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Dubey P, Gupta R, Mishra A, Kumar V, Bhadauria S, Bhatt MLB. Evaluation of correlation between CD44, radiotherapy response, and survival rate in patients with advanced stage of head and neck squamous cell carcinoma (HNSCC). Cancer Med 2022; 11:1937-1947. [PMID: 35274800 PMCID: PMC9089225 DOI: 10.1002/cam4.4497] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 11/13/2021] [Accepted: 11/26/2021] [Indexed: 02/06/2023] Open
Abstract
Purpose Cancer stem cells (CSCs) constitute a distinctive subpopulation of cancer cells that are competent in tumor initiation, invasion, recurrence, and resistance to chemoradiotherapy. CD44, a hyaluronic acid (HA) receptor has been considered as a potential CSC marker in head and neck cancer. The purpose of this study is to evaluate the correlation between CD44 and clinicopathological parameters, treatment response, survival, and recurrence. Methods The CD44 expression was examined by immunohistochemistry (IHC) in 90 samples of head and neck squamous cell carcinoma (HNSCC) confirmed patients. The expression of CD44 and its association with clinicopathological parameters, treatment response, and survival was determined. Results In all HNSCC patient samples, CD44 was expressed consistently at different intensities. Tumor size (p < 0.001), stage (p < 0.001), and treatment response (p < 0.001) showed statistically significant association with CD44 expression. Alcohol and CD44 were observed as independent predictors of response to radiotherapy using multivariate ordinal logistic regression analysis. Analysis of 2‐year overall survival (OS) showed that CD44 expression (p = 0.02), tumor size (p = 0.001), lymph node status (p < 0.001), stage (p < 0.001), and grade (p = 0.007) were significantly associated with OS. Using Cox regression analysis, lymph node status (p = 0.001), grade (p < 0.001), recurrence (p < 0.001), and CD44 expression (p = 0.003) were found to be potential independent predictors of OS. Conclusion Our findings suggest that CD44 contributes to resistance to radiotherapy and poor OS. The results also suggest that except for CD44 there could be other factors such as lymph node metastasis, grade, and alcohol which should be investigated as potential targets for therapy.
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Affiliation(s)
- Parul Dubey
- Department of Radiotherapy, King George's Medical University, Lucknow, India
| | - Rajeev Gupta
- Department of Radiotherapy, King George's Medical University, Lucknow, India
| | - Anupam Mishra
- Department of Otorhinolaryngology & Head Neck Surgery, King George's Medical University, Lucknow, India
| | - Vijay Kumar
- Department of Surgical Oncology, King George's Medical University, Lucknow, India
| | - Smrati Bhadauria
- Division of Toxicology & Experimental Medicine, Central Drug Research Institute (CSIR), Lucknow, India
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Allegra E, Bianco MR, Mignogna C, Caltabiano R, Grasso M, Puzzo L. Role of P16 Expression in the Prognosis of Patients With Laryngeal Cancer: A Single Retrospective Analysis. Cancer Control 2021; 28:10732748211033544. [PMID: 34538114 PMCID: PMC8450612 DOI: 10.1177/10732748211033544] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND A possible oncogenic role of human papillomavirus (HPV) in head and neck cancers (mainly oropharynx tumors) has been suggested. This significant association has been considered true for oropharynx tumors; however, the association between HPV infection and laryngeal carcinomas is yet to be established. The aim of this study was to evaluate the relationship between p16 expression and long-term overall, disease-free, and disease-specific survival (OS, DF, and DSS, respectively) in patients surgically treated for laryngeal carcinoma. MATERIALS AND METHODS Seventy-four previously untreated laryngeal carcinoma patients who underwent surgical treatment were considered for this retrospective study. The tissue specimens were processed for immunohistochemical p16 protein (surrogate HPV marker) detection. RESULTS Survival analysis of the p16 expression of the primary tumor showed that the 5-year OS rates were 90% and 29.7% for the p16-positive and negative groups, respectively (P = .003). The 5-year DFS and DSS also differed between both groups (P < .001), whereas the 5-year DSS seemed to be related to tumor/lymph node classification and p16 expression. However, only p16 expression was identified as an independent prognostic factor associated with OS and DSS. CONCLUSIONS Surgically treated p16-positive laryngeal cancer patients may represent a subset of patients with a better prognosis than their p16-negative counterparts.
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Affiliation(s)
- Eugenia Allegra
- Otolaryngology-Department of Health Science, 9325University of Catanzaro, Catanzaro, Italy
| | - Maria Rita Bianco
- Otolaryngology-Department of Health Science, 9325University of Catanzaro, Catanzaro, Italy
| | - Chiara Mignogna
- Centro Interdipartimentale dei Servizi, 9325University of Catanzaro, Catanzaro, Italy
| | - Rosario Caltabiano
- Department G.F. Ingrassia, Section of Anatomic Pathology, 60279University of Catania, Catania, Italy
| | - Maria Grasso
- Otolaryngology-Department of Health Science, 9325University of Catanzaro, Catanzaro, Italy
| | - Lidia Puzzo
- Department G.F. Ingrassia, Section of Anatomic Pathology, 60279University of Catania, Catania, Italy
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Role of Clinical-Demographic Data in Survival Rates of Advanced Laryngeal Cancer. ACTA ACUST UNITED AC 2021; 57:medicina57030267. [PMID: 33804150 PMCID: PMC8001944 DOI: 10.3390/medicina57030267] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/21/2021] [Accepted: 03/08/2021] [Indexed: 11/24/2022]
Abstract
Background and Objectives: Laryngeal cancer is one of the most common cancers in the upper aerodigestive tract, and tobacco and alcohol habits are the most relevant risk factors. The role of these risk factors in the incidence of laryngeal carcinomas is well known, yet only a few studies have been conducted on their role as risk factors of prognosis. The aim of the study was to assess the impact of clinical–demographic data on overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) in patients with advanced-stage laryngeal cancer (Stage III–IV) who underwent total laryngectomy. Materials and Methods: This retrospective study was carried out on patients with Stage III–IV laryngeal squamous cell carcinoma treated with total laryngectomy between 2004 and 2014. For each patient, clinical and anamnestic data were collected and collated in a database, including alcohol and smoking habits. Results: Considering the variable age, family history, alcohol, grading, subsite, stage, pT stage, pN stage, and adjuvant therapy, no statistical significance was found for five-year OS. Smoking was the only variable that was statistically significant (p = 0.0043). A relevant difference was noted in the five-year DFS between pN-negative and pN-positive tumors (74.3% vs. 55.26%, respectively; p = 0.056), and a statistically significant difference was found between non- and ≤20 cigarettes/day smokers and heavy smokers (77.78% vs. 53.66%, respectively; p = 0.021). The five-year disease-specific survival rate was 68.83%, and a significant difference was detected for the smoking and pN stage variables. Heavy smokers (43.90% died vs. 16.67% of the non- and ≤20 cigarettes/day smokers; p = 0.0057) and pN-positive (42.1% died vs. 20.51% of the pN-negative patients; p = 0.042) patients had a worse prognosis. Conclusion: Smoking in our study was found to be an important independent risk factor for worse OS and DSS in patients with advanced laryngeal cancer.
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ZSCAN4 facilitates chromatin remodeling and promotes the cancer stem cell phenotype. Oncogene 2020; 39:4970-4982. [PMID: 32507861 PMCID: PMC7314663 DOI: 10.1038/s41388-020-1333-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 04/03/2020] [Accepted: 05/14/2020] [Indexed: 01/01/2023]
Abstract
Cancer stem cells (CSCs) are cells within tumors that maintain the ability to self-renew, drive tumor growth, and contribute to therapeutic resistance and cancer recurrence. In this study, we investigate the role of Zinc finger and SCAN domain containing 4 (ZSCAN4) in human head and neck squamous cell carcinoma (HNSCC). The murine Zscan4 is involved in telomere maintenance and genomic stability of mouse embryonic stem cells. Our data indicate that the human ZSCAN4 is enriched for, marks and is co-expressed with CSC markers in HNSCC. We show that transient ZSCAN4 induction for just 2 days increases CSC frequency both in vitro and in vivo and leads to upregulation of pluripotency and CSC factors. Importantly, we define for the first time the role of ZSCAN4 in altering the epigenetic profile and regulating the chromatin state. Our data show that ZSCAN4 leads to a functional histone 3 hyperacetylation at the promoters of OCT3/4 and NANOG, leading to an upregulation of CSC factors. Consistently, ZSCAN4 depletion leads to downregulation of CSC markers, decreased ability to form tumorspheres and severely affects tumor growth. Our study suggests that ZSCAN4 plays an important role in the maintenance of the CSC phenotype, indicating it is a potential therapeutic target in HNSCC.
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Cancer Stem Cells in Head and Neck Carcinomas: Identification and Possible Therapeutic Implications. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1083:89-102. [PMID: 29139089 DOI: 10.1007/5584_2017_116] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The recurrence and/or lack of response of certain tumors to radio- and chemotherapy has been attributed to a small subpopulation of cells termed cancer stem cells (CSCs). CSCs have been identified in many tumors (including solid and hematological tumors). CSCs are characterized by their capacity for self-renewal, their ability to introduce heterogeneity within a tumor mass and its metastases, genomic instability, and their insensitivity to both radiation and chemotherapy. The latter highlights the clinical importance of studying this subpopulation since their resistance to traditional treatments may lead to metastatic disease and/or tumor relapse. Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignancy worldwide with the highest incidence occurring in East Asia and eastern and southern Africa. Several cellular subpopulations believed to have CSC properties have been isolated from HNSCCs, but at present, identification and characterization of CSCs remains an experimental challenge with no established or standardized protocols in place to confirm their identity. In this review we discuss current approaches to the study of CSCs with a focus on HNSCCs, particularly in the context of what this might mean from a therapeutic perspective.
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Irani S, Dehghan A. The Expression and Functional Significance of Vascular Endothelial-Cadherin, CD44, and Vimentin in Oral Squamous Cell Carcinoma. J Int Soc Prev Community Dent 2018; 8:110-117. [PMID: 29780735 PMCID: PMC5946518 DOI: 10.4103/jispcd.jispcd_408_17] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 01/15/2018] [Indexed: 01/29/2023] Open
Abstract
Objectives Ninety percent of head and neck cancers are squamous cell carcinoma which develops in the oral cavity. Metastasis is the main causative factor for death in 90% of all cancer-related deaths and begins with the invasion of tumor cells through the walls of small blood vessels or lymph vessels. A growing body of evidence has shown that vasculogenic mimicry (VM) facilitates tumor growth and cancer metastasis. The current study aimed to present the role of vascular endothelial (VE)-cadherin, CD44, and vimentin in inducing VM and epithelial-mesenchymal transition (EMT) and to identify the cancer stem cell (CSC) niche in different grades of oral squamous cell carcinoma (OSCC). Materials and Methods A total of 63 OSCC samples (21 samples each grade) were collected from the archive of Pathology Department of Besat educational hospital, Hamadan, Iran, from 2000 to 2015. VE-cadherin, CD44, and vimentin/periodic acid-Schiff (PAS) double-staining were used to validate VM. VM was identified by the detection of PAS-positive loops surrounded by tumor cells. Chi-square test was used to examine the differences between the variables. Significant level was set at 0.05. Pearson's correlation was used to assess the co-localization of the markers. Results There were statistically significant differences between tumor grade and the expression levels of VE-cadherin, CD44, and vimentin (P = 0.000). In addition, significant differences were found between tumor grade and microvessel density (P = 0.000) and between tumor grade and VM (P = 0.000). Conclusion Our results may disclose a definite relationship between VE-cadherin, CD44 and vimentin expression levels, VM formation, EMT, CSCs, and microvessel count in OSCC samples. For this reason, it is suggested that VE-cadherin, CD44, and vimentin are related to angiogenesis and VM formation in OSCC, therefore, in tumor progression and metastasis. Recently, antitumor angiogenic therapies have been challenged. The presence of VM may explain the failure of antiangiogenic treatments.
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Affiliation(s)
- Soussan Irani
- Department of Oral Pathology, Dental Research Centre, Research Centre for Molecular Medicine, Dental Faculty, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Arash Dehghan
- Department of Pathology, Besat Hospital, Hamadan University of Medical Sciences, Hamadan, Iran
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7
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Moncharmont C, Guy JB, Wozny AS, Gilormini M, Battiston-Montagne P, Ardail D, Beuve M, Alphonse G, Simoëns X, Rancoule C, Rodriguez-Lafrasse C, Magné N. Carbon ion irradiation withstands cancer stem cells' migration/invasion process in Head and Neck Squamous Cell Carcinoma (HNSCC). Oncotarget 2018; 7:47738-47749. [PMID: 27374096 PMCID: PMC5216975 DOI: 10.18632/oncotarget.10281] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 05/28/2016] [Indexed: 12/12/2022] Open
Abstract
Cancer Stem Cells (CSCs) in Head and Neck Squamous Cell Carcinoma (HNSCC) have extremely aggressive profile (high migratory and invasive potential). These characteristics can explain their resistance to conventional treatment. Efficacy of photon and carbon ion irradiation with addition of cetuximab (5 nM) is studied on clonogenic death, migration and invasion of two HNSCC populations: SQ20B and SQ20B/CSCs. SQ20B express E-cadherin and overexpress EGFR while SQ20B/CSCs express N-cadherin and low EGFR. Cetuximab strongly inhibits SQ20B proliferation but has no effect on SQ20B/CSCs. 2 Gy photon irradiation enhances migration and invasiveness in both populations (p < 0.05), while cetuximab only stops SQ20B migration (p < 0.005). Carbon irradiation significantly inhibits invasion in both populations (p < 0.05), and the association with cetuximab significantly inhibits invasion in both populations (p < 0.005). These results highlight CSCs characteristics: EGFRLow, cetuximab-resistant, and highly migratory. Carbon ion irradiation appears to be a very promising therapeutic modality counteracting migration/invasion process in both parental cells and CSCs in contrast to photon irradiation.
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Affiliation(s)
- Coralie Moncharmont
- Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, 69921, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, 69622, France.,Département de Radiothérapie, Institut de Cancérologie de la Loire - Lucien Neuwirth, St Priest en Jarez, 42270, France
| | - Jean-Baptiste Guy
- Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, 69921, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, 69622, France.,Département de Radiothérapie, Institut de Cancérologie de la Loire - Lucien Neuwirth, St Priest en Jarez, 42270, France
| | - Anne-Sophie Wozny
- Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, 69921, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, 69622, France.,Hospices Civils de Lyon, Lyon, 69229, France
| | - Marion Gilormini
- Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, 69921, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, 69622, France
| | - Priscilla Battiston-Montagne
- Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, 69921, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, 69622, France
| | - Dominique Ardail
- Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, 69921, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, 69622, France.,Hospices Civils de Lyon, Lyon, 69229, France
| | - Michael Beuve
- Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, 69622, France
| | - Gersende Alphonse
- Laboratoire de Radiobiologie Cellulaire et Moléculaire, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, 69622, France.,Hospices Civils de Lyon, Lyon, 69229, France
| | - Xavier Simoëns
- Département de Pharmacologie Clinique et d'Innovation, Institut de Cancérologie de la Loire - Lucien Neuwirth, St Priest en Jarez, 42270, France
| | - Chloé Rancoule
- Département de Radiothérapie, Institut de Cancérologie de la Loire - Lucien Neuwirth, St Priest en Jarez, 42270, France
| | - Claire Rodriguez-Lafrasse
- Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, 69921, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, 69622, France.,Hospices Civils de Lyon, Lyon, 69229, France
| | - Nicolas Magné
- Université Lyon 1, Faculté de Médecine-Lyon-Sud, Oullins, 69921, France.,Laboratoire de Radiobiologie Cellulaire et Moléculaire, Institut de Physique Nucléaire de Lyon, IPNL, Villeurbanne, 69622, France.,Département de Radiothérapie, Institut de Cancérologie de la Loire - Lucien Neuwirth, St Priest en Jarez, 42270, France
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8
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Shang W, Zhang Q, Huang Y, Shanti R, Alawi F, Le A, Jiang C. Cellular Plasticity-Targeted Therapy in Head and Neck Cancers. J Dent Res 2018; 97:654-664. [PMID: 29486673 DOI: 10.1177/0022034518756351] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Head and neck cancer is one of the most frequent human malignancies worldwide, with a high rate of recurrence and metastasis. Head and neck squamous cell carcinoma (HNSCC) is cellularly and molecularly heterogeneous, with subsets of undifferentiated cancer cells exhibiting stem cell-like properties, called cancer stem cells (CSCs). Epithelial-mesenchymal transition, gene mutation, and epigenetic modification are associated with the formation of cellular plasticity of tumor cells in HNSCC, contributing to the acquisition of invasive, recurrent, and metastatic properties and therapeutic resistance. Tumor microenvironment (TME) plays a supportive role in the initiation, progression, and metastasis of head and neck cancer. Stromal fibroblasts, vasculature, immune cells, cytokines, and hypoxia constitute the main components of TME in HNSCC, which contributes not only to the acquisition of CSC properties but also to the recurrence and therapeutic resistance of the malignancies. In this review, we discuss the potential mechanisms underlying the development of cellular plasticity, especially the emergence of CSCs, in HNSCC. We also highlight recent studies implicating the complex interplays among TME components, plastic CSCs, tumorigenesis, recurrence, and therapeutic resistance of HNSCC. Finally, we summarize the treatment modalities of HNSCC and reinforce the novel concept of therapeutic targeting CSCs in HNSCC.
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Affiliation(s)
- W Shang
- 1 Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Shandong, China.,4 School of Stomatology, Qingdao University, Shandong, China
| | - Q Zhang
- 2 Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Y Huang
- 3 Department of Orthodontics, The Affiliated Hospital of Qingdao University, Shandong, China.,4 School of Stomatology, Qingdao University, Shandong, China
| | - R Shanti
- 2 Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.,5 Department of Oral and Maxillofacial Surgery, Perelman Center for Advanced Medicine, Penn Medicine Hospital of the University of Pennsylvania, Philadelphia, PA, USA.,6 Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - F Alawi
- 7 Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - A Le
- 2 Department of Oral and Maxillofacial Surgery and Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.,5 Department of Oral and Maxillofacial Surgery, Perelman Center for Advanced Medicine, Penn Medicine Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - C Jiang
- 3 Department of Orthodontics, The Affiliated Hospital of Qingdao University, Shandong, China.,4 School of Stomatology, Qingdao University, Shandong, China
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9
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Franco T, Trapasso S, Puzzo L, Allegra E. Electronic Cigarette: Role in the Primary Prevention of Oral Cavity Cancer. CLINICAL MEDICINE INSIGHTS. EAR, NOSE AND THROAT 2016; 9:7-12. [PMID: 27773997 PMCID: PMC5068504 DOI: 10.4137/cment.s40364] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 08/28/2016] [Accepted: 08/24/2016] [Indexed: 11/17/2022]
Abstract
BACKGROUND Cigarette smoke has been identified as the main cause of oral cavity carcinoma. Recently, the electronic cigarette, a battery-operated device, was developed to help smokers stop their tobacco addiction. This study aimed to evaluate the safety of electronic cigarettes and to establish the possible role of such device in the primary prevention of oral cavity cancer. SUBJECTS AND METHODS This study included 65 subjects who were divided into three groups (smokers, e-cigarette smokers, and nonsmokers). All subjects were submitted to cytologic examination by scraping of oral mucosa. The slides were microscopically evaluated through a micronucleus assay test. RESULTS The prevalence of micronuclei was significantly decreased in the e-cigarette smoker group. There were no statistically significant differences in micronuclei distribution according to the type of cigarette, gender, and age. CONCLUSIONS The use of electronic cigarettes seems to be safe for oral cells and should be suggested as an aid to smoking cessation.
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Affiliation(s)
- Teresa Franco
- Otolaryngology—Head and Neck Surgery, Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Serena Trapasso
- Otolaryngology—Head and Neck Surgery, Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Lidia Puzzo
- Department of “G.F. Ingrassia”, Section of Anatomic Pathology, University of Catania, Catania, Italy
| | - Eugenia Allegra
- Otolaryngology—Head and Neck Surgery, Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
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10
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de Moraes FPP, Lourenço SV, Ianez RCF, de Sousa EA, Silva MMDC, Damascena AS, Kowalski LP, Soares FA, Coutinho-Camillo CM. Expression of stem cell markers in oral cavity and oropharynx squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2016; 123:113-122. [PMID: 27866975 DOI: 10.1016/j.oooo.2016.09.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 08/18/2016] [Accepted: 09/11/2016] [Indexed: 12/14/2022]
Abstract
OBJECTIVES The aim of this study was to analyze the expression of CD24, CD44, CD133, ALDH1, CD29 (integrin-β1), and Ki-67 in squamous cell carcinoma of the oral cavity and oropharynx. STUDY DESIGN Fifty-two tumors and 21 metastatic lymph nodes were evaluated by using immunohistochemistry. RESULTS Seven of 52 cases (13.5%) showed positive cytoplasmic staining of aldehyde dehydrogenase 1; integrin-β1 was expressed in 45 of 50 cases (90%); 30 of 52 cases (57.7%) had positive membranous staining of CD44; CD24 was expressed in 44 of 50 cases (88%); and three of 52 cases (5.8%) stained positively for membranous CD133. Median proliferation rate, measured by Ki-67, was 37.1% for tumors. Five-year cancer-specific survival rates for the CD44-negative and CD44-positive groups were 74% and 38%, respectively, although this difference did not reach statistical significance (P = .052). CONCLUSIONS Our study demonstrated the expression of putative stem cell markers in squamous cell carcinoma of the oral cavity and oropharynx, with participation of CD44-positive cells in association with poor survival outcome.
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Affiliation(s)
- Flávia Paiva Prudente de Moraes
- International Research Center, AC Camargo Cancer Center, São Paulo, SP, Brazil; Department of Pathology, AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - Silvia Vanessa Lourenço
- Department of General Pathology, Dental School, University of São Paulo, São Paulo, SP, Brazil
| | - Renata Carolina Fraga Ianez
- International Research Center, AC Camargo Cancer Center, São Paulo, SP, Brazil; Department of Pathology, AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - Elen Alves de Sousa
- International Research Center, AC Camargo Cancer Center, São Paulo, SP, Brazil; Department of Pathology, AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - Marlon Messias da Conceição Silva
- International Research Center, AC Camargo Cancer Center, São Paulo, SP, Brazil; Department of Pathology, AC Camargo Cancer Center, São Paulo, SP, Brazil
| | | | - Luiz Paulo Kowalski
- Department of Head and Neck Surgery and Otorhinolaryngology, AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - Fernando Augusto Soares
- Department of Pathology, AC Camargo Cancer Center, São Paulo, SP, Brazil; Department of General Pathology, Dental School, University of São Paulo, São Paulo, SP, Brazil
| | - Cláudia Malheiros Coutinho-Camillo
- International Research Center, AC Camargo Cancer Center, São Paulo, SP, Brazil; Department of Pathology, AC Camargo Cancer Center, São Paulo, SP, Brazil.
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11
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Marcu LG, Marcu D. In silico modelling of a cancer stem cell-targeting agent and its effects on tumour control during radiotherapy. Sci Rep 2016; 6:32332. [PMID: 27573059 PMCID: PMC5004146 DOI: 10.1038/srep32332] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 08/03/2016] [Indexed: 11/16/2022] Open
Abstract
Head and neck cancers (HNC), like most solid tumours, contain a subpopulation of cancer stem cells (CSC) that are commonly responsible for treatment failure. Conventional therapies are unsuccessful in controlling CSCs, thus novel, targeting therapies are needed. A promising agent is ATRA (All-trans-retinoic acid) that was shown to induce CSC differentiation, cell cycle redistribution and CSCs radiosensitisation. To add to the limited data, this work simulated the effects of ATRA on a virtual HNC and evaluated tumour response to radiotherapy. A Monte Carlo technique was employed to grow a HNC consisting of all lineages of cancer cells. The biologically realistic input parameters led to a pre-treatment CSC population of 5.9%. The Linear Quadratic model was employed to simulate radiotherapy. ATRA-induced differentiation, cell arrest and apoptosis were modelled, based on literature data. While the effect of differentiation was marginal, the strongest influence on CSC subpopulation was displayed by ATRA’s cell arrest effect via an exponential behaviour of the dose-response curve. The apoptotic effect induced by ATRA shows linear correlation between the percentage of apoptotic cells and dose required to eradicate CSCs. In conclusion, ATRA is a potent CSC-targeting agent with viable impact on tumour control when combined with radiotherapy.
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Affiliation(s)
- Loredana G Marcu
- Faculty of Science, University of Oradea, Oradea 410087, Romania.,School of Physical Sciences, The University of Adelaide, SA 5005, Australia
| | - David Marcu
- Faculty of Science, University of Oradea, Oradea 410087, Romania
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Marcu LG, Marcu D, Filip SM. In silico study of the impact of cancer stem cell dynamics and radiobiological hypoxia on tumour response to hyperfractionated radiotherapy. Cell Prolif 2016; 49:304-14. [PMID: 27079860 DOI: 10.1111/cpr.12251] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Accepted: 02/10/2016] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Advanced head and neck carcinomas (HNCs) are aggressive tumours, mainly due to hypoxia and a cancer stem cell (CSC) subpopulation. The aim of this study was to simulate tumour growth and behaviour during radiotherapy of three HNC groups (governed by different growth kinetics, hypoxia levels and CSC division pattern) to determine correlation between resistance factors and responses to hyperfractionated radiotherapy. METHODS An in silico HNC model was developed based on biologically realistic input parameters. During radiotherapy simulation, three parameters were studied: growth kinetics, hypoxia and probability of CSC symmetrical division. Both independent and combined effects on tumour response to hyperfractionated radiotherapy were assessed. RESULTS Oxic and very mildly hypoxic HNCs were revealed to be controlled by hyperfractionated radiotherapy, irrespective of growth kinetics and CSC division pattern. Moderately hypoxic tumours had different responses to radiotherapy: while slowly proliferating HNCs were still controllable, tumours with higher cell turnover were more resistant. In rapidly proliferating tumours, the number of fractions needed for tumour control increased exponentially with the probability of CSC symmetrical division, whereas in moderately growing HNC, this behaviour was linear. Severely hypoxic tumours could not be controlled by radiotherapy alone. Tumours with CSCs in a severely hypoxic niche required adjuvant therapies to be eradicated. CONCLUSIONS Growth kinetics strongly influence tumour responses to treatment. Slowly growing tumours showed linear dependence between dose and hypoxia/CSC, whereas rapidly growing tumours followed exponential behaviour.
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Affiliation(s)
- L G Marcu
- Faculty of Science, University of Oradea, Oradea, 410087, Romania.,School of Physical Sciences, The University of Adelaide, Adelaide, South Australia, 5005, Australia
| | - D Marcu
- Faculty of Science, University of Oradea, Oradea, 410087, Romania
| | - S M Filip
- Faculty of Science, University of Oradea, Oradea, 410087, Romania
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13
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Puzzo L, Caltabiano R, Parenti R, Trapasso S, Allegra E. Connexin 43 (Cx43) Expression in Laryngeal Squamous Cell Carcinomas: Preliminary Data on Its Possible Prognostic Role. Head Neck Pathol 2016; 10:292-7. [PMID: 26748803 PMCID: PMC4972757 DOI: 10.1007/s12105-016-0685-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 01/03/2016] [Indexed: 12/31/2022]
Abstract
The aim of the report is to evaluate the prognostic and predictive role of Connexin 43 (Cx43) expression in laryngeal squamous cell carcinomas. Eighty-seven previously untreated patients submitted to laryngectomy ± neck dissection ± radiotherapy were enrolled in this retrospective study. The original primary tumor slides were reassessed, tumor grade and stage reviewed, and Cx43 immunohistochemical analysis performed: only cytoplasmic membranous staining of Cx43 has been shown. Neither significant correlation has been showed for clinical T (p = 0.75) and N (p = 0.81), while significant correlation has been found with grading (p < 0.0001) and pathological N (p < 0.0001). Five year overall survival (OS) of the 87 patients was 54 %; 5 year OS was 59.6 % in Cx43 positive patients and 37.1 % in Cx43 negative patients, but also this difference did not reach statistical significance (p = 0.058). Our best findings were: poorly differentiated carcinomas had low or negative Cx43 expression; moderately differentiated tumors without node metastasis and no radiotherapy but with Cx43 expression had a better outcome; moderately differentiated tumors without node metastasis and no radiotherapy but without Cx43 expression had a worse outcome; moderately differentiated tumors with node metastasis and radiotherapy but without Cx43 expression had a better outcome. Interestingly, in G2 head and neck squamous cell carcinomas with lymph node metastasis at the time of diagnosis, Cx43 aberrant overexpression could identify a subset of patients with poor prognosis, far less responsive to radio/chemotherapy.
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Affiliation(s)
- Lidia Puzzo
- Department “G.F.Ingrassia”, Section of Anatomic Pathology, University of Catania, Via S. Sofia, 87, 95125 Catania, Italy
| | - Rosario Caltabiano
- Department “G.F.Ingrassia”, Section of Anatomic Pathology, University of Catania, Via S. Sofia, 87, 95125 Catania, Italy
| | - Rosalba Parenti
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Via S. Sofia, 64, 95125 Catania, Italy
| | - Serena Trapasso
- Department of Medical and Surgical Sciences – Section of Otolaryngology, Magna Graecia University of Catanzaro, Viale Europa, Località Germaneto, 88100 Catanzaro, Italy
| | - Eugenia Allegra
- Department of Medical and Surgical Sciences – Section of Otolaryngology, Magna Graecia University of Catanzaro, Viale Europa, Località Germaneto, 88100 Catanzaro, Italy
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Li YC, Chang JT, Chiu C, Lu YC, Li YL, Chiang CH, You GR, Lee LY, Cheng AJ. Areca nut contributes to oral malignancy through facilitating the conversion of cancer stem cells. Mol Carcinog 2015; 55:1012-23. [PMID: 26087469 DOI: 10.1002/mc.22344] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 05/08/2015] [Accepted: 05/13/2015] [Indexed: 01/06/2023]
Abstract
Oral cancer is one of the most frequent malignant diseases worldwide, and areca nut is a primary carcinogen causing this cancer in Southeast Asia. Previous studies to examine the effects of this carcinogen often used short-term and high-dose treatment of area nut extract as a research model, which do not recapitulate the conditions of patients with long-term and habitual use of this substance. To approach authentic mechanism of areca nut-induced oral carcinogenesis that occurs in human, we established four isogenic sublines of oral cells which were chronic exposed to areca nut extract. Without eliciting cytotoxicity or senescence, these four sublines cells exhibited significant increase in invasive ability, along with epithelial-mesenchymal transition. These cells also showed resistance to chemotherapeutic drug and irradiation, accompanying with the augmentation of ABCG2 protein efflux and increased ROS clearance. Moreover, these sublines possessed the characteristics of cancer stemness, as demonstrated by enriched CD24-/CD44+ and CD133+ sub-populations, enhanced spheroid cell formation, and induced expressions of pluripotent stemness regulators, including Gp96, Grp78, Slug, Sox9, Snail, and Foxc2. These stemness regulators were further shown up-regulations in oral cancer patients with areca nut-chewing habit, and were statistically correlated with CD44 expression, a stemness marker. In conclusion, our findings suggested that areca nut contributes to oral malignancy through facilitating the conversion of cancer stem cells. This study may further contribute to clinical applications in disease prevention, risk assessment or molecular therapeutics on areca nut- associated diseases.
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Affiliation(s)
- Yi-Chen Li
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Joseph T Chang
- Department of Radiation Oncology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Crystal Chiu
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ya-Ching Lu
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yan-Liang Li
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chang-Hsu Chiang
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Guo-Rung You
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Li-Yu Lee
- Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ann-Joy Cheng
- Department of Medical Biotechnology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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15
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Wei P, Niu M, Pan S, Zhou Y, Shuai C, Wang J, Peng S, Li G. Cancer stem-like cell: a novel target for nasopharyngeal carcinoma therapy. Stem Cell Res Ther 2015; 5:44. [PMID: 25158069 PMCID: PMC4055123 DOI: 10.1186/scrt433] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx, and is extremely common in southern regions of China. Although the standard combination of radiotherapy and chemotherapy has improved the efficiency in patients with NPC, relapse and early metastasis are still the common causes of mortality. Cancer stem-like cells (CSCs) or tumor initial cells are hypothesized to be involved in cancer metastasis and recurrence. Over the past decade, increasing numbers of studies have been carried out to identify CSCs from human NPC cells and tissues. The present paper will summarize the investigations on nasopharyngeal CSCs, including isolation, characteristics, and therapeutic approaches. Although there are still numerous challenges to translate basic research into clinical applications, understanding the molecular details of CSCs is essential for developing effective strategies to prevent the recurrence and metastasis of NPC.
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16
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Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation. Stem Cell Rev Rep 2015; 10:114-26. [PMID: 23955575 DOI: 10.1007/s12015-013-9467-y] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Although promising new radiation therapy techniques such as hadrontherapy are currently being evaluated in the treatment of head and neck malignancies, local control of head and neck squamous cell carcinoma (HNSCC) remains low. Here, we investigated the involvement of cancer stem-like cells (CSCs) in a radioresistant HNSCC cell line (SQ20B). Stem-like cells SQ20B/SidePopulation(SP)/CD44(+)/ALDH(high) were more resistant to both photon and carbon ion irradiation compared with non-CSCs. This was confirmed by a BrdU labeling experiment, which suggests that CSCs were able to proliferate and to induce tumorigenicity after irradiation. SQ20B/SP/CD44(+)/ALDH(high) were capable of an extended G2/M arrest phase in response to photon or carbon ion irradiation compared with non-CSCs. Moreover, our data strongly suggest that resistance of CSCs may result from an imbalance between exacerbated self-renewal and proliferative capacities and the decrease in apoptotic cell death triggering. In order to modulate these processes, two targeted pharmacological strategies were tested. Firstly, UCN-01, a checkpoint kinase (Chk1) inhibitor, induced the relapse of G2/M arrest and radiosensitization of SQ20B-CSCs. Secondly, all-trans retinoic acid (ATRA) resulted in an inhibition of ALDH activity, and induction of the differentiation and radiosensitization of SQ20B/SP/CD44(+)/ALDH(high) cells. The combination of ATRA and UCN-01 treatments with irradiation drastically decreased the surviving fraction at 2Gy of SQ20B-CSCs from 0.85 to 0.38 after photon irradiation, and from 0.45 to 0.21 in response to carbon ions. Taken together, our results suggest that the combination of UCN-01 and ATRA represent a promising pharmacological-targeted strategy that significantly sensitizes CSCs to photon or carbon ion radiation.
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Le JM, Squarize CH, Castilho RM. Histone modifications: Targeting head and neck cancer stem cells. World J Stem Cells 2014; 6:511-525. [PMID: 25426249 PMCID: PMC4178252 DOI: 10.4252/wjsc.v6.i5.511] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 09/10/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and is responsible for a quarter of a million deaths annually. The survival rate for HNSCC patients is poor, showing only minor improvement in the last three decades. Despite new surgical techniques and chemotherapy protocols, tumor resistance to chemotherapy remains a significant challenge for HNSCC patients. Numerous mechanisms underlie chemoresistance, including genetic and epigenetic alterations in cancer cells that may be acquired during treatment and activation of mitogenic signaling pathways, such as nuclear factor kappa-light-chain-enhancer-of activated B cell, that cause reduced apoptosis. In addition to dysfunctional molecular signaling, emerging evidence reveals involvement of cancer stem cells (CSCs) in tumor development and in tumor resistance to chemotherapy and radiotherapy. These observations have sparked interest in understanding the mechanisms involved in the control of CSC function and fate. Post-translational modifications of histones dynamically influence gene expression independent of alterations to the DNA sequence. Recent findings from our group have shown that pharmacological induction of post-translational modifications of tumor histones dynamically modulates CSC plasticity. These findings suggest that a better understanding of the biology of CSCs in response to epigenetic switches and pharmacological inhibitors of histone function may directly translate to the development of a mechanism-based strategy to disrupt CSCs. In this review, we present and discuss current knowledge on epigenetic modifications of HNSCC and CSC response to DNA methylation and histone modifications. In addition, we discuss chromatin modifications and their role in tumor resistance to therapy.
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18
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Akhavan-Niaki H, Samadani AA. Molecular insight in gastric cancer induction: an overview of cancer stemness genes. Cell Biochem Biophys 2014; 68:463-73. [PMID: 24078401 DOI: 10.1007/s12013-013-9749-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastric cancer is one of the most outgoing human cancers in the world. Two main functional types were described: Intestinal adenocarcinoma and diffuse one. The most important purpose of this review is to analyze and investigate the main genetic factors involved in tumorogenesis of stomach and the molecular mechanism of their expression regulation alongside with the importance of cancer stem cells and their relationship with gastric cancer. It is evident that proper diagnosis of molecular case of cancer may lead to absolute treatment and at least reduction in the disease severity. However, stemness factors such as Sox2, Oct3/4, and Nanog were related with induced pluripotent stem cells, proposing a correlation between these stemness factors and cancer stem cells. Moreover, aberrant induction by Helicobacter pylori of the intestinal-specific homeobox transcription factors, CDX1 and CDX2, also plays an important role in this modification. There are some genes which are directly activated by CDX1 in gastric cancer and distinguished stemness-related reprogramming factors like SALL4 and KLF5. Correspondingly, we also aimed to present the main important epigenetic changes such as DNA methylation, histone modification, and chromatin modeling of stemness genes in disease development. Remarkably, a better understanding of molecular bases of cancer may lead to novel diagnostic, therapeutic, and preventive approaches by some genetic and epigenetic changes such as gene amplifications, gene silencing by DNA methylation, losses of imprinting, LOH, and mutations. Consequently, genome-wide searches of gene expression are widely important for surveying the proper mechanisms of cancer emergence and development. Conspicuously, this review explains an outline of the molecular mechanism and new approaches in gastric cancer.
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Affiliation(s)
- Haleh Akhavan-Niaki
- Cellular and Molecular Biology Research Center, Babol University of Medical Sciences, Babol, Iran
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19
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Tulsyan S, Agarwal G, Lal P, Mittal B. Significant association of combination of OCT4, NANOG, and SOX2 gene polymorphisms in susceptibility and response to treatment in North Indian breast cancer patients. Cancer Chemother Pharmacol 2014; 74:1065-1078. [PMID: 25223935 DOI: 10.1007/s00280-014-2588-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 09/07/2014] [Indexed: 10/24/2022]
Abstract
PURPOSE Dysregulations of regulatory genes in embryonic stem cells (ESCs) gene polymorphisms may lead to breast cancer cell growth, differentiation, and tumor metastasis. METHODS Polymorphisms in OCT4 (rs3130932), NANOG (rs11055786), LIN28 (rs4274112), and SOX2 (rs11915160) genes were evaluated for susceptibility in 297 breast cancer females and 273 healthy controls from north Indian population. Response to neo-adjuvant chemotherapy was followed in 128 locally advanced breast cancer patients along with clinicopathological features. Genotyping was done using TaqMan allelic discrimination assays. Statistical analysis was performed using SPSS and multifactor dimensionality reduction (MDR). RESULTS For OCT4 gene polymorphism, protective effect of genotypes AC [P corr = 0.031, OR = 0.63 (0.44-0.91)] and AC+CC [P corr = 0.031, OR = 0.68 (0.48-0.95)] was seen in patients. However, no association of NANOG, LIN28, and SOX2 gene polymorphisms was found with overall breast cancer susceptibility. Further, significant association of AG+GG genotype [P corr = 0.021, OR = 6.08 (1.83-20.15)] and G allele [P corr = 0.021, OR = 3.07 (1.21-7.77)] of rs4274112 polymorphism was seen with positive lymph node. For OCT4, significant association of allele C was seen with patients having negative hormone receptor [P corr = 0.021, OR = 0.51 (0.29-0.90)], but no association of any of the studied polymorphisms individually was found with response to NACT. On MDR analysis, we found combination of SNPs SOX2 rs11915160, OCT4 rs3130932, and NANOG rs11055786 to be the best interaction model for predicting breast cancer risk [p for permutation test <10(-3), OR = 2.04 (1.43-2.910] and response to NACT [p for permutation test = 0.005, OR = 2.09 (1.24-3.52)]. CONCLUSION Combination of genetic variants of ESCs gene may have a profound effect in breast cancer risk and response to NACT.
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Affiliation(s)
- Sonam Tulsyan
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli road, Lucknow, 226 014, India
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20
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Allegra E, Trapasso S, Pisani D, Puzzo L. The Role of BMI1 as a Biomarker of Cancer Stem Cells in Head and Neck Cancer: A Review. Oncology 2014; 86:199-205. [DOI: 10.1159/000358598] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 01/02/2014] [Indexed: 11/19/2022]
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21
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Cancer stem cells accountability in progression of head and neck squamous cell carcinoma: the most recent trends! Mol Biol Int 2014; 2014:375325. [PMID: 24693428 PMCID: PMC3946131 DOI: 10.1155/2014/375325] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Revised: 01/02/2014] [Accepted: 01/13/2014] [Indexed: 12/18/2022] Open
Abstract
Cancer stem cells (CSCs) play a major role in local recurrence and metastatic spread in head and neck squamous cell carcinomas (HNSCC). Evidence suggests that cancer stem cells are resistant to conventional therapy. So the emerging concepts of the role of cancer stem cells in the pathobiology of HNSCC should be understood carefully to be able to create new paradigms in treatment plans.
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22
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Faber A, Aderhold C, Goessler UR, Hoermann K, Schultz JD, Umbreit C, Walliczek U, Stern-Straeter J. Interaction of a CD44+ head and neck squamous cell carcinoma cell line with a stromal cell-derived factor-1-expressing supportive niche: An in vitro model. Oncol Lett 2013; 7:82-86. [PMID: 24348826 PMCID: PMC3861560 DOI: 10.3892/ol.2013.1673] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Accepted: 09/19/2013] [Indexed: 01/15/2023] Open
Abstract
The cancer stem cell (CSC) theory implies that CSCs are surrounded by supportive stromal cells, which are known as the CSC niche. Stromal cell-derived factor-1 (SDF-1) shows a multitude of functional effects in head and neck squamous cell carcinoma (HNSCC) cells, including migration and polarization. Therefore, the SDF-1-CXCR4 axis may be involved in the pathophysiology of the progression, recurrence and metastasis of malignant diseases of the head and neck. In the present study, the CD44+ HNSCC UM-SCC-11A cell line was used as a model for CSCs. The interaction between the UM-SCC-11A cells and the supportive microenvironmental cells, including fibrocytes, human umbilical vein endothelial cells (HUVECs) and human microvascular vein endothelial cells (HMVECs) was evaluated. All the cell types that were tested were shown to secrete different concentrations of SDF-1 into the surrounding culture medium [mean (m)fibro, 1243.3±156.2 pg/ml; mHMVEC, 1061.4±23.2 pg/ml; mHUVEC, 849.6±110.9 pg/ml]. The migration of the UM-SCC-11A cells towards the supportive cells was increased by a higher supply of SDF-1 (contrfibro, 315.23±61.55 μm; mfibro, 477.73±143.7 μm; Pfibro=0.003; contrHMVEC, 123.41±66.68 μm; mHMVEC, 249.04±111.95 μm; PHMVEC=0.004; contrHUVEC, 189.7±93.26 μm; mHUVEC, 260.82±161.58 μm). The amount of the UM-SCC-11A cells that migrated towards the differentiated fibrocytes was significantly higher than that which migrated towards the HMVECs or HUVECs (Pfibro/HMVEC=2.12E-11; Pfibro/HUVEC=2.28E-5). Cell-cell interaction by podia formation of the UM-SCC-11A cells was observed in all the supportive cell types that were tested. Broadly based cell-cell contacts were observed. By contrast, digitiform podia formations presented by the UM-SCC-11A cells were determined using fluorescence microscopy. The SDF-1-CXCR4 axis is postulated to be a crucial pathway in the interaction between CSCs and their surrounding supportive cells. Understanding the cell-cell interactions in the CSC niche using in vitro models may aid in gaining further insight into these mechanisms and finding new strategies of therapy in this field.
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Affiliation(s)
- Anne Faber
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Christoph Aderhold
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Ulrich Reinhart Goessler
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Karl Hoermann
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Johannes David Schultz
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Claudia Umbreit
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Ute Walliczek
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
| | - Jens Stern-Straeter
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Mannheim D-68167, Germany
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Allegra E, Trapasso S, La Boria A, Aragona T, Pisani D, Belfiore A, Garozzo A. Prognostic role of salivary CD44sol levels in the follow-up of laryngeal carcinomas. J Oral Pathol Med 2013; 43:276-81. [DOI: 10.1111/jop.12129] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
| | | | | | | | - Davide Pisani
- Otolaryngology; University of Catanzaro; Catanzaro Italy
| | - Antonino Belfiore
- Department of Clinical and Experimental Medicine; Endocrinology Unit; University of Catanzaro; Catanzaro Italy
| | - Aldo Garozzo
- Otolaryngology; University of Catanzaro; Catanzaro Italy
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Szafarowski T, Szczepanski MJ. Cancer stem cells in head and neck squamous cell carcinoma. Otolaryngol Pol 2013; 68:105-11. [PMID: 24837904 DOI: 10.1016/j.otpol.2013.10.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 10/30/2013] [Accepted: 10/31/2013] [Indexed: 01/24/2023]
Abstract
Recent studies have demonstrated that cancer stem cells (CSC) play an important role in the pathobiology of head and neck squamous cell carcinomas (HNSCC). This subpopulation of undifferentiated, self-renewing cells is responsible for resistance to conventional anti-cancer therapy, cancer recurrence, metastasis and ability to form a heterogeneous tumor. CSC are identified on the basis of specific markers, including membrane proteins or cell enzymes, or by using their self-renewal properties. As their resistance to standard HNSCC treatment may eventually lead to the lack of treatment success, there is an urgent need to better understanding CSC biology and identify them as potential target new treatment modality.
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Affiliation(s)
- Tomasz Szafarowski
- Department of Otorhinolaryngology, Faculty of Medicine and Dentistry, Medical University of Warsaw, Head: prof. dr n. med. Antoni Krzeski, Warsaw, Poland
| | - Miroslaw J Szczepanski
- Department of Otorhinolaryngology, Faculty of Medicine and Dentistry, Medical University of Warsaw, Head: prof. dr n. med. Antoni Krzeski, Warsaw, Poland; Department of Clinical Immunology, University of Medical Sciences in Poznan, Head: prof. dr n. med. Grzegorz Dworacki, Poznan, Poland.
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Resveratrol inhibits alpha-melanocyte-stimulating hormone signaling, viability, and invasiveness in melanoma cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:632121. [PMID: 23762150 PMCID: PMC3676971 DOI: 10.1155/2013/632121] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2013] [Accepted: 05/07/2013] [Indexed: 12/14/2022]
Abstract
Melanoma is a malignancy with high potential to invasion and treatment resistance. The α -melanocyte-stimulating hormone ( α -MSH) signal transduction involving Wnt/ β -catenin, c-Kit, and microphthalmia-associated transcription factor (MITF), a known pathway to produce melanin, has been demonstrated as one of cancer stem cell characteristics. This study was aimed to examine the effect of resveratrol, an abundant ingredient of grape and medicinal plants, on α -MSH signaling, viability, and invasiveness in melanoma cells. By α -MSH treatment, the melanin production in B16 melanoma cells was augmented as a validation for activation of α -MSH signaling. The upregulated expression of α -MSH signaling-related molecules β -catenin, c-Kit, and MITF was suppressed by resveratrol and/or STI571 treatment. Nuclear translocation of MITF, a hallmark of α -MSH signaling activation, was inhibited by combined treatment of resveratrol and STI571. At effective concentration, resveratrol and/or STI571 inhibited cell viability and α -MSH-activated matrix metalloproteinase- (MMP-)9 expression and invasion capacity of B16 melanoma cells. In conclusion, resveratrol enhances STI571 effect on suppressing the α -MSH signaling, viability, and invasiveness in melanoma cells. It implicates that resveratrol may have potential to modulate the cancer stem cell characteristics of melanoma.
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