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1
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Li S, Townes T, Na'ara S. Current Advances and Challenges in the Management of Cutaneous Squamous Cell Carcinoma in Immunosuppressed Patients. Cancers (Basel) 2024; 16:3118. [PMID: 39335091 PMCID: PMC11430974 DOI: 10.3390/cancers16183118] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/23/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy and poses a significant risk to immunosuppressed patients, such as solid organ transplant recipients and those with hematopoietic malignancies, who are up to 100 times more likely to develop cSCC compared with the general population. This review summarizes the current state of treatment for cSCC in immunosuppressed patients, focusing on prevention, prophylaxis, surgical and non-surgical treatments, and emerging therapies. Preventative measures, including high-SPF sunscreen and prophylactic retinoids, are crucial for reducing cSCC incidence in these patients. Adjusting immunosuppressive regimens, particularly favoring mTOR inhibitors over calcineurin inhibitors, has been shown to lower cSCC risk. Surgical excision and Mohs micrographic surgery remain the primary treatments, with adjuvant radiation therapy recommended for high-risk cases. Traditional chemotherapy and targeted therapies like EGFR inhibitors have been utilized, though their efficacy varies. Immunotherapy, particularly with agents like cemiplimab and pembrolizumab, has shown promise, but its use in immunosuppressed patients requires further investigation due to potential risks of organ rejection and exacerbation of underlying conditions. Treatment of cSCC in immunosuppressed patients is multifaceted, involving preventive strategies, tailored surgical approaches, and cautious use of systemic therapies. While immunotherapy has emerged as a promising option, its application in immunosuppressed populations necessitates further research to optimize safety and efficacy. Future studies should focus on the integration of personalized medicine and combination therapies to improve outcomes for this vulnerable patient group.
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Affiliation(s)
- Sophie Li
- The Department of Head and Neck Surgery, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
| | - Thomas Townes
- The Department of Head and Neck Surgery, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
| | - Shorook Na'ara
- The Department of Head and Neck Surgery, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
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2
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Giri A, Bauman JR. Pembrolizumab as monotherapy in locally advanced cutaneous squamous cell carcinoma. Expert Rev Anticancer Ther 2022; 22:1029-1038. [DOI: 10.1080/14737140.2022.2125382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Anshu Giri
- Department of Hematology and Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
| | - Jessica R. Bauman
- Department of Hematology and Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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3
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Beauvais DM, Nelson SE, Adams KM, Stueven NA, Jung O, Rapraeger AC. Plasma membrane proteoglycans syndecan-2 and syndecan-4 engage with EGFR and RON kinase to sustain carcinoma cell cycle progression. J Biol Chem 2022; 298:102029. [PMID: 35569509 PMCID: PMC9190016 DOI: 10.1016/j.jbc.2022.102029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 04/18/2022] [Accepted: 04/20/2022] [Indexed: 12/20/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) is a causal factor in carcinoma, yet many carcinoma patients are resistant to EGFR inhibitors. Potential insight into this resistance stems from prior work that showed EGFR in normal epithelial cells docks to the extracellular domain of the plasma membrane proteoglycan syndecan-4 (Sdc4) engaged with α3β1 and α6β4 integrins. We now report that this receptor complex is modified by the recruitment of syndecan-2 (Sdc2), the Recepteur d'Origine Nantais (RON) tyrosine kinase, and the cellular signaling mediator Abelson murine leukemia viral oncogene homolog 1 (ABL1) in triple-negative breast carcinoma and head and neck squamous cell carcinoma, where it contributes to EGFR kinase-independent proliferation. Treatment with a peptide mimetic of the EGFR docking site in the extracellular domain of Sdc4 (called SSTNEGFR) disrupts the entire complex and causes a rapid, global arrest of the cell cycle. Normal epithelial cells do not recruit these additional receptors to the adhesion mechanism and are not arrested by SSTNEGFR. Although EGFR docking with Sdc4 in the tumor cells is required, cell cycle progression does not depend on EGFR kinase. Instead, progression depends on RON kinase, activated by its incorporation into the complex. RON activates ABL1, which suppresses p38 mitogen-activated protein kinase and prevents a p38-mediated signal that would otherwise arrest the cell cycle. These findings add to the growing list of receptor tyrosine kinases that support tumorigenesis when activated by their association with syndecans at sites of matrix adhesion and identify new potential targets for cancer therapy.
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Affiliation(s)
- DeannaLee M Beauvais
- Department of Human Oncology, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Scott E Nelson
- Department of Human Oncology, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Kristin M Adams
- Department of Human Oncology, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Noah A Stueven
- Department of Human Oncology, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Oisun Jung
- Department of Human Oncology, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Alan C Rapraeger
- Department of Human Oncology, University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
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Janani B, Vijayakumar M, Priya K, Kim JH, Prabakaran DS, Shahid M, Al-Ghamdi S, Alsaidan M, Othman Bahakim N, Hassan Abdelzaher M, Ramesh T. EGFR-Based Targeted Therapy for Colorectal Cancer—Promises and Challenges. Vaccines (Basel) 2022; 10:vaccines10040499. [PMID: 35455247 PMCID: PMC9030067 DOI: 10.3390/vaccines10040499] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 02/05/2023] Open
Abstract
Colorectal carcinoma (CRC) is the most lethal and common form of cancer in the world. It was responsible for almost 881,000 cancer deaths in 2018. Approximately 25% of cases are diagnosed at advanced stages with metastasis—this poses challenges for effective surgical control and future tumor-related mortality. There are numerous diagnostic methods that can be used to reduce the risk of colorectal carcinoma. Among these, targeted nanotherapy aims to eliminate the tumor and any metastasis. Active targeting can increase the effectiveness and quantity of drugs delivered to the target site. Antibodies that target overexpressed receptors on cell surfaces and indicators are coupled with drug-loaded carriers. The major target receptors of chemotherapeutic drugs delivery include VEGFR, EGFR, FGFR, HER2, and TGF. On account of its major and diverse roles in cancer, it is important to target EGFR in particular for better tumor selection, as EGFR is overexpressed in 25 to 82% of colorectal carcinoma cases. The EGFR monoclonal immunoglobulins cetuximab/panitumumab can thus be used to treat colorectal cancer. This review examines carriers that contain cetuximab-conjugated therapeutic drugs as well as their efficacy in anticancer activities.
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Affiliation(s)
- Balakarthikeyan Janani
- Department of Biochemistry, PSG College of Arts and Science (Autonomous), Bharathiar University, Coimbatore 641014, Tamil Nadu, India;
| | - Mayakrishnan Vijayakumar
- Department of Integrative Bioscience and Biotechnology, College of Life Sciences, Sejong University, 209 Neugdong-ro, Gwangjin-gu, Seoul 05006, Korea; (M.V.); (J.H.K.)
| | - Kannappan Priya
- Department of Biochemistry, PSG College of Arts and Science (Autonomous), Bharathiar University, Coimbatore 641014, Tamil Nadu, India;
- Correspondence: (K.P.); (T.R.)
| | - Jin Hee Kim
- Department of Integrative Bioscience and Biotechnology, College of Life Sciences, Sejong University, 209 Neugdong-ro, Gwangjin-gu, Seoul 05006, Korea; (M.V.); (J.H.K.)
| | - D. S. Prabakaran
- Department of Radiation Oncology, College of Medicine, Chungbuk National University, Chungdae-ro 1, Seowon-gu, Cheongju 28644, Korea;
- Department of Biotechnology, Ayya Nadar Janaki Ammal College (Autonomous), Srivilliputhur Main Road, Sivakasi 626124, Tamil Nadu, India
| | - Mohammad Shahid
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.S.); (N.O.B.); (M.H.A.)
| | - Sameer Al-Ghamdi
- Family and Community Medicine Department, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
| | - Mohammed Alsaidan
- Internal Medicine Department, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
| | - Nasraddin Othman Bahakim
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.S.); (N.O.B.); (M.H.A.)
| | - Mohammad Hassan Abdelzaher
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.S.); (N.O.B.); (M.H.A.)
- Department of Medical Biochemistry, Faculty of Medicine, Al-Azhar University (Assiut Branch), Assiut 71515, Egypt
| | - Thiyagarajan Ramesh
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; (M.S.); (N.O.B.); (M.H.A.)
- Correspondence: (K.P.); (T.R.)
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5
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MCM-2, Ki-67, and EGFR downregulated expression levels in advanced stage laryngeal squamous cell carcinoma. Sci Rep 2021; 11:14607. [PMID: 34272446 PMCID: PMC8285532 DOI: 10.1038/s41598-021-94077-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 07/06/2021] [Indexed: 12/29/2022] Open
Abstract
We present the conceptual study investigated the capacity of minichromosome maintenance-2 (MCM-2), Ki-67, and epidermal growth factor receptor (EGFR) to assess the severity and progression of laryngeal squamous cell carcinoma (LSCC) disease and to study the correlations among these markers. A total of 30 patients with LSCC with immunohistochemistry (IHC) staining for MCM-2, Ki-67 and EGFR were examined. Mean expression levels of the three markers were evaluated for comparing between early and advanced stages of LSCC. The mean MCM-2, Ki-67, and EGFR expression levels were significantly decreased in advanced-stage compared with early-stage LSCC. Pearson correlation analysis showed a statistically significant correlation between the MCM-2 and Ki-67. Regarding subgroup analyses, MCM-2, Ki-67, and EGFR showed significant differences between early- and advanced-stage LSCC with non-recurrence, while for the recurrent subgroup LSCC, only MCM-2 revealed a significant difference between early- and advanced-stage LSCC. Altogether, these results support the role for downregulation of MCM-2, Ki-67 and EGFR in advanced-stage LSCC and correlation of MCM-2 and Ki-67 expressions that would be a promising strategy to predict prognosis of LSCC including severity and progression. We contextualize our findings and advocate the position of the biological markers, especially MCM-2, as an emerging evaluation tool for LSCC disease.
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6
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Chen Y, Cong R, Ji C, Ruan W. The prognostic role of C-reactive protein in patients with head and neck squamous cell carcinoma: A meta-analysis. Cancer Med 2020; 9:9541-9553. [PMID: 33201589 PMCID: PMC7774749 DOI: 10.1002/cam4.3520] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 09/04/2020] [Accepted: 09/14/2020] [Indexed: 12/22/2022] Open
Abstract
Background The prognostic role of the C‐reactive protein (CRP) in head and neck squamous cell carcinoma (HNSCC) has not been well investigated. This meta‐analysis aimed to evaluate the prognostic relevance of elevated CRP levels in patients with HNSCC. Methods A relevant literature search was performed in PubMed, Web of Science, and Embase up to September 1, 2020. The pooled odds ratio and hazard ratio (HR) with 95% confidence interval (CI) were applied to evaluate the difference in overall survival (OS), progress‐free survival (PFS), and cancer‐specific survival (CSS) between patients with high CRP and those without. The pooled odds ratio (OR) with 95% CI were used to assess the association between CRP and clinicopathological features. Results A total of 17 studies, including 4449 patients, were included. Pooled results showed that an elevated CRP was associated with worse OS (HR = 1.48, 95% CI: 1.24‐1.77), CSS (HR = 1.85, 95% CI: 1.38‐2.46), and PFS (HR = 1.73, 95% CI: 1.38‐2.17). Male patients, lymph node metastases, and higher tumor stage were related to elevated CRP level (OR = 1.67, 95% CI: 1.34‐2.09; OR = 2.40, 95% CI: 1.44‐3.99; OR = 1.39, 95% CI: 1.12‐1.74). Conclusion Our meta‐analysis demonstrated that an elevated pretreatment of CRP indicates poor prognosis in HNSCC. Therefore, CRP is an indicator of the prognosis of patients with HNSCC and can be recommended for assessing prognoses in clinical work.
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Affiliation(s)
- Yanglan Chen
- Department of Stomatology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province, China
| | - Rong Cong
- Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chengjian Ji
- Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wenhua Ruan
- Department of Stomatology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province, China
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7
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Polverini PJ, Lingen MW. A History of Innovations in the Diagnosis and Treatment of Oral and Head and Neck Cancer. J Dent Res 2019; 98:489-497. [PMID: 31008698 DOI: 10.1177/0022034519833645] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Historical records as far back as 3000 BCE show that oral and head and neck cancer was a disease process well known to Egyptian physicians. Luminaries such as Hippocrates, Galen, Pott, and Virchow were instrumental in shaping our understanding of the etiology and pathogenesis of cancer. During the 20th century, evidence-based medicine catalyzed the development of rigorous science-based diagnostic and treatment protocols. The use of surgery, therapeutic radiation, and chemotherapy as single-treatment agents or in combination with one another gradually emerged as the preferred approach to cancer therapy. The recognition of tobacco, alcohol, and human papillomavirus as etiological agents in oral and head and neck cancer prompted the development of new diagnostic aids and treatment strategies to mitigate cancer progression. More in-depth mechanistic insights into the multistep process of oral and head and neck cancer were made possible by the use of the hamster buccal pouch and mouse models. New technologies, such as the sequencing of the human genome, metabolomics, and proteomics, have provided the foundation for what we today call precision medicine. The future success of tailored medical treatment for cancer patients will depend on the discovery of new druggable targets with improved therapeutic efficacy. As the precision and sensitivity of existing tools for prevention and risk assessment improve, greater accuracy will be achieved in predicting health outcomes.
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Affiliation(s)
- P J Polverini
- 1 Department of Periodontics and Oral Medicine, Division of Oral Medicine, Pathology, and Radiology, University of Michigan School of Dentistry, Ann Arbor, MI, USA.,2 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.,3 University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - M W Lingen
- 4 Department of Pathology, University of Chicago, Chicago, IL, USA
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8
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Ribeiro IP, Rodrigues JM, Mascarenhas A, Kosyakova N, Caramelo F, Liehr T, Melo JB, Carreira IM. Cytogenetic, genomic, and epigenetic characterization of the HSC-3 tongue cell line with lymph node metastasis. J Oral Sci 2018; 60:70-81. [PMID: 29479029 DOI: 10.2334/josnusd.16-0811] [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: 11/01/2022]
Abstract
Oral carcinoma develops from squamous epithelial cells by the acquisition of multiple (epi) genetic alterations that target different genes and molecular pathways. Herein, we performed a comprehensive genomic and epigenetic characterization of the HSC-3 cell line through karyotyping, multicolor fluorescence in situ hybridization, array comparative genomic hybridization, and methylation-specific multiplex ligation-dependent probe amplification. HSC-3 turned out to be a near-triploid cell line with a modal number of 61 chromosomes. Banding and molecular cytogenetic analyses revealed that nonrandom gains of chromosomal segments occurred more frequently than losses. Overall, gains of chromosome 1, 3q, 5p, 7p, 8q, 9q, 10, 11p, 11q13, 12, 13, 14, 17, 18p, 20, Yp, and Xq were observed. The largest region affected by copy number loss was observed at chromosome 18q. Several of the observed genomic imbalances and their mapped genes were already associated with oral carcinoma and/or adverse prognosis, invasion, and metastasis in cancer. The most common rearrangements observed were translocations in the centromeric/near-centromeric regions. RARB, ESR1, and CADM1 genes were methylated and showed copy number losses, whereas TP73 and GATA5 presented with methylation and copy number gains. Thus, the current study presents a comprehensive characterization of the HSC-3 cell line; the use of this cell line may contribute to enriching the resources available for oral cancer research, especially for the testing of therapeutic agents.
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Affiliation(s)
- Ilda P Ribeiro
- Cytogenetics and Genomics Laboratory, Faculty of Medicine, University of Coimbra.,Center of Investigation on Environment Genetics and Oncobiology, Faculty of Medicine, University of Coimbra
| | - Joana M Rodrigues
- Cytogenetics and Genomics Laboratory, Faculty of Medicine, University of Coimbra
| | | | - Nadezda Kosyakova
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University
| | - Francisco Caramelo
- Laboratory of Biostatistics and Medical Informatics, Faculty of Medicine, University of Coimbra
| | - Thomas Liehr
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University
| | - Joana B Melo
- Cytogenetics and Genomics Laboratory, Faculty of Medicine, University of Coimbra.,Center of Investigation on Environment Genetics and Oncobiology, Faculty of Medicine, University of Coimbra
| | - Isabel M Carreira
- Cytogenetics and Genomics Laboratory, Faculty of Medicine, University of Coimbra.,Center of Investigation on Environment Genetics and Oncobiology, Faculty of Medicine, University of Coimbra
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9
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Cañueto J, Cardeñoso E, García JL, Santos-Briz Á, Castellanos-Martín A, Fernández-López E, Blanco Gómez A, Pérez-Losada J, Román-Curto C. Epidermal growth factor receptor expression is associated with poor outcome in cutaneous squamous cell carcinoma. Br J Dermatol 2017; 176:1279-1287. [PMID: 27510450 DOI: 10.1111/bjd.14936] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2016] [Indexed: 12/27/2022]
Abstract
BACKGROUND Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans after basal cell carcinoma, and its incidence is dramatically rising. CSCC is rarely problematic, but given its high frequency, the absolute number of complicated cases is also high. It is necessary to identify molecular markers in order to recognize those CSCCs with poor prognosis. There is controversy concerning the role of epidermal growth factor receptor (EGFR) as a marker of prognosis in CSCC. In addition, EGFR-targeted therapies have emerged in recent years and a better understanding of the role of EGFR in CSCC may be of help for some patients in predicting prognosis and guiding curative management. OBJECTIVES To evaluate the role of EGFR as a prognostic factor in CSCC. METHODS We evaluated clinical and histopathological features, including events of poor clinical evolution, in a series of 94 cases of CSCC. We also analysed EGFR expression by immunohistochemistry, fluorescent in situ hybridization and quantitative polymerase chain reaction. RESULTS We detected EGFR in 85 cases (90%), with overexpression in 33 cases (35%), and aberrant EGFR expression in the cytoplasm in 50 cases (53%). EGFR overexpression in the primary tumours was associated with lymph node progression, tumour-nodes-metastasis stage progression and proliferation (Ki-67 staining) in CSCC. EGFR overexpression and poor grade of differentiation were the strongest independent variables defining lymph node metastasis and progression in CSCC in a logistic regression model. CONCLUSIONS We demonstrate that EGFR overexpression has prognostic implications associated with lymph node metastasis and progression in CSCC.
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Affiliation(s)
- J Cañueto
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
| | - E Cardeñoso
- Departamento de Dermatología, Hospital Virgen de la Concha, Avenida de Requejo, Zamora, Spain
| | - J L García
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain.,Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Campus Miguel de Unamuno, s/n. 37007, Salamanca, Spain
| | - Á Santos-Briz
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
| | - A Castellanos-Martín
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain.,Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Campus Miguel de Unamuno, s/n. 37007, Salamanca, Spain
| | - E Fernández-López
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
| | - A Blanco Gómez
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain.,Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Campus Miguel de Unamuno, s/n. 37007, Salamanca, Spain
| | - J Pérez-Losada
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain.,Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Campus Miguel de Unamuno, s/n. 37007, Salamanca, Spain
| | - C Román-Curto
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, 37007, Salamanca, Spain
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10
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Suresh A, Kuriakose MA, Mohanta S, Siddappa G. Carcinogenesis and Field Cancerization in Oral Squamous Cell Carcinoma. CONTEMPORARY ORAL ONCOLOGY 2017:1-30. [DOI: 10.1007/978-3-319-14911-0_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Nema R, Vishwakarma S, Agarwal R, Panday RK, Kumar A. Emerging role of sphingosine-1-phosphate signaling in head and neck squamous cell carcinoma. Onco Targets Ther 2016; 9:3269-3280. [PMID: 27330306 PMCID: PMC4898435 DOI: 10.2147/ott.s99989] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer type, with an annual incidence of approximately half a million people worldwide. It has a high recurrence rate and an extremely low survival rate. This is due to limited availability of effective therapies to reduce the rate of recurrence, resulting in high morbidity and mortality of patients with advanced stages of the disease. HNSCC often develops resistance to chemotherapy and targeted drug therapy. Thus, to overcome the problem of drug resistance, there is a need to explore novel drug targets. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in inflammation, tumor progression, and angiogenesis. S1P is synthesized intracellularly by two sphingosine kinases (SphKs). It can be exported to the extracellular space, where it can activate a family of G-protein-coupled receptors. Alternatively, S1P can act as an intracellular second messenger. SphK1 regulates tumor progression, invasion, metastasis, and chemoresistance in HNSCC. SphK1 expression is highly elevated in advanced stage HNSCC tumors and correlates with poor survival. In this article, we review current knowledge regarding the role of S1P receptors and enzymes of S1P metabolism in HNSCC carcinogenesis. Furthermore, we summarize the current perspectives on therapeutic approaches for targeting S1P pathway for treating HNSCC.
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Affiliation(s)
- Rajeev Nema
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, India
| | - Supriya Vishwakarma
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, India
| | - Rahul Agarwal
- Jawaharlal Nehru Cancer Hospital & Research Centre, Indrapuri, Bhopal, India
| | | | - Ashok Kumar
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, India
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12
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Nimotuzumab increases the anti-tumor effect of photodynamic therapy in an oral tumor model. Oncotarget 2016; 6:13487-505. [PMID: 25918252 PMCID: PMC4537029 DOI: 10.18632/oncotarget.3622] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 04/08/2015] [Indexed: 12/23/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) represents 90% of all oral cancers and is characterized with poor prognosis and low survival rate. Epidermal growth factor receptor (EGFR) is highly expressed in oral cancer and is a target for cancer therapy and prevention. In this present work, we evaluate the efficacy of photodynamic therapy (PDT) in combination with an EGFR inhibitor, nimotuzumab in oral cancer cell lines and OSCC xenograft tumor model. PDT is a promising and minimally invasive treatment modality that involves the interaction of a photosensitizer, molecular oxygen and light to destroy tumors. We demonstrated that EGFR inhibitors nimotuzumab and cetuximab exhibits anti-angiogenic properties by inhibiting the migration and invasion of oral cancer cell lines and human endothelial cells. The EGFR inhibitors also significantly reduced tube formation of endothelial cells. Chlorin e6-PDT in combination with nimotuzumab and cetuximab reduced cell proliferation in different oral cancer and endothelial cells. Furthermore, our in vivo studies showed that the combination therapy of PDT and nimotuzumab synergistically delayed tumor growth when compared with control and PDT treated tumors. Downregulation of EGFR, Ki-67 and CD31 was observed in the tumors treated with combination therapy. Analysis of the liver and kidney function markers showed no treatment related toxicity. In conclusion, PDT outcome of oral cancer can be improved when combined with EGFR inhibitor nimotuzumab.
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Jeong WJ, Cha PH, Choi KY. Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer. World J Gastroenterol 2014; 20:9862-9871. [PMID: 25110417 PMCID: PMC4123368 DOI: 10.3748/wjg.v20.i29.9862] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/14/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Administration of monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) such as cetuximab and panitumumab in combination with conventional chemotherapy substantially prolongs survival of patients with metastatic colorectal cancer (mCRC). However, the efficacy of these mAbs is limited due to genetic variation among patients, in particular K-ras mutations. The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC. Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF, MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors. Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation, our understanding of their mode of action is limited. Rational drug development based on stringent preclinical data, biomarker validation, and proper selection of patients is of paramount importance in the treatment of mCRC. In this review, we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFR-Ras-ERK and PI3K signalings.
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14
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Liu SA, Jiang RS, Wang WY, Lin JC. Somatic mutations in the D-loop of mitochondrial DNA in head and neck squamous cell carcinoma. Head Neck 2014; 37:878-83. [DOI: 10.1002/hed.23680] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 01/14/2014] [Accepted: 03/07/2014] [Indexed: 11/06/2022] Open
Affiliation(s)
- Shih-An Liu
- Department of Otolaryngology; Taichung Veterans General Hospital; Taichung Taiwan
- Faculty of Medicine, School of Medicine; National Yang-Ming University; Taipei Taiwan
| | - Rong-San Jiang
- Department of Otolaryngology; Taichung Veterans General Hospital; Taichung Taiwan
| | - Wen-Yi Wang
- Department of Nursing; Hung-Kuang University; Taichung Taiwan
| | - Jin-Ching Lin
- Department of Radiation Oncology; Taichung Veterans General Hospital; Taichung Taiwan
- Faculty of Medicine, School of Medicine; National Yang-Ming University; Taipei Taiwan
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15
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Chang PY, Kuo YB, Wu TL, Liao CT, Sun YC, Yen TC, Chan EC. Association and prognostic value of serum inflammation markers in patients with leukoplakia and oral cavity cancer. Clin Chem Lab Med 2014; 51:1291-300. [PMID: 23154424 DOI: 10.1515/cclm-2012-0504] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Accepted: 10/04/2012] [Indexed: 11/15/2022]
Abstract
BACKGROUND Oral cavity cancer ranks as the fourth leading cancer in men in Taiwan. The development of a serum biomarker panel for early detection and disease monitoring is, therefore, warranted. METHODS Nine inflammation-associated markers were investigated in 46 patients with leukoplakia, 151 patients with untreated oral cavity squamous cell carcinoma (OSCC), and 111 age- and gender-matched healthy controls using enzyme-linked immunosorbent assay. During a subsequent 28-month surveillance of OSCC patients, serum samples were prospectively collected at predetermined intervals following the completion of therapy. RESULTS Logistic regression analysis showed matrix metalloproteases (MMP)-2, MMP-9, C-reactive protein (CRP), transforming growth factor-β1 (TGF-β1), and E-selectin having the best discrimination power between groups and significant elevation trends of those five markers were noted from control to OSCC. By combining those five markers, a 0.888 and 0.938 area under curve by ROC curve analysis with 67.4% and 80% overall sensitivity and fixed 90% specificity for leukoplakia and OSCC groups were demonstrated. In the follow-up period, 25 OSCC patients developed recurring or secondary tumors. All examined markers had decreased in relapse-free patients following treatment. However, in patients with relapse, interleukin-6, CRP, and serum amyloid A remained at elevated levels. Statistical analysis showed that patients with CRP ≧2 mg/L and E-selectin ≧85 ng/mL at baseline had highest probability of relapse (odds ratio=3.029, p<0.05). CONCLUSIONS The results indicate that inflammation plays a crucial role in the pathogenesis process of OSCC. By examining the inflammation markers, physicians could potentially identify patients at risk of cancer transformation or relapse.
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Affiliation(s)
- Pi-Yueh Chang
- Department of Laboratory Medicine, Chang-Gung Memorial Hospital, Taoyuan County, Taiwan
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16
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Rassouli A, Saliba J, Castano R, Hier M, Zeitouni AG. Systemic inflammatory markers as independent prognosticators of head and neck squamous cell carcinoma. Head Neck 2014; 37:103-10. [DOI: 10.1002/hed.23567] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 08/11/2013] [Accepted: 12/09/2013] [Indexed: 12/17/2022] Open
Affiliation(s)
- Alipasha Rassouli
- Department of Otolaryngology - Head and Neck Surgery; McGill University; Montreal Quebec Canada
| | - Joe Saliba
- Department of Otolaryngology - Head and Neck Surgery; McGill University; Montreal Quebec Canada
| | - Roberto Castano
- Department of Otolaryngology - Head and Neck Surgery; Université de Montréal; Montreal Quebec Canada
| | - Michael Hier
- Department of Otolaryngology - Head and Neck Surgery; McGill University; Montreal Quebec Canada
| | - Anthony G. Zeitouni
- Department of Otolaryngology - Head and Neck Surgery; McGill University; Montreal Quebec Canada
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17
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Lee CC, Ho HC, Chien SH, Hsiao SH, Hung SK, Huang TT, Yu CC, Chang SM, Huang HH, Su YC. Association of acute phase protein-haptoglobin, and epithelial-mesenchymal transition in buccal cancer: a preliminary report. Clin Chem Lab Med 2014; 51:429-37. [PMID: 23093274 DOI: 10.1515/cclm-2012-0197] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Accepted: 05/24/2012] [Indexed: 11/15/2022]
Abstract
BACKGROUND The aim of this study was to determine the influence of inflammation on acute phase protein and epithelial-mesenchymal transition (EMT) in buccal cancer. METHODS Western blotting was carried out to investigate the expression of haptoglobin and epithelial-mesenchymal transition in oral cancer cell lines with or without IL-6 stimulation. We studied patients with buccal cancer patients without distant metastasis at diagnosis. Correlation between cellular haptoglobin, EMT, and clinical characteristics of buccal cancer was analyzed to assess the prognostic value of cellular haptoglobin level and EMT. The relationship of haptoglobin, and EMT expression with survival was assessed using Cox proportional hazard models. RESULTS Western blotting analysis showed that increased haptoglobin protein was associated with overexpression of vimentin. Under IL-6 stimulation, overexpression of haptoglobin, EMT-associated motile phenotype was noted in OC2 cell lines. Overexpression of haptoglobin was also associated with an increased risk for locoregional recurrence [hazard ratio (HR) 1.04; p=0.011] after adjusting for age, gender, disease site, stage, and treatment modality. CONCLUSIONS Increased cellular expression of haptoglobin is associated with EMT in oral cancer cell lines and this phenomenon could be exaggerated with IL-6. Cellular expression of haptoglobin is related to locoregional recurrence rate in buccal cancer patients.
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Affiliation(s)
- Ching-Chih Lee
- Department of Otolaryngology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan
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18
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Abdulmajeed AA, Farah CS. Can immunohistochemistry serve as an alternative to subjective histopathological diagnosis of oral epithelial dysplasia? BIOMARKERS IN CANCER 2013; 5:49-60. [PMID: 24179398 PMCID: PMC3798313 DOI: 10.4137/bic.s12951] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Many attempts have been made to identify objective molecular biomarkers to diagnose and prognosticate oral epithelial dysplasia (OED) because histopathological interpretation is subjective and lacks sensitivity. The majority of these efforts describe changes in gene expression at protein level in OED as determined by immunohistochemistry (IHC). However, the literature on these putative markers of oral cancer progression is vast and varied. The main purpose of this article is to review current knowledge on biomarkers of protein expression for OED by IHC approaches. We further discuss these findings in terms of the proposed essential hallmarks of cancer cells to better understand their role in oral oncogenesis.
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Affiliation(s)
- Ahmad A Abdulmajeed
- The University of Queensland, UQ Centre for Clinical Research, Herston, School of Dentistry, Brisbane, Australia
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19
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Zhu X, Zhang F, Zhang W, He J, Zhao Y, Chen X. Prognostic role of epidermal growth factor receptor in head and neck cancer: A meta-analysis. J Surg Oncol 2013; 108:387-97. [PMID: 24038070 DOI: 10.1002/jso.23406] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Accepted: 07/21/2013] [Indexed: 12/13/2022]
Affiliation(s)
- Xiaoli Zhu
- Department of Otorhinolaryngology; Peking Union Medical College Hospital; Beijing PR China
| | - Fengmei Zhang
- Institutes for Advanced Interdisciplinary Research; East China Normal University; Shanghai PR China
| | - Wei Zhang
- Institutes for Advanced Interdisciplinary Research; East China Normal University; Shanghai PR China
- School of Life Science; Wenzhou Medical College; Wenzhou, Zhejiang Province PR China
| | - Jing He
- Institutes for Advanced Interdisciplinary Research; East China Normal University; Shanghai PR China
| | - Yulan Zhao
- School of Life Science; East China Normal University; Shanghai PR China
| | - Xingming Chen
- Department of Otorhinolaryngology; Peking Union Medical College Hospital; Beijing PR China
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20
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Boeckx C, Baay M, Wouters A, Specenier P, Vermorken JB, Peeters M, Lardon F. Anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: focus on potential molecular mechanisms of drug resistance. Oncologist 2013; 18:850-64. [PMID: 23821327 DOI: 10.1634/theoncologist.2013-0013] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Targeted therapy against the epidermal growth factor receptor (EGFR) is one of the most promising molecular therapeutics for head and neck squamous cell carcinoma (HNSCC). EGFR is overexpressed in a wide range of malignancies, including HNSCC, and initiates important signal transduction pathways in HNSCC carcinogenesis. However, primary and acquired resistance are serious problems and are responsible for low single-agent response rate and tumor recurrence. Therefore, an improved understanding of the molecular mechanisms of resistance to EGFR inhibitors may provide valuable indications to identify biomarkers that can be used clinically to predict response to EGFR blockade and to establish new treatment options to overcome resistance. To date, no predictive biomarker for HNSCC is available in the clinic. Therapeutic resistance to anti-EGFR therapy may arise from mechanisms that can compensate for reduced EGFR signaling and/or mechanisms that can modulate EGFR-dependent signaling. In this review, we will summarize some of these molecular mechanisms and describe strategies to overcome that resistance.
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Affiliation(s)
- Carolien Boeckx
- Center for Oncological Research Antwerp, Laboratory of Cancer Research and Clinical Oncology, University of Antwerp, Wilrijk, Belgium
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21
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Ripamonti F, Albano L, Rossini A, Borrelli S, Fabris S, Mantovani R, Neri A, Balsari A, Magnifico A, Tagliabue E. EGFR through STAT3 modulates ΔN63α expression to sustain tumor-initiating cell proliferation in squamous cell carcinomas. J Cell Physiol 2013; 228:871-8. [PMID: 23018838 DOI: 10.1002/jcp.24238] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Accepted: 09/24/2012] [Indexed: 01/01/2023]
Abstract
Many squamous cell carcinomas (SCCs) are characterized by high levels of EGFR and by overexpression of the ΔNp63α isoform. Here, we investigated the regulation of ΔNp63α expression upon EGFR activation and the role of the EGFR-ΔNp63α axis in proliferation of SCC tumor-initiating cells (TICs). SCC cell lines A-431, Cal-27, and SCC-25 treated with EGF showed a time-dependent increase in ΔNp63α expression at the protein and mRNA levels, which was blocked by the tyrosine kinase inhibitor (TKI) Lapatinib. RNA interference experiments suggested the role of STAT3 in regulating ΔNp63α expression downstream of EGFR. Inactivation of EGFR by the monoclonal antibody Cetuximab and RNA interference against STAT3 or ΔNp63α impaired the TICs ability to grow under non-differentiating conditions. Radiation treatment, which triggers EGFR activation, induced ΔNp63α accumulation without affecting TICs proliferation, whereas the combination Cetuximab plus radiation significantly reduced TICs growth under non-differentiating conditions. Together, our findings provide evidence that ΔNp63α expression is regulated by EGFR activation through STAT3 and that the EGFR-ΔNp63α axis is crucial for proliferation of TICs present in SCCs.
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Affiliation(s)
- Francesca Ripamonti
- Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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22
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AbdulMajeed AA, Dalley AJ, Farah CS. Loss of ELF3 immunoexpression is useful for detecting oral squamous cell carcinoma but not for distinguishing between grades of epithelial dysplasia. Ann Diagn Pathol 2013; 17:331-40. [PMID: 23643910 DOI: 10.1016/j.anndiagpath.2013.03.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 03/23/2013] [Indexed: 10/26/2022]
Abstract
Early diagnosis and targeted therapy are crucial to mitigating the morbidity and mortality of oral squamous cell carcinoma. Among the potentially malignant oral disorders, epithelial dysplasia has known association with malignant transformation, but defensible gradation of dysplasia severity presents unmet challenges. Published microarray data has denoted dysregulation of CLSP, ELF3, IFI44, USP18, and CXCL13 genes in potentially malignant oral disorders. The present study investigated the diagnostic potential of these gene products to grade oral epithelial dysplasia severity. Archived biopsies from independent patient cohorts comprised "training" (n=107) and "test" (n=278) sample sets. Immunoreactivity for candidate markers was determined in the "training" set of normal oral mucosa (NOM), mild dysplasia (MD), moderate to severe dysplasia, and oral squamous cell carcinoma (OSCC). The diagnostic potential of ELF3 immunoscoring to improve detection and severity gradation of epithelial dysplasia was assessed with the "test" set. A reciprocal relationship between disease severity and immunoreactivity score for CLSP and ELF3 was observed (MD/NOM to OSCC: P<.08, Mann-Whitney U test), whereas elevated IFI44 immunostaining was present for OSCC compared to MD/NOM (P<.08, Mann-Whitney U test). Loss of ELF3 immunostaining effectively distinguished OSCC from non-malignant tissues (sensitivity=0.81; specificity=0.56; area under the curve [AUC]=0.68) but did not distinguish dysplasia from NOM (sensitivity=0.55; specificity=0.40; AUC=0.47) or moderate to severe dysplasia from MD (sensitivity=0.63; specificity=0.51; AUC=0.57). The results confirm via immunohistochemistry the relevance of published CLSP, ELF3, and IFI44 (but not USP18 or CXCL13) gene expression data to potentially malignant oral lesion severity. Loss of ELF3 immunostaining discriminated OSCC from dysplasia but was unreliable for grading dysplasia severity.
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Affiliation(s)
- Ahmad A AbdulMajeed
- The University of Queensland, UQ Centre for Clinical Research, Herston, QLD 4029, Australia.
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23
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Braakhuis BJM, Brakenhoff RH, Leemans CR. Treatment choice for locally advanced head and neck cancers on the basis of risk factors: biological risk factors. Ann Oncol 2013; 23 Suppl 10:x173-7. [PMID: 22987957 DOI: 10.1093/annonc/mds299] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Patients with locally advanced head and neck squamous cell carcinoma often experience relapse, the cause of poor survival statistics. Relapse occurs following the three main types of treatment, surgery with or without post-operative (chemo)radiotherapy, or chemoradiation (containing cisplatin). Cancer relapse can result from (i) outgrowth of residual tumour cells, sometimes with a number too small to be detected by routine histopathology or (ii) development of another carcinoma in a field of pre-neoplastic cells that has remained after treatment of the primary carcinoma. At this moment, clinical staging is not enough to identify patients who will develop relapse and who need tailored treatment. This review describes the latest knowledge of mechanisms of cancer relapse, addresses the biomarkers of potential interest detectable in the tissue of the tumour or its surgical margins and discusses three biomarkers, human papillomavirus, TP53 and epidermal growth receptor in more detail. Once a marker panel has been established, treatment should be focussed on the patients at risk of relapse by improved tailoring of existing treatment modalities. Also, the implementation of more targeting therapies based on the characteristics of the discovered markers should lead to better survival rates.
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Affiliation(s)
- B J M Braakhuis
- Department of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
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24
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Rainsbury JW, Ahmed W, Williams HK, Roberts S, Paleri V, Mehanna H. Prognostic biomarkers of survival in oropharyngeal squamous cell carcinoma: systematic review and meta-analysis. Head Neck 2012; 35:1048-55. [PMID: 22997051 DOI: 10.1002/hed.22950] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Human papillomavirus (HPV) positivity improves prognosis in patients with oropharyngeal squamous cell carcinoma (OPSCC). Combining HPV status with other biomarkers may improve its prognostic power. METHODS The approach was a literature search for longitudinal studies of biomarkers in OPSCC, with systematic review and meta-analysis. RESULTS In all, 3130 articles were identified; 32 satisfied the inclusion and exclusion criteria. On meta-analysis, there was a significant overall survival (OS) benefit for patients with HPV positive and p16 positive tumors. There was some evidence of improved OS of OPSCC patients with raised bcl2; amplification of 11q3 and loss of 16q genes; and low c-met, ki67, IMD, PLK, FHIT, nuclear surviving, or nuclear cyclin D1. However, none of these was suitable for meta-analysis. CONCLUSION Survival from OPSCC is associated with several biomarkers, which constitute potential targets for research into improving the prognostic power of HPV in OPSCC. Larger trials are needed, with standardization of cut-points and adherence to consensus reporting guidelines.
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Affiliation(s)
- James W Rainsbury
- Institute of Head and Neck Studies and Education (InHANSE), University Hospital, Coventry, United Kingdom
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25
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Kreppel M, Krakowezki A, Kreppel B, Drebber U, Wedemeyer I, Mauch C, Zöller JE, Scheer M. Podoplanin expression in cutaneous head and neck squamous cell carcinoma-prognostic value and clinicopathologic implications. J Surg Oncol 2012; 107:376-83. [DOI: 10.1002/jso.23238] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Accepted: 07/13/2012] [Indexed: 11/09/2022]
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Topical polyethylene glycol as a novel chemopreventive agent for oral cancer via targeting of epidermal growth factor response. PLoS One 2012; 7:e38047. [PMID: 22675506 PMCID: PMC3366973 DOI: 10.1371/journal.pone.0038047] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Accepted: 05/02/2012] [Indexed: 12/19/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a major cause of morbidity and mortality underscoring the need for safe and effective chemopreventive strategies. Targeting epidermal growth factor receptor (EGFR) is attractive in that it is an early critical event in HNSCC pathogenesis. However, current agents lack efficacy or have unacceptable toxicity. Several groups have demonstrated that the over-the-counter medication, polyethylene glycol (PEG) has remarkable chemopreventive efficacy against colon carcinogenesis. Importantly, we reported that this effect is mediated through EGFR internalization/degradation. In the current study, we investigated the chemopreventive efficacy of this agent against HNSCC, using both the well validated animal model 4-NQO (4-nitroquinoline 1-oxide) rat model and cell culture with the human HNSCC cell line SCC-25. We demonstrated that daily topical application of 10% PEG-8000 in the oral cavity (tongue and cavity wall) post 4NQO initiation resulted in a significant reduction in tumor burden (both, tumor size and tumors/tumor bearing rat) without any evidence of toxicity. Immunohistochemical studies depicted decreased proliferation (number of Ki67-positive cells) and reduced expression of EGFR and its downstream effectors cyclin D1 in the tongue mucosa of 4NQO-rats treated with PEG. We showed that EGFR was also markedly downregulated in SCC-25 cells by PEG-8000 with a concomitant induction of G1-S phase cell-cycle arrest, which was potentially mediated through upregulated p21(cip1/waf1). In conclusion, we demonstrate, for the first time, that PEG has promising efficacy and safety as a chemopreventive efficacy against oral carcinogenesis.
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Ohsfeldt E, Huang SH, Baycin-Hizal D, Kristoffersen L, Le TMT, Li E, Hristova K, Betenbaugh MJ. Increased expression of the integral membrane proteins EGFR and FGFR3 in anti-apoptotic Chinese hamster ovary cell lines. Biotechnol Appl Biochem 2012; 59:155-62. [PMID: 23586824 DOI: 10.1002/bab.1000] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Accepted: 01/04/2012] [Indexed: 01/12/2023]
Abstract
Membrane proteins such as receptor tyrosine kinases (RTKs) have a vital role in many cellular functions, making them potential targets for therapeutic research. In this study, we investigated the coexpression of the anti-apoptosis gene Bcl-x(L) with model membrane proteins as a means of increasing membrane protein expression in mammalian cells. Chinese hamster ovary (CHO) cells expressing heterologous Bcl-x(L) and wild-type CHO cells were transfected with either epidermal growth factor receptor or fibroblast growth factor receptor 3. The CHO-Bcl-x(L) cell lines showed increased expression of both RTK proteins as compared with the wild-type CHO cell lines in transient expression analysis, as detected by Western blot and flow cytometry after 15 days of antibiotic selection in stable expression pools. Increased expression was also seen in clonal isolates from the CHO-Bcl-x(L) cell lines, whereas the clonal cell line expression was minimal in wild-type CHO cell lines. Our results demonstrate that application of the anti-apoptosis gene Bcl-x(L) can increase expression of RTK proteins in CHO cells. This approach may be applied to improve stable expression of other membrane proteins in the future using mammalian cell lines with Bcl-x(L) or perhaps other anti-apoptotic genes.
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Affiliation(s)
- Erika Ohsfeldt
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
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28
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Iyer NG, Nixon IJ, Palmer F, Kim L, Whitcher M, Katabi N, Ghossein R, Shah JP, Patel SG, Ganly I. Surgical management of squamous cell carcinoma of the soft palate: factors predictive of outcome. Head Neck 2011; 34:1071-80. [PMID: 22109978 DOI: 10.1002/hed.21878] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Squamous cell carcinoma of the soft palate (SCCSP) is uncommon. The aim of this study was to report our experience and identify factors predictive of outcome. METHODS Between 1976 and 2005, 186 patients with SCCSP were treated with curative intent. In all, 150 patients had primary surgery, of whom 112 patients (75%) had cT1/T2 tumors and 103 patients (69%) had cN0 necks. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were determined by the Kaplan-Meier method and factors predictive of outcome were identified. RESULTS Five-year OS, DSS, and RFS for surgical patients were, respectively, 52%, 71%, and 56%. DSS for cT1T2N0 and cT1T2N+ were 79% and 56%, respectively. For OS and DSS, multivariate analysis showed cN classification was predictive of outcome. For RFS and distant RFS, margin status was a significant predictor, whereas the cT classification was a significant predictor for local RFS. CONCLUSIONS Outcomes of patients with early-stage SCCSP managed by surgery were excellent. These patients may be suitable for transoral robotic or endoscopic surgical procedures.
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Affiliation(s)
- N Gopalakrishna Iyer
- Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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Expression of Y-box-binding protein YB-1 allows stratification into long- and short-term survivors of head and neck cancer patients. Br J Cancer 2011; 105:1864-73. [PMID: 22095225 PMCID: PMC3251888 DOI: 10.1038/bjc.2011.491] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background: Histology-based classifications and clinical parameters of head and neck squamous cell carcinoma (HNSCC) are limited in their clinical capacity to provide information on prognosis and treatment choice of HNSCC. The primary aim of this study was to analyse Y-box-binding protein-1 (YB-1) protein expression in different grading groups of HNSCC patients, and to correlate these findings with the disease-specific survival (DSS). Methods: We investigated the expression and cellular localisation of the oncogenic transcription/translation factor YB-1 by immunohistochemistry on tissue micro arrays in a total of 365 HNSCC specimens and correlated expression data with clinico-pathological parameters including DSS. Results: Compared with control tissue from healthy individuals, a significantly (P<0.01) increased YB-1 protein expression was observed in high-grade HNSCC patients. By univariate survival data analysis, HNSCC patients with elevated YB-1 protein expression had a significantly (P<0.01) decreased DSS. By multivariate Cox regression analysis, high YB-1 expression and nuclear localisation retained its significance as a statistically independent (P<0.002) prognostic marker for DSS. Within grade 2 group of HNSCC patients, a subgroup defined by high nuclear and cytoplasmic YB-1 levels (co-expression pattern) in the cells of the tumour invasion front had a significantly poorer 5-year DSS rate of only 38% compared with overall 55% for grade 2 patients. Vice versa, the DSS rate was markedly increased to 74% for grade 2 cancer patients with low YB-1 protein expression at the same localisation. Conclusion: Our findings point to the fact that YB-1 expression in combination with histological classification in a double stratification strategy is superior to classical grading in the prediction of tumour progression in HNSCC.
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Coló AEL, Simoes ACQ, Carvalho AL, Melo CM, Fahham L, Kowalski LP, Soares FA, Neves EJ, Reis LFL, Carvalho AF. Functional microarray analysis suggests repressed cell-cell signaling and cell survival-related modules inhibit progression of head and neck squamous cell carcinoma. BMC Med Genomics 2011; 4:33. [PMID: 21489260 PMCID: PMC3095999 DOI: 10.1186/1755-8794-4-33] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2010] [Accepted: 04/13/2011] [Indexed: 01/22/2023] Open
Abstract
Background Cancer shows a great diversity in its clinical behavior which cannot be easily predicted using the currently available clinical or pathological markers. The identification of pathways associated with lymph node metastasis (N+) and recurrent head and neck squamous cell carcinoma (HNSCC) may increase our understanding of the complex biology of this disease. Methods Tumor samples were obtained from untreated HNSCC patients undergoing surgery. Patients were classified according to pathologic lymph node status (positive or negative) or tumor recurrence (recurrent or non-recurrent tumor) after treatment (surgery with neck dissection followed by radiotherapy). Using microarray gene expression, we screened tumor samples according to modules comprised by genes in the same pathway or functional category. Results The most frequent alterations were the repression of modules in negative lymph node (N0) and in non-recurrent tumors rather than induction of modules in N+ or in recurrent tumors. N0 tumors showed repression of modules that contain cell survival genes and in non-recurrent tumors cell-cell signaling and extracellular region modules were repressed. Conclusions The repression of modules that contain cell survival genes in N0 tumors reinforces the important role that apoptosis plays in the regulation of metastasis. In addition, because tumor samples used here were not microdissected, tumor gene expression data are represented together with the stroma, which may reveal signaling between the microenvironment and tumor cells. For instance, in non-recurrent tumors, extracellular region module was repressed, indicating that the stroma and tumor cells may have fewer interactions, which disable metastasis development. Finally, the genes highlighted in our analysis can be implicated in more than one pathway or characteristic, suggesting that therapeutic approaches to prevent tumor progression should target more than one gene or pathway, specially apoptosis and interactions between tumor cells and the stroma.
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Affiliation(s)
- Anna E L Coló
- Hospital AC Camargo, Rua Taguá, 440, São Paulo, SP, 01508-010, Brazil.
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Lallemant B, Evrard A, Chambon G, Sabra O, Kacha S, Lallemant JG, Lumbroso S, Brouillet JP. Gene expression profiling in head and neck squamous cell carcinoma: Clinical perspectives. Head Neck 2011; 32:1712-9. [PMID: 20949446 DOI: 10.1002/hed.21491] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND To date, more than 60 gene expression profiling (GEP) studies have been published in the field of head and neck squamous cell carcinoma (HNSCC) with variable objectives, methods, and results. METHODS The purpose of this study was to present a state-of-the-art review of GEP in HNSCC focusing on the current advances and perspectives for clinical applications. RESULTS Gene expression signatures have been developed to identify screening and diagnostic molecular markers, to improve tumor staging (cervical lymph node and distant metastasis prediction), to differentiate lung metastasis of HNSCC from primary lung squamous cell carcinoma, to predict tumor response to chemoradiotherapy, and to provide outcome predictors. CONCLUSION Some transcriptional signatures that could improve HNSCC management have been identified, but further analyses are required to properly validate and to precisely evaluate their clinical relevance. After an exploratory phase, the completion of large scale projects with stringent methodology is now necessary to transfer GEP from bench to bedside.
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Affiliation(s)
- Benjamin Lallemant
- Service d'ORL et Chirurgie maxillo-faciale, Centre Hospitalier Universitaire de Nîmes, Place du Pr. Robert Debre, 30029 Nîmes Cedex 9, France.
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32
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Krasinskas AM. EGFR Signaling in Colorectal Carcinoma. PATHOLOGY RESEARCH INTERNATIONAL 2011; 2011:932932. [PMID: 21403829 PMCID: PMC3042643 DOI: 10.4061/2011/932932] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2010] [Accepted: 01/05/2011] [Indexed: 11/23/2022]
Abstract
The epidermal growth factor receptor (EGFR) and its downstream signaling pathways are involved in the development and progression of several human tumors, including colorectal cancer. Much attention has been given to the EGFR pathway as of lately because both EGFR and some downstream components serve as targets for anticancer therapy. In addition to playing a critical role in targeted therapy, alterations in this pathway can have prognostic implications. The EGFR pathway and its impact on colorectal carcinogenesis and prognosis are the emphasis of this paper. Since prognosis is tightly related to response to various therapies, the predictive value of the components of this pathway will be briefly discussed, but this is not the focus of this paper.
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Affiliation(s)
- Alyssa M Krasinskas
- Department of Pathology, University of Pittsburgh Medical Center, Presbyterian Hospital, A610, 200 Lothrop Street, Pittsburgh, PA 15213-2546, USA
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Establishment and Molecular Cytogenetic Characterization of a Cell Culture Model of Head and Neck Squamous Cell Carcinoma (HNSCC). Genes (Basel) 2010; 1:388-412. [PMID: 24710094 PMCID: PMC3966227 DOI: 10.3390/genes1030388] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Revised: 09/30/2010] [Accepted: 10/28/2010] [Indexed: 02/06/2023] Open
Abstract
Cytogenetic analysis of head and neck squamous cell carcinoma (HNSCC) established several biomarkers that have been correlated to clinical parameters during the past years. Adequate cell culture model systems are required for functional studies investigating those potential prognostic markers in HNSCC. We have used a cell line, CAL 33, for the establishment of a cell culture model in order to perform functional analyses of interesting candidate genes and proteins. The cell line was cytogenetically characterized using array CGH, spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH). As a starting point for the investigation of genetic markers predicting radiosensitivity in tumor cells, irradiation experiments were carried out and radiation responses of CAL 33 have been determined. Radiosensitivity of CAL 33 cells was intermediate when compared to published data on tumor cell lines.
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Paleri V, Wight RG, Silver CE, Haigentz M, Takes RP, Bradley PJ, Rinaldo A, Sanabria A, Bień S, Ferlito A. Comorbidity in head and neck cancer: A critical appraisal and recommendations for practice. Oral Oncol 2010; 46:712-9. [DOI: 10.1016/j.oraloncology.2010.07.008] [Citation(s) in RCA: 165] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Revised: 07/19/2010] [Accepted: 07/19/2010] [Indexed: 11/26/2022]
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Abstract
A common belief is that the earlier that cancer is detected, the better the chance exists for reduced mortality and morbidity. The advent of new and emerging molecular, genetic, and imaging technologies has broadened the possible strategies for early detection and prevention, but a beneficial impact on mortality needs to be supported by clinical evidence. Molecular markers are being identified that are enhancing our ability to predict and detect cancer before it develops and at the earliest signs of impending carcinogenic transformation. Of the innumerable molecular markers in development, a standalone early detection marker with acceptable sensitivity and specificity is available for bladder cancer, although for most cancer sites there are promising avenues of research that will likely produce results in the next decade. The perfect molecular marker would be one that is inherently related to the disease, specifically to the processes of malignant tumorigenesis or to the defense mechanisms of the individual. For example, mutations associated with increased cancer risk often produce gene products that interfere with tumor-suppressor pathways (eg, DNA repair or cell-cycle control) or support oncogenic pathways (eg, through genetic instability or silencing the apoptotic pathway). Finding molecular markers associated with these processes, and where in the process they produce their actions, can lead to interventions based on maintaining support for the normal process and interrupting the action of the products of the mutation. The search for molecular markers for cancer prevention and early detection presents a formidable challenge that requires a systematic and scientifically sound validation process. The search encompasses a broad range of scientific disciplines, including biochemistry, genetics, histology, immunology, informatic technologies, and epidemiology; strategies to identify and understand molecular markers are approached with multidisciplinary teams focused on understanding the mechanistic basis of cancer and the processes and pathways that underlie carcinogenesis.
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Affiliation(s)
- Barbara K Dunn
- National Cancer Institute, Division of Cancer Prevention, Bethesda, MD 20892-7340, USA.
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36
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Dasgupta S, Koch R, Westra WH, Califano JA, Ha PK, Sidransky D, Koch WM. Mitochondrial DNA mutation in normal margins and tumors of recurrent head and neck squamous cell carcinoma patients. Cancer Prev Res (Phila) 2010; 3:1205-11. [PMID: 20660573 PMCID: PMC3040952 DOI: 10.1158/1940-6207.capr-10-0018] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mitochondrial DNA (mtDNA) mutations were reported in primary head and neck squamous cell carcinoma (HNSCC) patients. However, very little information is available on the mtDNA mutation pattern in the histologically negative surgical margins and tumors of HNSCC patients who experienced tumor recurrence. The present study aimed at understanding the nature and timing of mtDNA mutation in histologically negative margins, and tumors in HNSCC patients who developed local recurrence during the follow-ups. The entire 16.5-kb mitochondrial genome was sequenced in matched normal lymphocytes, histologically normal margins, and tumors of 50 recurrent HNSCC patients. The mtDNA mutations were then compared with clinical parameters. Forty-eight percent (24 of 50) of patients harbored at least one somatic mtDNA mutation in the tumor, and a total of 37 somatic mtDNA mutations were detected. The mtDNA mutations were mostly heteroplasmic in nature and nucleotide transitions (A<-->G; T<-->C). Forty-six percent of the mutations (17 of 37) were detected in the tumors and were also detectable in the corresponding histologically normal margin of the patients. The mtDNA mutations involved both coding and noncoding regions of the mtDNA. The majority (9 of 17, 53%) of the noncoding mutations involved tRNAs. Seventy-five percent (15 of 20) of the coding mtDNA mutations were nonsynonymous in nature and mainly affected cytochrome c oxidase (Complex IV), frequently altered in different human mitochondrial diseases including cancer. Analysis of mtDNA mutation could be an invaluable tool for molecular assessment of histologically negative margins and as well for monitoring HNSCC patients with locoregional recurrences.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/pathology
- Case-Control Studies
- DNA Mutational Analysis
- DNA, Mitochondrial/analysis
- DNA, Mitochondrial/genetics
- Genome, Mitochondrial
- Head and Neck Neoplasms/genetics
- Head and Neck Neoplasms/metabolism
- Head and Neck Neoplasms/mortality
- Head and Neck Neoplasms/pathology
- Health
- Humans
- Middle Aged
- Mutation/physiology
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/metabolism
- Neoplasm Recurrence, Local/mortality
- Neoplasm Recurrence, Local/pathology
- Survival Analysis
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Affiliation(s)
- Santanu Dasgupta
- Department of Otolaryngology, Johns Hopkins University School of Medicine, 601 North Caroline Street, JHOC 6221, Baltimore, MD 21287, USA
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Shaw R, Robinson M. The increasing clinical relevance of human papillomavirus type 16 (HPV-16) infection in oropharyngeal cancer. Br J Oral Maxillofac Surg 2010; 49:423-9. [PMID: 20727631 DOI: 10.1016/j.bjoms.2010.06.023] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2010] [Accepted: 06/24/2010] [Indexed: 12/21/2022]
Abstract
Human papillomavirus type 16 (HPV-16) has been established beyond doubt as a causative agent in oropharyngeal squamous cell carcinoma (SCC). The incidence of oropharyngeal cancer has risen in recent decades, as has the proportion of patients who have a biologically relevant HPV-16 infection. Combined data from 14 recently published studies (2006-2010) show that 57% of 1316 reported cases of oropharyngeal SCC were HPV-16 positive. They had significantly better prognosis (hazard ratio (HR) for 5-year overall survival range 0.05-0.64), although smoking and higher T stage often appear as confounding factors to this favourable prognostic benefit. HPV-16 therefore has increasing importance as a clinically useful prognostic biomarker, but a benefit in survival has been seen in the use of surgery, radiotherapy, and chemotherapy, so specific changes in the preferred methods of treatment are hard to justify. Future trials that include oropharyngeal SCC will consider HPV-16 routinely as a stratification factor, and its use as a predictive biomarker awaits the development of effective targeted treatments. The undeniable and impressive prognostic significance of HPV-16 should hasten its addition to standard pathological reporting of oropharyngeal SCC, and ultimately to its inclusion in TNM staging systems of the American Joint Committee on Cancer (AJCC) and the International Union against Cancer (UICC).
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Affiliation(s)
- Richard Shaw
- School of Cancer Studies, University of Liverpool, Liverpool, UK.
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Vergez S, Delord JP, Thomas F, Rochaix P, Caselles O, Filleron T, Brillouet S, Canal P, Courbon F, Allal BC. Preclinical and clinical evidence that Deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography is a reliable tool for the detection of early molecular responses to erlotinib in head and neck cancer. Clin Cancer Res 2010; 16:4434-45. [PMID: 20660574 DOI: 10.1158/1078-0432.ccr-09-2795] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE There is a clinical need to identify predictive markers of the responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography with computed tomography ((18)FDG-PET/CT) could be a tool of choice for monitoring the early effects of this class of agent on tumor activity. EXPERIMENTAL DESIGN Using models of human head and neck carcinoma (CAL33 and CAL166 cell lines), we first tested in vitro and in vivo whether the in vivo changes in (18)FDG-PET/CT uptake were associated with the molecular and cellular effects of the EGFR-TKI erlotinib. Then, the pathologic and morphologic changes and the (18)FDG-PET/CT uptake before and after erlotinib exposure in patients were analyzed. RESULTS Erlotinib strongly inhibited extracellular signal-regulated kinase-1/2 (ERK-1/2) phosphorylation both in the preclinical models and in patients. Western blotting, immunofluorescence, and immunohistochemistry showed that erlotinib did not modify Glut-1 expression at the protein level either in cell line models or in tumor tissue from mouse xenografts or in patients. Phospho-ERK-1/2 inhibition was associated with a reduction in (18)FDG uptake in animal and human tumors. The biological volume was more accurate than the standardized uptake value for the evaluation of the molecular responses. CONCLUSION These results show that the (18)FDG-PET/CT response is a reliable surrogate marker of the effects of erlotinib in head and neck carcinoma.
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Affiliation(s)
- Sébastien Vergez
- Université Paul Sabatier and Institut Claudius Regaud, Toulouse Cedex, France
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Tumormarker und Prognosefaktoren bei Plattenepithelkarzinomen der Kopf-Hals-Region. HNO 2010; 58:713-23; quiz 724-5. [DOI: 10.1007/s00106-010-2108-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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40
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Clark C, Shah S, Herman-Ferdinandez L, Ekshyyan O, Abreo F, Rong X, McLarty J, Lourie A, Milligan EJ, Nathan CAO. Teasing out the best molecular marker in the AKT/mTOR pathway in head and neck squamous cell cancer patients. Laryngoscope 2010; 120:1159-65. [PMID: 20513033 PMCID: PMC2997737 DOI: 10.1002/lary.20917] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVES/HYPOTHESIS No reliable molecular biomarker is currently available for clinical application in the management of head and neck cancer patients. The AKT/mTOR pathway is activated in 90% to 100% of head and neck squamous cell cancer (HNSCC) and could be promising biomarkers closely linked to cancer incidence. STUDY DESIGN Retrospective study of HNSCC and non-cancer patients. METHODS Oral mucosa from noncancer patients were compared to HNSCC tumors and junctional zone mucosa. The candidate biomarkers mTOR, AKT, 4EBP1, and S6 kinase, signaling components upstream and downstream of mTOR that appear dysregulated in HNSCC, were evaluated using immunohistochemistry (IHC) and Western blot analysis. RESULTS Expression of phosphorylated AKT and phosphorylated mTOR were significantly higher in cancer patient tumors compared to noncancer oral mucosa samples (P = .004 and P = .026, respectively) by Western blot analysis. Expression of p-mTOR and p-4EBP1 were higher in patient junctional zones compared to tumors (p = 0.017 and p = 0.022, respectively) and no difference in p-AKT or p-S6 expression in HNSCC patients' junctional zone compared to tumors. IHC-demonstrated p-mTOR expression was 81.9% sensitive and 100% specific in differentiating cancer from noncancer mucosa, whereas p-4EBP1 expression by IHC was only 50.0% sensitive and 95.5% specific in differentiating normal mucosa from HNSCC (P < .01). CONCLUSIONS Phosphorylated mTOR appears to be a reliable biomarker by both Western blot analysis (P = .026) and IHC in human head and neck cancer (P < .001). Moreover, phosphorylated AKT, which is immediately upstream of mTOR, is a potential biomarker that should be further studied. Clinical trials with mTOR inhibitors are being evaluated for HNSCC, and selecting patients that are likely to respond to these inhibitors requires identifying and validating predictive biomarkers of response.
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Affiliation(s)
- Cheryl Clark
- Department of Otolaryngology-Head and Neck Surgery, LSUHSC, Shreveport, LA
- Feist-Weiller Cancer Center, LSUHSC, Shreveport, LA
| | - Shivang Shah
- Department of Otolaryngology-Head and Neck Surgery, LSUHSC, Shreveport, LA
| | | | - Oleksandr Ekshyyan
- Department of Otolaryngology-Head and Neck Surgery, LSUHSC, Shreveport, LA
- Feist-Weiller Cancer Center, LSUHSC, Shreveport, LA
| | - Fleurette Abreo
- Department of Otolaryngology-Head and Neck Surgery, LSUHSC, Shreveport, LA
- Department of Pathology, LSUHSC, Shreveport, LA
| | - Xiaohua Rong
- Department of Otolaryngology-Head and Neck Surgery, LSUHSC, Shreveport, LA
- Feist-Weiller Cancer Center, LSUHSC, Shreveport, LA
| | | | | | - Edward J. Milligan
- Department of Otolaryngology-Head and Neck Surgery, LSUHSC, Shreveport, LA
- Overton Brooks VA Medical Center, Shreveport, LA
| | - Cherie-Ann O. Nathan
- Department of Otolaryngology-Head and Neck Surgery, LSUHSC, Shreveport, LA
- Feist-Weiller Cancer Center, LSUHSC, Shreveport, LA
- Overton Brooks VA Medical Center, Shreveport, LA
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Pannone G, Sanguedolce F, Santoro A, Fierro P, Panetti M, Fierro D, Maiello F, De Maria S, Giannattasio A, Serpico R, Lo Muzio L, Metafora S, Bufo P. Detection of novel Human papilloma virus type 82 in laryngeal cancer: case report. Auris Nasus Larynx 2010; 37:648-50. [PMID: 20417042 DOI: 10.1016/j.anl.2010.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2009] [Revised: 02/10/2010] [Accepted: 03/04/2010] [Indexed: 10/19/2022]
Abstract
Human papilloma virus infection is thought to play a role in laryngeal carcinogenesis; the variable association reported in literature may be due to wide range of HPV genotypes. We report the case of a 51-year-old man affected by laryngeal squamous cell carcinoma; analysis of DNA extracted by cancer cells by an innovative molecular virology assay (INNO-LiPA HPV Genotyping Extra) showed the presence of two high-risk HPV genotypes, HPV-73 and -82. Immunohistochemical examination confirmed positivity for both capsid protein and viral oncogenic protein E7. Such association has never been reported in literature so far, and a brief discussion on the importance of assessing HPV status in laryngeal cancer is provided.
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Affiliation(s)
- G Pannone
- Department of Surgical Sciences, Institute of Pathology and Cytopathology, University of Foggia, Viale Pinto, Foggia, Italy
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Perez CA, Donald CE, Raez LE, Santos ES. Epidermal growth factor receptor pathway as therapeutic development in head and neck cancers: present and future. Oncol Rev 2009. [DOI: 10.1007/s12156-009-0022-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Ganguli-Indra G, Wasylyk C, Liang X, Millon R, Leid M, Wasylyk B, Abecassis J, Indra A. CTIP2 expression in human head and neck squamous cell carcinoma is linked to poorly differentiated tumor status. PLoS One 2009; 4:e5367. [PMID: 19399189 PMCID: PMC2671404 DOI: 10.1371/journal.pone.0005367] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2008] [Accepted: 03/31/2009] [Indexed: 02/07/2023] Open
Abstract
Background We have demonstrated earlier that CTIP2 is highly expressed in mouse skin during embryogenesis and in adulthood. CTIP2 mutant mice die at birth with epidermal differentiation defects and a compromised epidermal permeability barrier suggesting its role in skin development and/or homeostasis. CTIP2 has also been suggested to function as tumor suppressor in cells, and several reports have described a link between chromosomal rearrangements of CTIP2 and human T cell acute lymphoblast leukemia (T-ALL). The aim of the present study was to look into the pattern of CTIP2 expression in Head and Neck Squamous Cell Carcinoma (HNSCC). Methodology/Principal Findings In the present study, we analyzed CTIP2 expression in human HNSCC cell lines by western blotting, in paraffin embedded archival specimens by immunohistochemistry (IHC), and in cDNA samples of human HNSCC by qRT-PCR. Elevated levels of CTIP2 protein was detected in several HNSCC cell lines. CTIP2 staining was mainly detected in the basal layer of the head and neck normal epithelium. CTIP2 expression was found to be significantly elevated in HNSCC (p<0.01), and increase in CTIP2 expression was associated with poorly differentiated tumor status. Nuclear co-localization of CTIP2 protein and cancer stem cell (CSC) marker BMI1 was observed in most, if not all of the cells expressing BMI1 in moderately and poorly differentiated tumors. Conclusions/Significance We report for the first time expression of transcriptional regulator CTIP2 in normal human head and neck epithelia. A statistically significant increase in the expression of CTIP2 was detected in the poorly differentiated samples of the human head and neck tumors. Actual CTIP2, rather than the long form of CTIP2 (CTIP2L) was found to be more relevant to the differentiation state of the tumors. Results demonstrated existence of distinct subsets of cancer cells, which express CTIP2 and underscores the use of CTIP2 and BMI1 co-labeling to distinguish tumor initiating cells or cancer stem cells (CSCs) from surrounding cancer cells.
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MESH Headings
- Base Sequence
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Cell Differentiation
- Cell Line, Tumor
- DNA Primers/genetics
- DNA, Neoplasm/genetics
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Gene Expression
- Head and Neck Neoplasms/genetics
- Head and Neck Neoplasms/metabolism
- Head and Neck Neoplasms/pathology
- Humans
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Polycomb Repressive Complex 1
- Proto-Oncogene Proteins/genetics
- Proto-Oncogene Proteins/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Repressor Proteins/genetics
- Repressor Proteins/metabolism
- Tumor Suppressor Proteins/genetics
- Tumor Suppressor Proteins/metabolism
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Affiliation(s)
- Gitali Ganguli-Indra
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America
- * E-mail: (GGI); (AI)
| | - Christine Wasylyk
- IGBMC, Inserm U596 and CNRS UMR 7104, Illkirch, France
- Université Louis Pasteur, Strasbourg, France
| | - Xiaobo Liang
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America
| | | | - Mark Leid
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America
- Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon, United States of America
| | - Bohdan Wasylyk
- IGBMC, Inserm U596 and CNRS UMR 7104, Illkirch, France
- Université Louis Pasteur, Strasbourg, France
| | | | - Arup Indra
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon, United States of America
- Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon, United States of America
- * E-mail: (GGI); (AI)
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Kissel HD, Galipeau PC, Li X, Reid BJ. Translation of an STR-based biomarker into a clinically compatible SNP-based platform for loss of heterozygosity. Cancer Biomark 2009; 5:143-58. [PMID: 19407369 PMCID: PMC2861428 DOI: 10.3233/cbm-2009-0618] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Loss of heterozygosity (LOH) has been shown to be a promising biomarker of cancer risk in patients with premalignant conditions. In this study we describe analytical validation in clinical biopsy samples of a SNP-based pyrosequencing panel targeting regions of LOH on chromosomes 17p and 9p including TP53 and CDKN2A tumor suppressor genes. Assays were tested for analytic specificity, sensitivity, efficiency, and reproducibility. Accuracy was evaluated by comparing SNP-based LOH results to those obtained by previously well-studied short tandem repeat polymorphisms (STRs) in DNA derived from different tissue sources including fresh-frozen endoscopic biopsies, samples from surgical resections, and formalin-fixed paraffin-embedded sections. A 17p/9p LOH panel comprised of 43 SNPs was designed to amplify with universal assay conditions in a two-step PCR and sequence-by-synthesis reaction that can be completed in two hours and 10 minutes. The methods presented can be a model for developing a SNP-based LOH approach targeted to any chromosomal region of interest for other premalignant conditions and this panel could be incorporated as part of a biomarker for cancer risk prediction, early detection, or as entry criteria for randomized trials.
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Affiliation(s)
- Heather D Kissel
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Abstract
The outcome for patients with head and neck squamous cell carcinoma remains poor, despite improvements in diagnosis and treatment over the past three decades. This has triggered great interest in the genetic events that underpin the aetiology and clinical behaviour of this group of cancers. As a result, the genetic profile for head and neck squamous cell carcinomas at different sub-sites has been relatively well characterised at the chromosomal level. Various studies have shown links between specific aberrations in head and neck squamous cell carcinoma and clinical outcome, e.g. loss of heterozygosity at 2q and 18q is commonly associated with poor prognosis, and loss of heterozygosity at 9p21 is associated with recurrence. However, there is as yet no significant clinical application of this genetic knowledge as regards the screening, diagnosis or treatment of head and neck squamous cell carcinoma. Here, we summarise the current state of knowledge, and highlight the most promising areas of research that may facilitate the translation of genetic data into clinical benefit.
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