Hypoxia Inducing Factor; HNSCC: Head and Neck Stem Cell Carcinoma; ITGB: Integrin Mediated Cell Adhesion; JAK: Janus Kinases; KEAP: Kelch like ECH Associated Protein; KRAS: Kirsten Rat Sarcoma; LCSC’s: Liver Cancer Stem Cells; LGR: Leucine Rich Repeat Containing G Protein Coupled Receptor; Lrig: Leucine Rich Repeats and Immunoglobulin Like Domains; LSQCC : Squamous Cell Carcinoma; MAPK: Mitogen Activated Protein Kinase; MSI: Micro Satellite Inhibition; MSS: Micro Satellite Stability; Myc: Myelocytomatosis Oncogene Cellular Homolog; NF: Nuclear Factor; NPSC’S: Neutral Stem Cell Progenitors; NSCLC: Non Small Cell Lung Cancer; OCT: Octamer Binding Transcription Factor; PCa: Prostate Cancer; PI: Phospho Inositide; PTEN: Phosphatase and Tensin Homolog; RAF: Rapidly Accelereated Fibrosarcoma; RAS: Rat Sarcoma; RET: Receptor Tyrosin Kinases for Members of the Gndf Members of Extracellular Signaling Molecules; RIT: Wild Type GTP Binding Protein; ROS: Reactive Oxygen Species; RTK: Receptor Tyrosine Kinase; RUNX: Runt Related Transcription Factor; SCLC: Small Cell Lung Cancer; SOX: Sry Box Transcription Factors; SSEA: Stage Specifc Embryonic Antigen; STAT: Signal Transducer and Activator of Transcription Proteins; TGF: Tumor Growth Factor; TP53: Tumor Progression 53; VEGFR: Vascular Epidermal Growth Factor; Wnt-Catenin- Beta: Wingless Integrin Catenin Beta Pathway INTRODUCTION Day by day one of the increased global burden threatening diseases is Cancer. Nearly, on the estimation of about 14.1 million cancer cases were recorded in the world by 2012. 7.4 million Cases were seen in men and 6.7 million in women. This number is expected to increase by 24 million by 2035. Lung cancer, the most common cancer which contributes 13% of the total number of new cases was diagnosed in 2012 worldwide. Likewise, Breast cancer (women) the second most common cancer (1.7 million) and Colorectal cancer, the third most common cancer (nearly 1.4 million) new cases were diagnosed in 2012 [1]. Cancer probabilities are increasing day by day which is the second common disease in India with a maximum mortality rate of 0.3 million deaths per year [2]. Failure expression of clinical therapies in treating cancer patients is due to recurrence or relapse. Recurrence properties extrapolate Intra and inter tumor heterogeneity of cancer between the same or different cancer patients or within the tumor of different types. The facial expression of cancer doesn’t show any correlation between phenotype and genotype. Cancer initiation and progression rely on the theory of Clonal evolution which is a neutral drift dynamic theory [3, 4]. The dynamicity operates through selective sweeps with the help of drivers and passengers that are carried along during the development of cancer [5]. A single tumor biopsy sample doesn’t give insights into the tumor characteristics or its genomic landscape. Intratumor heterogeneity can be elucidated through the evaluation of topologically distinct regions with existing techniques that determine clonal heterogeneity [5, 6]. Tumor behavior and response to therapy explain the inter tumor heterogeneity even though the tumor origin is from the same organ [7]. Intra and inter tumor progression will also be influenced by a group of a subset of cells named as Cancer Stem Cells (CSC’s) having self-renewal with differentiation [8]. These stem cells explain the differences between different tumor cells in the form of gradient differentiation between them [9, 10]. In this scenario, studying tumors and their heterogeneity considering the theory of CSC in different cancer types explains the insights of targeted clinical cellular therapy. Here, in this review, an overview of several aspects that contribute CSC based tumour heterogeneity based on their cell surface markers has been presented. We also discussed the nature of 7 1