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WILCZAK MAGDALENA, SURMAN MAGDALENA, PRZYBYłO MA. Melanoma-derived extracellular vesicles transfer proangiogenic factors. Oncol Res 2025; 33:245-262. [PMID: 39866233 PMCID: PMC11753996 DOI: 10.32604/or.2024.055449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 09/27/2024] [Indexed: 01/28/2025] Open
Abstract
Angiogenesis, the expansion of pre-existing vascular networks, is crucial for normal organ growth and tissue repair, but is also involved in various pathologies, including inflammation, ischemia, diabetes, and cancer. In solid tumors, angiogenesis supports growth, nutrient delivery, waste removal, and metastasis. Tumors can induce angiogenesis through proangiogenic factors including VEGF, FGF-2, PDGF, angiopoietins, HGF, TNF, IL-6, SCF, tryptase, and chymase. This balance is disrupted in tumors, and extracellular vesicles (EVs) contribute to this by transferring proangiogenic factors and increasing their expression in endothelial cells (ECs). Malignant melanoma, a particular type of skin cancer, accounts for only 1% of skin cancer cases but more than 75% of deaths. Its incidence has risen significantly, with a 40% increase between 2012 and 2022, especially in fair-skinned populations. Advanced metastatic stages have a high mortality due to delayed diagnosis. This review examines the molecular basis of angiogenesis in melanoma, focusing on melanoma-derived EVs and their possible use in new antiangiogenic therapies.
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Affiliation(s)
- MAGDALENA WILCZAK
- Department of Glycoconjugate Biochemistry, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, 30-387, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, 30-348, Poland
| | - MAGDALENA SURMAN
- Department of Glycoconjugate Biochemistry, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, 30-387, Poland
| | - MAłGORZATA PRZYBYłO
- Department of Glycoconjugate Biochemistry, Faculty of Biology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, 30-387, Poland
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Cazzato G, Ingravallo G, Ribatti D. Angiogenesis Still Plays a Crucial Role in Human Melanoma Progression. Cancers (Basel) 2024; 16:1794. [PMID: 38791873 PMCID: PMC11120419 DOI: 10.3390/cancers16101794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/03/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
Angiogenesis plays a pivotal role in tumor progression, particularly in melanoma, the deadliest form of skin cancer. This review synthesizes current knowledge on the intricate interplay between angiogenesis and tumor microenvironment (TME) in melanoma progression. Pro-angiogenic factors, including VEGF, PlGF, FGF-2, IL-8, Ang, TGF-β, PDGF, integrins, MMPs, and PAF, modulate angiogenesis and contribute to melanoma metastasis. Additionally, cells within the TME, such as cancer-associated fibroblasts, mast cells, and melanoma-associated macrophages, influence tumor angiogenesis and progression. Anti-angiogenic therapies, while showing promise, face challenges such as drug resistance and tumor-induced activation of alternative angiogenic pathways. Rational combinations of anti-angiogenic agents and immunotherapies are being explored to overcome resistance. Biomarker identification for treatment response remains crucial for personalized therapies. This review highlights the complexity of angiogenesis in melanoma and underscores the need for innovative therapeutic approaches tailored to the dynamic TME.
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Affiliation(s)
- Gerardo Cazzato
- Section of Molecular Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Giuseppe Ingravallo
- Section of Molecular Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Domenico Ribatti
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, 70124 Bari, Italy;
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Vergara IA, Aivazian K, Carlino MS, Guminski AD, Maher NG, Shannon KF, Ch'ng S, Saw RPM, Long GV, Wilmott JS, Scolyer RA. Genomic Profiling of Metastatic Basal cell Carcinoma Reveals Candidate Drivers of Disease and Therapeutic Targets. Mod Pathol 2023; 36:100099. [PMID: 36788083 DOI: 10.1016/j.modpat.2023.100099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/30/2022] [Accepted: 12/26/2022] [Indexed: 01/11/2023]
Abstract
Basal cell carcinomas (BCCs) are human beings' most common malignant tumors. Most are easily managed by surgery or topical therapies, and metastasis is rare. Although BCCs can become locally advanced, metastatic BCCs are very uncommon and may be biologically distinct. We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant activation of Hedgehog signaling and alterations in GLI transcriptional regulators and Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from 3 patients provided evidence of a clonal origin in all cases. Mutations associated with YAP inhibition were found exclusively in 2 hematogenously-spread lung metastases, and metastatic BCCs were enriched for mutations in the YAP/TAZ-binding domain of TEAD genes. Accordingly, YAP/TAZ nuclear localization was associated with metastatic types and Hippo mutations, suggesting an enhanced oncogenic role in hematogenously-spread metastases. Mutations in RET, HGF, and phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling were enriched compared with a cohort of low clinical-risk BCCs. Our results implicate Hippo and PI3K/AKT dysregulation in metastatic progression of BCCs, making these potential therapeutic targets in metastatic disease. The common clonal origin of matched recurrent and metastatic BCCs suggests that molecular profiling can assist in determining the nature/origin of poorly differentiated metastatic tumors of uncertain type. Genes and pathways enriched for mutations in this cohort are candidate drivers of metastasis and can be used to identify patients at high risk of metastasis who may benefit from aggressive local treatment and careful clinical follow-up.
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Affiliation(s)
- Ismael A Vergara
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia
| | - Karina Aivazian
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia
| | - Matteo S Carlino
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Department of Medicine, Blacktown Hospital, Blacktown, New South Wales, Australia; Department of Medicine, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia
| | - Alexander D Guminski
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia
| | - Nigel G Maher
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia
| | - Kerwin F Shannon
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
| | - Sydney Ch'ng
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
| | - Robyn P M Saw
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
| | - Georgina V Long
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia
| | - James S Wilmott
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia
| | - Richard A Scolyer
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia.
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Kim JH, Jeong SY, Jang HJ, Park ST, Kim HS. FGFR4 Gly388Arg Polymorphism Reveals a Poor Prognosis, Especially in Asian Cancer Patients: A Meta-Analysis. Front Oncol 2021; 11:762528. [PMID: 34737965 PMCID: PMC8560792 DOI: 10.3389/fonc.2021.762528] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 10/04/2021] [Indexed: 12/11/2022] Open
Abstract
The fibroblast growth factor-4 receptor (FGFR4) is a member of receptor tyrosine kinase. The FGFR4 Gly388Arg polymorphism in the transmembrane domain of the receptor has been shown to increase genetic susceptibility to cancers. However, its prognostic impact in cancer patients still remains controversial. Herein, we performed this meta-analysis to evaluate the clinicopathological and prognostic impacts of the FGFR4 Gly388Arg polymorphism in patients with cancer. We carried out a computerized extensive search using PubMed, Medline, and Ovid Medline databases up to July 2021. From 44 studies, 11,574 patients were included in the current meta-analysis. Regardless of the genetic models, there was no significant correlation of the FGFR4 Gly388Arg polymorphism with disease stage 3/4. In the homozygous model (Arg/Arg vs. Gly/Gly), the Arg/Arg genotype tended to show higher rate of lymph node metastasis compared with the Gly/Gly genotype (odds ratio = 1.21, 95% confidence interval (CI): 0.99-1.49, p = 0.06). Compared to patients with the Arg/Gly or Arg/Arg genotype, those with the Gly/Gly genotype had significantly better overall survival (hazard ratios (HR) = 1.19, 95% CI: 1.05-1.35, p = 0.006) and disease-free survival (HR = 1.25, 95% CI: 1.03-1.53, p = 0.02). In conclusion, this meta-analysis showed that the FGFR4 Gly388Arg polymorphism was significantly associated with worse prognosis in cancer patients. Our results suggest that this polymorphism may be a valuable genetic marker to identify patients at higher risk of recurrence or mortality.
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Affiliation(s)
- Jung Han Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, College of Medicine, Hallym University, Seoul, South Korea
| | - Soo Young Jeong
- Department of Obstetrics and Gynecology, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, College of Medicine, Hallym University, Seoul, South Korea
| | - Hyun Joo Jang
- Division of Gastroenterology, Department of Internal Medicine, Dongtan Sacred-Heart Hospital, Hallym University Medical Center, College of Medicine, Hallym University, Hwasung, South Korea
| | - Sung Taek Park
- Department of Obstetrics and Gynecology, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, College of Medicine, Hallym University, Seoul, South Korea
| | - Hyeong Su Kim
- Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, College of Medicine, Hallym University, Seoul, South Korea
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Yeo MK, Bae GE. Comparison of Benign and Malignant Pilomatricomas Using Whole-exome Sequencing. Cancer Genomics Proteomics 2021; 17:795-802. [PMID: 33099480 DOI: 10.21873/cgp.20233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/02/2020] [Accepted: 09/07/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Malignant pilomatricoma (MP) is a rare cancer of the hair matrix with only a few cases reported in literature. Given the rarity of this cancer and the lack of relevant genetic data, very little is known about the nature of the molecular pathophysiology except the involvement of the Catenin Beta 1 (CTNNB1)/Wnt/β-catenin signaling pathway in some cases. MATERIALS AND METHODS We describe the whole-exome genomic profiling of four samples from two patients: 1) an MP from patient I, 2) a coexisting benign pilomatricoma (BP) from patient I, 3) a BP from an age and location-matched control patient II, and 4) normal skin tissue from patient II. RESULTS We detected a pathogenic somatic missense mutation in fibroblast growth factor receptor 4 (FGFR4) (c.1162G>A, p. Gly388Arg) in MP and coexisting BP in patient I, whereas the control BP harbored the classical CTNNB1 mutant. CONCLUSION This study, the first comparative analysis of benign and MP through whole-exome analysis, identified a novel oncogenic mutation in FGFR4.
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Affiliation(s)
- Min-Kyung Yeo
- Department of Pathology, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Go Eun Bae
- Department of Pathology, Chungnam National University School of Medicine, Daejeon, Republic of Korea
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Mangantig E, MacGregor S, Iles MM, Scolyer RA, Cust AE, Hayward NK, Montgomery GW, Duffy DL, Thompson JF, Henders A, Bowdler L, Rowe C, Cadby G, Mann GJ, Whiteman DC, Long GV, Ward SV, Khosrotehrani K, Barrett JH, Law MH. Germline variants are associated with increased primary melanoma tumor thickness at diagnosis. Hum Mol Genet 2020; 29:3578-3587. [PMID: 33410475 PMCID: PMC7788289 DOI: 10.1093/hmg/ddaa222] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 07/29/2020] [Accepted: 10/08/2020] [Indexed: 11/13/2022] Open
Abstract
Germline genetic variants have been identified, which predispose individuals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness. To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness. The analyses utilized 10 604 individuals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated individuals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 individuals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry. We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P < 5 × 10−8) with tumor thickness. Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.
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Affiliation(s)
- Ernest Mangantig
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Pulau Pinang, Malaysia
| | - Stuart MacGregor
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Mark M Iles
- Leeds Institute for Data Analytics, University of Leeds, Leeds LS2 9JT, UK
| | - Richard A Scolyer
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, 2065, Australia.,Department of Tissue Oncology and Diagnostic Pathology, Royal Prince Alfred Hospital, Sydney, New South Wales, 2050, Australia.,Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, 2050, Australia.,Department of Tissue Oncology and Diagnostic Pathology, New South Wales Health Pathology, Sydney, New South Wales, 2000, Australia
| | - Anne E Cust
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, 2065, Australia.,Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, 2050, Australia.,School of Public Health, The University of Sydney, Sydney, New South Wales, 2006, Australia
| | - Nicholas K Hayward
- Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Grant W Montgomery
- Molecular Biology, The University of Queensland, Brisbane, Queensland, 4102, Australia
| | - David L Duffy
- Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - John F Thompson
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, 2065, Australia.,Department of Tissue Oncology and Diagnostic Pathology, Royal Prince Alfred Hospital, Sydney, New South Wales, 2050, Australia.,Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, 2050, Australia
| | - Anjali Henders
- Molecular Biology, The University of Queensland, Brisbane, Queensland, 4102, Australia.,Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Lisa Bowdler
- Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Casey Rowe
- Experimental Dermatology Group, Diamantina Institute, The University of Queensland, Brisbane, Queensland, 4102, Australia.,Department of Dermatology, Princess Alexandra Hospital, Brisbane, Queensland, 4102, Australia
| | - Gemma Cadby
- School of Population and Global Health, The University of Western Australia, Perth, Western Australia, 6009, Australia
| | - Graham J Mann
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, 2065, Australia.,Centre for Cancer Research, Westmead Institute for Medical Research, University of Sydney, New South Wales, 2145, Australia.,John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, 2601, Australia
| | - David C Whiteman
- Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
| | - Georgina V Long
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, 2065, Australia.,Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, 2050, Australia.,Department of Medical Oncology, Mater Hospital, North Sydney, NSW, 2060, Australia.,Department of Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia
| | - Sarah V Ward
- School of Population and Global Health, The University of Western Australia, Perth, Western Australia, 6009, Australia
| | - Kiarash Khosrotehrani
- Experimental Dermatology Group, Diamantina Institute, The University of Queensland, Brisbane, Queensland, 4102, Australia.,Department of Dermatology, Princess Alexandra Hospital, Brisbane, Queensland, 4102, Australia
| | - Jennifer H Barrett
- Leeds Institute for Data Analytics, University of Leeds, Leeds LS2 9JT, UK
| | - Matthew H Law
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
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Ye Y, Li J, Jiang D, Li J, Xiao C, Li Y, Han C, Zhao C. FGFR4 Gly388Arg Polymorphism Affects the Progression of Gastric Cancer by Activating STAT3 Pathway to Induce Epithelial to Mesenchymal Transition. Cancer Res Treat 2020; 52:1162-1177. [PMID: 32599983 PMCID: PMC7577822 DOI: 10.4143/crt.2020.138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/24/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose Fibroblast growth factor receptor 4 (FGFR4) plays a critical role in cancer progression involving in tumor proliferation, invasion, and metastasis. This study clarified the role of FGFR4-Arg388 variant in gastric cancer (GC), and more importantly highlighted the possibility of this single nucleotide polymorphism (SNP) as potential therapeutic targets. Materials and Methods FGFR4 polymorphism was characterized in advanced GC patients to perform statistical analysis. FGFR4-dependent signal pathways involving cell proliferation, invasion, migration, and resistance to oxaliplatin (OXA) in accordance with the SNP were also assessed in transfected GC cell lines. Results Among 102 GC patients, the FGFR4-Arg388 patients showed significantly higher tumor stage (p=0.047) and worse overall survival (p=0.033) than the Gly388 patients. Immunohistochemical results showed that FGFR4-Arg388 patients were more likely to have higher vimentin (p=0.025) and p-STAT3 (p=0.009) expression compared with FGFR4-Gly388 patients. In transfected GC cells, the overexpression of FGFR4-Arg388 variant increased proliferation and invasion of GC cells, increasing resistance of GC cells to OXA compared with cells overexpressing the Gly388 allele. Conclusion The exploration mechanism may be through FGFR4-Arg388/STAT3/epithelial to mesenchymal transition axis regulating pivotal oncogenic properties of GC cells. The FGFR4-Arg388 variant may be a biomarker and a candidate target for adjuvant treatment of GC.
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Affiliation(s)
- Yanwei Ye
- Department of Gastrointestinal Surgery and Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jie Li
- Department of General Surgery, Tongchuan People's Hospital, Shanxi, China
| | - Dongbao Jiang
- Department of Thyroid, and Breast Surgery, Xinxiang Central Hospital, Xinxiang, China
| | - Jingjing Li
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chuangfeng Xiao
- Department of Gastrointestinal Surgery and Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yingze Li
- Department of Gastrointestinal Surgery and Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chao Han
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chunlin Zhao
- Department of Gastrointestinal Surgery and Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Chow WA, Yee JK, Tsark W, Wu X, Qin H, Guan M, Ross JS, Ali SM, Millis SZ. Recurrent secondary genomic alterations in desmoplastic small round cell tumors. BMC MEDICAL GENETICS 2020; 21:101. [PMID: 32393201 PMCID: PMC7216377 DOI: 10.1186/s12881-020-01034-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 04/26/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Desmoplastic small round cell tumor (DSRCT) is a rare, highly aggressive, translocation-associated soft-tissue sarcoma that primarily affects children, adolescents, and young adults, with a striking male predominance. It is characterized by t(11;22) generating a novel EWSR1-WT1 fusion gene. Secondary genomic alterations are rarely described. METHODS Tumor tissue from 83 DSRCT patients was assayed by hybrid-capture based comprehensive genomic profiling, FoundationOne® Heme next generation sequencing analysis of 406 genes and RNA sequencing of 265 genes. Tumor mutation burden was calculated from a minimum of 1.4 Mb sequenced DNA. Microsatellite instability status was determined by a novel algorithm analyzing 114 specific loci. RESULTS Comprehensive genomic profiling identified several genomically-defined DSRCT subgroups. Recurrent genomic alterations were most frequently detected in FGFR4, ARID1A, TP53, MSH3, and MLL3 genes. With the exception of FGFR4, where the genomic alterations predicted activation, most of the alterations in the remaining genes predicted gene inactivation. No DSRCT were TMB or MSI high. CONCLUSIONS In summary, recurrent secondary somatic alterations in FGFR4, ARID1A, TP53, MSH3, and MLL3 were detected in 82% of DSRCT, which is significantly greater than previously reported. These alterations may have both prognostic and therapeutic implications.
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Affiliation(s)
- Warren A Chow
- Department of Medical Oncology & Therapeutics Research, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA.
| | - Jiing-Kuan Yee
- Department of Translational Research & Cellular Therapeutics, City of Hope, Duarte, CA, USA
| | - Walter Tsark
- Center for Comparative Medicine, City of Hope, Duarte, CA, USA
| | - Xiwei Wu
- Integrative Genomics Core of Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Hanjun Qin
- Integrative Genomics Core of Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Min Guan
- Department of Medical Oncology & Therapeutics Research, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA
| | - Jeffrey S Ross
- Foundation Medicine, Inc, Cambridge, MA, USA.,Department of Pathology, Upstate Medical University, Syracuse, NY, USA
| | - Siraj M Ali
- Foundation Medicine, Inc, Cambridge, MA, USA
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Ye Y, Jiang D, Li J, Han C, Wang X, Wang F, Li J. Role of fibroblast growth factor 4 in the growth and metastasis of colorectal cancer. Int J Oncol 2020; 56:1565-1573. [PMID: 32236572 DOI: 10.3892/ijo.2020.5029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 02/20/2020] [Indexed: 11/05/2022] Open
Abstract
The role of fibroblast growth factor receptor 4 (FGFR4) in colorectal cancer (CRC) is poorly characterized. Therefore, the objective of the current study was to investigate the expression levels of FGFR4 in colorectal cancer and its prognostic value, and clarify the role of FGFR4 in the proliferation and metastasis of colorectal cancer cells. Immunohistochemistry was used to detect the association between FGFR4 expression and clinicopathological features in colorectal cancer tissues. The effect of FGFR4 silencing on tumor cell proliferation, cell cycle, apoptosis, migration and invasion was evaluated via lentiviral transfection of the colorectal cancer cell line SW620. Western blot analysis was used to detect the changes of epithelial‑mesenchymal transition (EMT) markers, following FGFR4 silencing. FGFR4 is upregulated in CRC tissues compared with normal tissues. Patients with high FGFR4 expression exhibited a lower 5‑year survival rate compared with patients with low FGFR4 expression (64 vs. 74%). FGFR4 silencing reduced proliferation, inhibited cell invasion, arrested cells in S phase and promoted apoptosis in colorectal cancer cells. FGFR4 silencing partially reversed EMT progression and FGFR4 this effect was enhanced in the presence of XAV939 (a β‑catenin inhibitor). The current data suggest that FGFR4 may be associated with prognosis in patients with colorectal cancer. In vitro functional tests revealed that FGFR4 may represent an effective therapeutic target for colorectal cancer. FGFR4 may also regulate EMT via the Wnt/β‑catenin pathway.
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Affiliation(s)
- Yanwei Ye
- Department of Gastrointestinal Surgery and Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Dongbao Jiang
- Department of Gastrointestinal Surgery and Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Jie Li
- Department of Gastrointestinal Surgery and Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Chao Han
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Xinru Wang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Feng Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Jingjing Li
- Department of Gastroenterology, Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
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10
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Li L, Zhang S, Li H, Chou H. FGFR3 promotes the growth and malignancy of melanoma by influencing EMT and the phosphorylation of ERK, AKT, and EGFR. BMC Cancer 2019; 19:963. [PMID: 31619201 PMCID: PMC6796326 DOI: 10.1186/s12885-019-6161-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 09/13/2019] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Overexpression of fibroblast growth factor receptor 3 (FGFR3) has been linked to tumor progression in many types of cancer. The role of FGFR3 in melanoma remains unclear. In this study, we aimed to uncover the role of FGFR3 in the growth and metastasis of melanoma. METHODS FGFR3 knockdown and overexpression strategies were employed to investigate the effects of FGFR3 on colony formation, cell apoptosis, proliferation, migration, and in vitro invasion, along with the growth and metastasis of melanoma in a xenografts mouse model. The protein expression levels of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), epidermal growth factor receptor (EGFR), and epithelial-mesenchymal transition (EMT) markers were determined by Western blot analysis. RESULTS The mRNA expression of FGFR3 was higher in melanoma tissues than normal healthy tissues. FGFR3 expression in cutaneous malignant melanoma (CMM) tissues was positively correlated with the Breslow thickness and lymph node metastasis. In A357 cells, knockdown of the FGFR3 gene decreased the colony formation ability, cell proliferation, invasion, and migration, but increased the caspase 3 activity and the apoptosis rate; overexpression of FGFR3 increased the colony formation ability, cell proliferation, invasion, and migration, but decreased the caspase 3 activity and apoptosis rates. FGFR3 knockdown also upregulated E-cadherin, downregulated N-cadherin and vimentin, and decreased the phosphorylation levels of ERK, AKT, and EGFR. In the MCC xenografts mice, knockdown of FGFR3 decreased tumor growth and metastasis. CONCLUSIONS FGFR3, which is highly expressed in CMM tissues, is correlated with increased Breslow thickness and lymph node metastasis. FGFR3 promotes melanoma growth, metastasis, and EMT behaviors, likely by affecting the phosphorylation levels of ERK, AKT, and EGFR.
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MESH Headings
- Animals
- Antigens, CD/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Cadherins/metabolism
- Cell Line, Tumor
- Cell Movement/genetics
- Cell Proliferation/genetics
- Epithelial-Mesenchymal Transition/genetics
- ErbB Receptors/metabolism
- Heterografts
- Humans
- MAP Kinase Signaling System
- Male
- Melanoma/metabolism
- Melanoma/pathology
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasm Invasiveness/genetics
- Phosphorylation
- Proto-Oncogene Proteins c-akt/metabolism
- Receptor, Fibroblast Growth Factor, Type 3/genetics
- Receptor, Fibroblast Growth Factor, Type 3/metabolism
- Skin Neoplasms/metabolism
- Skin Neoplasms/pathology
- Transfection
- Vimentin/metabolism
- Melanoma, Cutaneous Malignant
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Affiliation(s)
- Lei Li
- Department of Plastic and Cosmetic Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, 450003 Henan China
| | - Shuai Zhang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China
| | - Hao Li
- Department of Plastic and Cosmetic Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, 450003 Henan China
| | - Haiyan Chou
- Department of Plastic and Cosmetic Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, 450003 Henan China
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11
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Vlacic G, Hoda MA, Klikovits T, Sinn K, Gschwandtner E, Mohorcic K, Schelch K, Pirker C, Peter-Vörösmarty B, Brankovic J, Dome B, Laszlo V, Cufer T, Rozman A, Klepetko W, Grasl-Kraupp B, Hegedus B, Berger W, Kern I, Grusch M. Expression of FGFR1-4 in Malignant Pleural Mesothelioma Tissue and Corresponding Cell Lines and its Relationship to Patient Survival and FGFR Inhibitor Sensitivity. Cells 2019; 8:E1091. [PMID: 31527449 PMCID: PMC6769772 DOI: 10.3390/cells8091091] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/05/2019] [Accepted: 09/07/2019] [Indexed: 02/07/2023] Open
Abstract
Malignant pleural mesothelioma (MPM) is a devastating malignancy with limited therapeutic options. Fibroblast growth factor receptors (FGFR) and their ligands were shown to contribute to MPM aggressiveness and it was suggested that subgroups of MPM patients could benefit from FGFR-targeted inhibitors. In the current investigation, we determined the expression of all four FGFRs (FGFR1-FGFR4) by immunohistochemistry in tissue samples from 94 MPM patients. From 13 of these patients, we were able to establish stable cell lines, which were subjected to FGFR1-4 staining, transcript analysis by quantitative RT-PCR, and treatment with the FGFR inhibitor infigratinib. While FGFR1 and FGFR2 were widely expressed in MPM tissue and cell lines, FGFR3 and FGFR4 showed more restricted expression. FGFR1 and FGFR2 showed no correlation with clinicopathologic data or patient survival, but presence of FGFR3 in 42% and of FGFR4 in 7% of patients correlated with shorter overall survival. Immunostaining in cell lines was more homogenous than in the corresponding tissue samples. Neither transcript nor protein expression of FGFR1-4 correlated with response to infigratinib treatment in MPM cell lines. We conclude that FGFR3 and FGFR4, but not FGFR1 or FGFR2, have prognostic significance in MPM and that FGFR expression is not sufficient to predict FGFR inhibitor response in MPM cell lines.
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MESH Headings
- Acrylamides/pharmacology
- Antineoplastic Agents/pharmacology
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Female
- Gene Expression Profiling
- Humans
- Lung Neoplasms/diagnosis
- Lung Neoplasms/drug therapy
- Lung Neoplasms/pathology
- Male
- Mesothelioma/diagnosis
- Mesothelioma/drug therapy
- Mesothelioma/pathology
- Mesothelioma, Malignant
- Middle Aged
- Phenylurea Compounds/pharmacology
- Protein Kinase Inhibitors/pharmacology
- Pyrimidines/pharmacology
- Quinazolines/pharmacology
- Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- Receptor, Fibroblast Growth Factor, Type 1/metabolism
- Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 2/metabolism
- Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 3/metabolism
- Receptor, Fibroblast Growth Factor, Type 4/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 4/metabolism
- Survival Analysis
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Affiliation(s)
- Gregor Vlacic
- University Clinic for Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia.
| | - Mir A Hoda
- Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria.
| | - Thomas Klikovits
- Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria.
| | - Katharina Sinn
- Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria.
| | - Elisabeth Gschwandtner
- Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria.
| | - Katja Mohorcic
- University Clinic for Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia.
| | - Karin Schelch
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.
| | - Christine Pirker
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.
| | - Barbara Peter-Vörösmarty
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.
| | - Jelena Brankovic
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.
| | - Balazs Dome
- Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria.
- Department of Tumor Biology, National Koranyi Institute of Pulmonology, 1085 Budapest, Hungary.
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, 1085 Budapest, Hungary.
| | - Viktoria Laszlo
- Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria.
- Department of Tumor Biology, National Koranyi Institute of Pulmonology, 1085 Budapest, Hungary.
| | - Tanja Cufer
- University Clinic for Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia.
| | - Ales Rozman
- University Clinic for Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia.
| | - Walter Klepetko
- Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria.
| | - Bettina Grasl-Kraupp
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.
| | - Balazs Hegedus
- Department of Thoracic Surgery, University Medicine Essen-Ruhrlandklinik, 45239 Essen, Germany.
| | - Walter Berger
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.
| | - Izidor Kern
- University Clinic for Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia.
| | - Michael Grusch
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.
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12
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Fibroblast Growth Factor Receptor Signaling in Skin Cancers. Cells 2019; 8:cells8060540. [PMID: 31167513 PMCID: PMC6628025 DOI: 10.3390/cells8060540] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 05/31/2019] [Accepted: 06/03/2019] [Indexed: 12/19/2022] Open
Abstract
Fibroblast growth factor (FGF)/Fibroblast growth factor receptor (FGFR) signaling regulates various cellular processes during the embryonic development and in the adult organism. In the skin, fibroblasts and keratinocytes control proliferation and survival of melanocytes in a paracrine manner via several signaling molecules, including FGFs. FGF/FGFR signaling contributes to the skin surface expansion in childhood or during wound healing, and skin protection from UV light damage. Aberrant FGF/FGFR signaling has been implicated in many disorders, including cancer. In melanoma cells, the FGFR expression is low, probably because of the strong endogenous mutation-driven constitutive activation of the downstream mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) signaling pathway. FGFR1 is exceptional as it is expressed in the majority of melanomas at a high level. Melanoma cells that acquired the capacity to synthesize FGFs can influence the neighboring cells in the tumor niche, such as endothelial cells, fibroblasts, or other melanoma cells. In this way, FGF/FGFR signaling contributes to intratumoral angiogenesis, melanoma cell survival, and development of resistance to therapeutics. Therefore, inhibitors of aberrant FGF/FGFR signaling are considered as drugs in combination treatment. The ongoing LOGIC-2 phase II clinical trial aims to find out whether targeting the FGF/FGFR signaling pathway with BGJ398 may be a good therapeutic strategy in melanoma patients who develop resistance to v-Raf murine sarcoma viral oncogene homolog B (BRAF)/MEK inhibitors.
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13
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Xin Z, Song X, Jiang B, Gongsun X, Song L, Qin Q, Wang Q, Shi M, Liu X. Blocking FGFR4 exerts distinct anti-tumorigenic effects in esophageal squamous cell carcinoma. Thorac Cancer 2018; 9:1687-1698. [PMID: 30267473 PMCID: PMC6275831 DOI: 10.1111/1759-7714.12883] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 08/26/2018] [Accepted: 08/29/2018] [Indexed: 02/06/2023] Open
Abstract
Background The FGFR family can be activated by FGFs and plays important roles in regulating cell growth, differentiation, migration, and angiogenesis. Recent studies have suggested that FGFR4 could regulate several processes, including tumor progression. Esophageal squamous cell carcinoma (ESCC) is a malignancy with high global occurrence. However, the molecule mechanism and the potential roles of FGFR4 in ESCC remain unknown. Methods Immunohistochemistry and Western blotting were used to detect FGFR4 expression in ESCC samples and cell lines. Cell counting kit‐8, and clonogenic, transwell, flow cytometric, and tumor xenograft in nude mice assays were utilized to determine the effect of blocking FGFR4 in proliferation, invasion, migration, and apoptosis of ESCC cells. Results FGFR4 is frequently overexpressed in ESCC tissue and cell lines. in vitro assays have shown that blocking FGFR4 by a specific blocker, H3B‐6527, significantly decreases proliferation, invasion, and migration, and alters epithelial‐mesenchymal transition markers in ESCC cells. In addition, FGFR4 blockade is associated with the induction of apoptosis and affects PI3K/Akt and MAPK/ERK pathways. Moreover, FGFR4 blockade could significantly inhibit the growth of xenograft tumors in vivo. Conclusion Our findings suggest that blocking FGFR4 significantly suppresses the malignant behaviors of ESCC and indicate that FGFR4 is a potential target for the treatment of ESCC.
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Affiliation(s)
- Zhongwei Xin
- Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China
| | - Xuemin Song
- Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China
| | - Bin Jiang
- Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China
| | - Xin Gongsun
- Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China
| | - Liang Song
- Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China
| | - Qiming Qin
- Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China
| | - Qiang Wang
- Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China
| | - Mo Shi
- Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China
| | - Xiangyan Liu
- Department of Thoracic Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China
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14
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Herraiz C, Jiménez-Cervantes C, Sánchez-Laorden B, García-Borrón JC. Functional interplay between secreted ligands and receptors in melanoma. Semin Cell Dev Biol 2018; 78:73-84. [PMID: 28676423 DOI: 10.1016/j.semcdb.2017.06.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 06/26/2017] [Indexed: 12/11/2022]
Abstract
Melanoma, the most aggressive form of skin cancer, results from the malignant transformation of melanocytes located in the basement membrane separating the epidermal and dermal skin compartments. Cutaneous melanoma is often initiated by solar ultraviolet radiation (UVR)-induced mutations. Melanocytes intimately interact with keratinocytes, which provide growth factors and melanocortin peptides acting as paracrine regulators of proliferation and differentiation. Keratinocyte-derived melanocortins activate melanocortin-1 receptor (MC1R) to protect melanocytes from the carcinogenic effect of UVR. Accordingly, MC1R is a major determinant of susceptibility to melanoma. Despite extensive phenotypic heterogeneity and high mutation loads, the molecular basis of melanomagenesis and the molecules mediating the crosstalk between melanoma and stromal cells are relatively well understood. Mutations of intracellular effectors of receptor tyrosine kinase (RTK) signalling, notably NRAS and BRAF, are major driver events more frequent than mutations in RTKs. Nevertheless, melanomas often display aberrant signalling from RTKs such as KIT, ERRB1-4, FGFR, MET and PDGFR, which contribute to disease progression and resistance to targeted therapies. Progress has also been made to unravel the role of the tumour secretome in preparing the metastatic niche. However, key aspects of the melanoma-stroma interplay, such as the molecular determinants of dormancy, remain poorly understood.
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Affiliation(s)
- Cecilia Herraiz
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia, and Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, El Palmar, Murcia, Spain
| | - Celia Jiménez-Cervantes
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia, and Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, El Palmar, Murcia, Spain
| | - Berta Sánchez-Laorden
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, San Juan de Alicante, Spain
| | - José C García-Borrón
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Murcia, and Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Ciencias de la Salud, El Palmar, Murcia, Spain.
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15
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Xiong SW, Ma J, Feng F, Fu W, Shu SR, Ma T, Wu C, Liu GC, Zhu J. Functional FGFR4 Gly388Arg polymorphism contributes to cancer susceptibility: Evidence from meta-analysis. Oncotarget 2018; 8:25300-25309. [PMID: 28445975 PMCID: PMC5421931 DOI: 10.18632/oncotarget.15811] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 02/07/2017] [Indexed: 02/06/2023] Open
Abstract
Fibroblast growth factor receptor 4 (FGFR4) is a member of receptor tyrosine kinase family. A functional Gly388Arg (rs351855 G>A) polymorphism in FGFR4 gene causes a glycine-to-arginine change at codon 388 within the transmembrane domain of the receptor. Although the FGFR4 rs351855 G>A polymorphism has been implicated in cancer development, its association with cancer risk remains controversial. Here, we have systematically analyzed the association between the rs351855 G>A polymorphism and cancer risk by performing a meta-analysis of 27 studies consisting of 8,682 cases and 9,731 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to measure the strength of the association. The rs351855 G>A polymorphism was associated with an increased cancer risk under the recessive model (OR=1.19, 95% CI=1.01-1.41). Stratified analysis by cancer type indicated the rs351855 G>A polymorphism was associated with an increased risk of breast and prostate cancer, but a decreased risk of lung cancer. This meta-analysis demonstrates the FGFR rs351855 G>A polymorphism is associated with increased cancer risk and suggests it could potentially serve as a chemotherapeutic target or biomarker to screen high-risk individuals.
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Affiliation(s)
- Si-Wei Xiong
- Department of Urology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, Guangdong, China
| | - Jianqun Ma
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China
| | - Fen Feng
- Department of Gastroenterology, The First People's Hospital of Foshan (Affiliated Foshan Hospital of Sun Yat-sen University), Foshan 528000, Guangdong, China
| | - Wen Fu
- Department of Pediatric Urology, Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Shan-Rong Shu
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong, China
| | - Tianjiao Ma
- Department of Internal Medicine, Harbin Medical University, Harbin 150081, Heilongjiang, China
| | - Caixia Wu
- Molecular Epidemiology Laboratory and Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China
| | - Guo-Chang Liu
- Department of Pediatric Urology, Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Jinhong Zhu
- Molecular Epidemiology Laboratory and Department of Laboratory Medicine, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China
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16
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Ezzat S, Wang R, Pintilie M, Asa SL. FGFR4 polymorphic alleles modulate mitochondrial respiration: A novel target for somatostatin analog action in pituitary tumors. Oncotarget 2018; 8:3481-3494. [PMID: 27966451 PMCID: PMC5356897 DOI: 10.18632/oncotarget.13843] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 11/16/2016] [Indexed: 01/09/2023] Open
Abstract
We reported that a single nucleotide polymorphism (SNP) at codon 388 of the fibroblast growth factor receptor 4 (FGFR4-Gly388Arg) can result in distinct proteins that alter pituitary cell growth and function. Here, we examined the differential properties of the available therapeutic somatostatin analogs, octreotide and pasireotide, in pituitary tumor cells expressing the different FGFR4 isoforms. Consistent with their enhanced growth properties, FGFR4-R388-expressing cells show higher mitochondrial STAT3 serine phosphorylation driving basal and maximal oxygen consumption rate (OCR) than pituitary cells expressing the more common FGFR4-G388 isoform. While both somatostatin analogs reduce the OCR in FGFR4-G388 cells, pasireotide was more effective in decreasing OCR in cells expressing the variant FGFR4-R388 isoform. Down-regulation of somatostatin receptor 5 (SSTR5) abrogated the effect of pasireotide, demonstrating its involvement in mediating this action. The effects on OCR were recapitulated by introducing a constitutively active serine STAT3 but not by a tyrosine-active mutant. Moreover, pharmacologic inhibition demonstrated the role for the phosphatase PP2A in mediating the dephosphorylation of STAT3-S727 by pasireotide. Our data indicate that FGFR4 polymorphic isoforms mediate signaling that yields mitochondrial therapeutic targets of relevance to the actions of different somatostatin analogs.
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Affiliation(s)
- Shereen Ezzat
- Department of Medicine, The Endocrine Oncology Site Group, Princes Margaret Cancer Centre, and the Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
| | - Ri Wang
- Department of Statistics, University of Waterloo, Toronto, Canada
| | - Melania Pintilie
- Department of Biostatistics, University of Toronto, Toronto, Canada
| | - Sylvia L Asa
- Department of Pathology, University Health Network, Toronto, Canada
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17
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The FGFR4-388arg Variant Promotes Lung Cancer Progression by N-Cadherin Induction. Sci Rep 2018; 8:2394. [PMID: 29402970 PMCID: PMC5799167 DOI: 10.1038/s41598-018-20570-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 01/22/2018] [Indexed: 02/07/2023] Open
Abstract
The FGFR4-388Arg variant has been related to poor prognosis in several types of cancer, including lung cancer. The mechanism underlying this association has not been addressed in detail in patients with this pathology. Here, we report that this FGFR4 variant induces MAPK and STAT3 activation and causes pro-oncogenic effects in NSCLC in vitro and in vivo. This variant induces the expression of EMT-related genes, such as N-cadherin, vimentin, Snail1 and Twist1. Indeed, the induction of N-cadherin protein expression by this variant is essential for its pro-tumorigenic role. The presence of the FGFR4-388Arg variant correlates with higher N-cadherin expression levels in clinical NSCLC samples and with poorer outcome in patients with FGFR expression. These results support the prognostic role of this FGFR variant in lung cancer and show that these effects may be mediated by the induction of N-cadherin expression and an EMT phenotype.
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18
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Porubsky C, Teer JK, Zhang Y, Deschaine M, Sondak VK, Messina JL. Genomic analysis of a case of agminated Spitz nevi and congenital-pattern nevi arising in extensive nevus spilus. J Cutan Pathol 2017; 45:180-183. [PMID: 29210482 DOI: 10.1111/cup.13082] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 11/02/2017] [Accepted: 11/17/2017] [Indexed: 12/30/2022]
Abstract
Nevus spilus is a melanocytic neoplasm characterized by a tan macular background punctuated by multiple hyperpigmented macules or papules that represent various types of nevi. These include junctional and compound nevi, Spitz nevi, and rarely blue nevi. We report a unique case of widespread, multiple nevi spili giving rise to agminated Spitz nevi and congenital-pattern compound nevi. We performed genetic analysis to further characterize the mutational profile of this rare entity.
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Affiliation(s)
- Caitlin Porubsky
- Department of Dermatology, PCOM Mednet/North Fulton Hospital Medical Campus, Roswell, Georgia
| | - Jamie K Teer
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida.,Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, Florida
| | - Yonghong Zhang
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida
| | - Maria Deschaine
- Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, Florida
| | - Vernon K Sondak
- Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida
| | - Jane L Messina
- Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, Florida.,Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida
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19
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Chen L, Lei Z, Ma X, Huang Q, Zhang X, Zhang Y, Hao P, Yang M, Zhao X, Chen J, Liu G, Zheng T. Prognostic significance of fibroblast growth factor receptor 4 polymorphisms on biochemical recurrence after radical prostatectomy in a Chinese population. Sci Rep 2016; 6:33604. [PMID: 27640814 PMCID: PMC5027536 DOI: 10.1038/srep33604] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 08/30/2016] [Indexed: 12/16/2022] Open
Abstract
Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane receptor with ligand-induced tyrosine kinase activity and is involved in various biological and pathological processes. Several polymorphisms of FGFR4 are associated with the incidence and mortality of numerous cancers, including prostate cancer. In this study, we investigated whether the polymorphisms of FGFR4 influence the biochemical recurrence of prostate cancer in Chinese men after radical prostatectomy. Three common polymorphisms (rs1966265, rs2011077, and rs351855) of FGFR4 were genotyped from 346 patients with prostate cancer by using the Sequenom MassARRAY system. Kaplan–Meier curves and Cox proportional hazard models were used for survival analysis. Results showed biochemical recurrence (BCR) free survival was significantly affected by the genotypes of rs351855 but not influenced by rs1966265 and rs2011077. After adjusting for other variables in multivariable analysis, patients with rs351855 AA/AG genotypes showed significantly worse BCR-free survival than those with the GG genotype (HR = 1.873; 95% CI, 1.209–2.901; P = 0.005). Hence, FGFR4 rs351855 could be a novel independent prognostic factor of BCR after radical prostatectomy in the Chinese population. This functional polymorphism may also provide a basis for surveillance programs. Additional large-scale studies must be performed to validate the significance of this polymorphism in prostate cancer.
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Affiliation(s)
- Luyao Chen
- Department of Urology, Chinese PLA General Hospital, Beijing, China
| | - Zhengwei Lei
- Department of Urology, Chinese PLA General Hospital, Beijing, China
| | - Xin Ma
- Department of Urology, Chinese PLA General Hospital, Beijing, China
| | - Qingbo Huang
- Department of Urology, Chinese PLA General Hospital, Beijing, China
| | - Xu Zhang
- Department of Urology, Chinese PLA General Hospital, Beijing, China
| | - Yong Zhang
- Department of Urology, Puai Hospital, Wuhan, China
| | - Peng Hao
- Department of Urology, Puai Hospital, Wuhan, China
| | | | - Xuetao Zhao
- Department of Urology, Puai Hospital, Wuhan, China
| | - Jun Chen
- Department of Urology, Puai Hospital, Wuhan, China
| | - Gongxue Liu
- Department of Urology, Puai Hospital, Wuhan, China
| | - Tao Zheng
- Department of Urology, Puai Hospital, Wuhan, China
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A Polymorphism in the FGFR4 Gene Is Associated With Risk of Neuroblastoma and Altered Receptor Degradation. J Pediatr Hematol Oncol 2016; 38:131-8. [PMID: 26840079 PMCID: PMC4758892 DOI: 10.1097/mph.0000000000000506] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Outcomes for children with high-risk neuroblastoma are poor, and improved understanding of the mechanisms underlying neuroblastoma pathogenesis, recurrence, and treatment resistance will lead to improved outcomes. Aberrant growth factor receptor expression and receptor tyrosine kinase signaling are associated with the pathogenesis of many malignancies. A germline polymorphism in the FGFR4 gene is associated with increased receptor expression and activity and with decreased survival, treatment resistance, and aggressive disease for many malignancies. We therefore investigated the role of this FGFR4 polymorphism in neuroblastoma pathogenesis. MATERIALS AND METHODS Germline DNA from neuroblastoma patients and matched controls was assessed for the FGFR4 Gly/Arg388 polymorphism by RT-PCR. Allele frequencies were assessed for association with neuroblastoma patient outcomes and prognostic features. Degradation rates of the FGFR4 Arg388 and Gly388 receptors and rates of receptor internalization into the late endosomal compartment were measured. RESULTS Frequency of the FGFR4 AA genotype and the prevalence of the A allele were significantly higher in patients with neuroblastoma than in matched controls. The Arg388 receptor demonstrated slower degradation than the Gly388 receptor in neuroblastoma cells and reduced internalization into multivesicular bodies. CONCLUSIONS The FGFR4 Arg388 polymorphism is associated with an increased prevalence of neuroblastoma in children, and this association may be linked to differences in FGFR4 degradation rates. Our study provides the first evidence of a role for FGFR4 in neuroblastoma, suggesting that FGFR4 genotype and the pathways regulating FGFR4 trafficking and degradation may be relevant for neuroblastoma pathogenesis.
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Ulaganathan VK, Sperl B, Rapp UR, Ullrich A. Germline variant FGFR4 p.G388R exposes a membrane-proximal STAT3 binding site. Nature 2015; 528:570-4. [PMID: 26675719 DOI: 10.1038/nature16449] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 11/14/2015] [Indexed: 12/27/2022]
Abstract
Variant rs351855-G/A is a commonly occurring single-nucleotide polymorphism of coding regions in exon 9 of the fibroblast growth factor receptor FGFR4 (CD334) gene (c.1162G>A). It results in an amino-acid change at codon 388 from glycine to arginine (p.Gly388Arg) in the transmembrane domain of the receptor. Despite compelling genetic evidence for the association of this common variant with cancers of the bone, breast, colon, prostate, skin, lung, head and neck, as well as soft-tissue sarcomas and non-Hodgkin lymphoma, the underlying biological mechanism has remained elusive. Here we show that substitution of the conserved glycine 388 residue to a charged arginine residue alters the transmembrane spanning segment and exposes a membrane-proximal cytoplasmic signal transducer and activator of transcription 3 (STAT3) binding site Y(390)-(P)XXQ(393). We demonstrate that such membrane-proximal STAT3 binding motifs in the germline of type I membrane receptors enhance STAT3 tyrosine phosphorylation by recruiting STAT3 proteins to the inner cell membrane. Remarkably, such germline variants frequently co-localize with somatic mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Using Fgfr4 single nucleotide polymorphism knock-in mice and transgenic mouse models for breast and lung cancers, we validate the enhanced STAT3 signalling induced by the FGFR4 Arg388-variant in vivo. Thus, our findings elucidate the molecular mechanism behind the genetic association of rs351855 with accelerated cancer progression and suggest that germline variants of cell-surface molecules that recruit STAT3 to the inner cell membrane are a significant risk for cancer prognosis and disease progression.
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Affiliation(s)
- Vijay K Ulaganathan
- Max Planck Institute for Biochemistry, Department of Molecular Biology, Am Klopferspitz 18, 82152, Martinsried. Germany
| | - Bianca Sperl
- Max Planck Institute for Biochemistry, Department of Molecular Biology, Am Klopferspitz 18, 82152, Martinsried. Germany
| | - Ulf R Rapp
- Max Planck Institute for Heart and Lung Research, Molecular Mechanisms of Lung Cancer, Parkstrasse 1, 61231 Bad Nauheim, Germany
| | - Axel Ullrich
- Max Planck Institute for Biochemistry, Department of Molecular Biology, Am Klopferspitz 18, 82152, Martinsried. Germany
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Shi S, Li X, You B, Shan Y, Cao X, You Y. High Expression of FGFR4 Enhances Tumor Growth and Metastasis in Nasopharyngeal Carcinoma. J Cancer 2015; 6:1245-54. [PMID: 26535066 PMCID: PMC4622855 DOI: 10.7150/jca.12825] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Accepted: 08/28/2015] [Indexed: 01/02/2023] Open
Abstract
Background: FGF receptor (FGFR) family can be activated by FGFs and play important roles in regulating cell growth, differentiation, migration and angiogenesis. Recent studies suggested that FGFR4 could regulate several processes including tumor progression. Nasopharyngeal carcinoma (NPC) is a malignancy with a high occurrence in Southeast Asia and Southern China. However, the molecule mechanism and the potential roles of FGFR4 in NPC remain unknown Methods: Immunohistochemistry and western blot were used to investigate the expression of FGFR4 in NPC samples. Then we used statistical analysis to evaluate the diagnostic value and the associations of FGFR4 expression with clinical parameters. In vitro studies, the effects of FGFR4 on proliferation and migration of NPC cell line CNE2 were measured by the starvation-refeeding experiment, CCK8 assay, wounding healing assay and transwell migration assay. The changes of the epithelial-mesenchymal transition (EMT) markers in CNE2 cells after knocking down the expression of FGFR4 were measured by Western blot and immunofluorescence analysis. Results: FGFR4 was overexpressed in NPC as compared with the inflammatory tissues. High expression of FGFR4 was correlated with Ki67 expression, clinical stages and prognosis in NPC patients (P<0.05).While in vitro, the upregulation of FGFR4 was accompanied with CNE2 cells released from serum starvation. Moreover, it could increase cell proliferation and migration by regulating EMT markers in CNE2 cells. Conclusion: Our data suggested that FGFR4 might induce NPC progression and act as a potential therapeutic target in NPC.
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Affiliation(s)
- Si Shi
- 1. Department of Otorhinolaryngology Head and Neck surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Xingyu Li
- 2. Department of Pathology, Medical School of Nantong University, Nantong, Jiangsu Province, China
| | - Bo You
- 1. Department of Otorhinolaryngology Head and Neck surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Ying Shan
- 1. Department of Otorhinolaryngology Head and Neck surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Xiaolei Cao
- 2. Department of Pathology, Medical School of Nantong University, Nantong, Jiangsu Province, China
| | - Yiwen You
- 1. Department of Otorhinolaryngology Head and Neck surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
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Heinzle C, Erdem Z, Paur J, Grasl-Kraupp B, Holzmann K, Grusch M, Berger W, Marian B. Is fibroblast growth factor receptor 4 a suitable target of cancer therapy? Curr Pharm Des 2015; 20:2881-98. [PMID: 23944363 DOI: 10.2174/13816128113199990594] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Accepted: 08/06/2013] [Indexed: 12/17/2022]
Abstract
Fibroblast growth factors (FGF) and their tyrosine kinase receptors (FGFR) support cell proliferation, survival and migration during embryonic development, organogenesis and tissue maintenance and their deregulation is frequently observed in cancer development and progression. Consequently, increasing efforts are focusing on the development of strategies to target FGF/FGFR signaling for cancer therapy. Among the FGFRs the family member FGFR4 is least well understood and differs from FGFRs1-3 in several aspects. Importantly, FGFR4 deletion does not lead to an embryonic lethal phenotype suggesting the possibility that its inhibition in cancer therapy might not cause grave adverse effects. In addition, the FGFR4 kinase domain differs sufficiently from those of FGFRs1-3 to permit development of highly specific inhibitors. The oncogenic impact of FGFR4, however, is not undisputed, as the FGFR4-mediated hormonal effects of several FGF ligands may also constitute a tissue-protective tumor suppressor activity especially in the liver. Therefore it is the purpose of this review to summarize all relevant aspects of FGFR4 physiology and pathophysiology and discuss the options of targeting this receptor for cancer therapy.
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Affiliation(s)
| | | | | | | | | | | | | | - Brigitte Marian
- Institute of Cancer Research, Department of Medicine 1, Medical University Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
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Garay T, Molnár E, Juhász É, László V, Barbai T, Dobos J, Schelch K, Pirker C, Grusch M, Berger W, Tímár J, Hegedűs B. Sensitivity of Melanoma Cells to EGFR and FGFR Activation but Not Inhibition is Influenced by Oncogenic BRAF and NRAS Mutations. Pathol Oncol Res 2015; 21:957-68. [PMID: 25749811 DOI: 10.1007/s12253-015-9916-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 02/17/2015] [Indexed: 11/28/2022]
Abstract
BRAF and NRAS are the two most frequent oncogenic driver mutations in melanoma and are pivotal components of both the EGF and FGF signaling network. Accordingly, we investigated the effect of BRAF and NRAS oncogenic mutation on the response to the stimulation and inhibition of epidermal and fibroblast growth factor receptors in melanoma cells. In the three BRAF mutant, two NRAS mutant and two double wild-type cell lines growth factor receptor expression had been verified by qRT-PCR. Cell proliferation and migration were determined by the analysis of 3-days-long time-lapse videomicroscopic recordings. Of note, a more profound response was found in motility as compared to proliferation and double wild-type cells displayed a higher sensitivity to EGF and FGF2 treatment when compared to mutant cells. Both baseline and induced activation of the growth factor signaling was assessed by immunoblot analysis of the phosphorylation of the downstream effectors Erk1/2. Low baseline and higher inducibility of the signaling pathway was characteristic in double wild-type cells. In contrast, oncogenic BRAF or NRAS mutation did not influence the response to EGF or FGF receptor inhibitors in vitro. Our findings demonstrate that the oncogenic mutations in melanoma have a profound impact on the motogenic effect of the activation of growth factor receptor signaling. Since emerging molecularly targeted therapies aim at the growth factor receptor signaling, the appropriate mutational analysis of individual melanoma cases is essential in both preclinical studies and in the clinical trials and practice.
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Affiliation(s)
- Tamás Garay
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, H-1091, Budapest, Hungary
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Bedussi F, Bottini A, Memo M, Fox SB, Sigala S, Generali D. Targeting fibroblast growth factor receptor in breast cancer: a promise or a pitfall? Expert Opin Ther Targets 2014; 18:665-78. [PMID: 24833241 DOI: 10.1517/14728222.2014.898064] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
INTRODUCTION Fibroblast growth factors (FGFs) along with their receptors (FGFRs) are involved in several cellular functions, from embryogenesis to metabolism. Because of the ability of FGFR signalling to induce cell proliferation, migration and survival in cancer, these have been found to become overactivated by several mechanisms, including gene amplification, chromosomal translocation and mutations. New evidences indicate that FGFs and FGFRs may act in an oncogenic fashion to promote multiple steps of cancer progression by inducing mitogenic and survival signals, as well as promoting epithelial-to-mesenchymal transition, invasion and tumour angiogenesis. This review focuses on the predictive and prognostic role of FGFRs, the role of FGFR signalling and how it may be most appropriately therapeutically targeted in breast cancer. AREAS COVERED Activation of the FGFR pathway is a common event in many cancer types and for this reason FGFR is an important potential target in cancer treatment. Relevant literature was reviewed to identify current and future role of FGFR family as a possible guide for selecting those patients who would be poor or good responders to the available or the upcoming target therapies for breast cancer treatment. EXPERT OPINION The success of a personalised medicine approach using targeted therapies ultimately depends on being capable of identifying the patients who will benefit the most from any given drug. Outlining the molecular mechanisms of FGFR signalling and discussing the role of this pathway in breast cancer, we would like to endorse the incorporation of specific patient selection biomakers with the rationale for therapeutic intervention with FGFR-targeted therapy in breast cancer.
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Affiliation(s)
- Francesca Bedussi
- University of Brescia Medical School, Department of Molecular and Translational Medicine, Section of Pharmacology , Brescia , Italy
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Nakano-Tateno T, Tateno T, Hlaing MM, Zheng L, Yoshimoto K, Yamada S, Asa SL, Ezzat S. FGFR4 polymorphic variants modulate phenotypic features of Cushing disease. Mol Endocrinol 2014; 28:525-33. [PMID: 24625004 DOI: 10.1210/me.2013-1412] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Cushing disease is a potentially lethal condition resulting from hormone excess, usually due to a small pituitary tumor that fails to respond to negative feedback inhibition. A minority of patients develop larger, more aggressive tumors of the same lineage but with modest hormone excess. Here we show that a common polymorphism in the fibroblast growth factor receptor 4 (FGFR4) transmembrane domain yields receptor isoforms with distinct properties that mediate these biological differences. Forced expression of the major FGFR4-G388 variant allele supports pY-signal transducer and activator of transcription (STAT3) responses. In contrast, expression of the minor FGFR4-R388 allele enhances STAT3 serine phosphorylation, driving cellular growth. In addition, FGFR4-R388 enhances glucocorticoid receptor phosphorylation and nuclear translocation. Consistent with these findings, glucocorticoid administration resulted in enhanced hormone negative feedback in mice with knock-in of the FGFR4 variant allele. Moreover, clinical data from patients with pituitary tumors revealed that those homozygous for the R388 allele have a higher frequency of silent corticotroph macroadenomas than FGFR4-G388 carriers, who were more likely to have small but hormonally active microadenomas. These findings demonstrate that the FGFR4 transmembrane polymorphic variants can modulate cellular growth and sensitivity to glucocorticoid hormone negative feedback through distinct STAT3 modifications of relevance to the human forms of Cushing disease.
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Affiliation(s)
- Tae Nakano-Tateno
- Departments of Medicine (T.N.-T., T.T., M.M.H., L.Z., S.E.) and Laboratory Medicine and Pathobiology (T.N.-T., T.T., S.L.A.), University of Toronto, Toronto, Ontario, Canada M5S 2J7; The Endocrine Oncology Site Group (T.N.-T., T.T., S.L.A., S.E.), Princess Margaret Hospital, Toronto, Ontario, Canada M5T 2M9; Ontario Cancer Institute (T.N.-T., T.T., S.L.A., S.E.), University Health Network, Toronto, Ontario, Canada M5G-1X5; Department of Medical Pharmacology (K.Y.), Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, 770-0855, Japan; and Hypothalamic and Pituitary Surgery (S.Y.), Toranomon Hospital, Tokyo 105-0001, Japan
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Chung HJ, Mahalingam M. Angiogenesis, vasculogenic mimicry and vascular invasion in cutaneous malignant melanoma – implications for therapeutic strategies and targeted therapies. Expert Rev Anticancer Ther 2014; 14:621-39. [DOI: 10.1586/14737140.2014.883281] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Fibroblast growth factor receptor 4 (FGFR4): a targetable regulator of drug resistance in colorectal cancer. Cell Death Dis 2014; 5:e1046. [PMID: 24503538 PMCID: PMC3944229 DOI: 10.1038/cddis.2014.10] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Revised: 12/21/2013] [Accepted: 12/23/2013] [Indexed: 12/18/2022]
Abstract
The discovery of underlying mechanisms of drug resistance, and the development of novel agents to target these pathways, is a priority for patients with advanced colorectal cancer (CRC). We previously undertook a systems biology approach to design a functional genomic screen and identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of drug resistance. The aim of this study was to examine the role of FGFR4 in drug resistance using RNAi and the small-molecule inhibitor BGJ398 (Novartis). We found that FGFR4 is highly expressed at the RNA and protein levels in colon cancer tumour tissue compared with normal colonic mucosa and other tumours. Silencing of FGFR4 reduced cell viability in a panel of colon cancer cell lines and increased caspase-dependent apoptosis. A synergistic interaction was also observed between FGFR4 silencing and 5-fluorouracil (5-FU) and oxaliplatin chemotherapy in colon cancer cell lines. Mechanistically, FGFR4 silencing decreased activity of the pro-survival STAT3 transcription factor and expression of the anti-apoptotic protein c-FLIP. Furthermore, silencing of STAT3 resulted in downregulation of c-FLIP protein expression, suggesting that FGFR4 may regulate c-FLIP expression via STAT3. A similar phenotype and downstream pathway changes were observed following FGFR4 silencing in cell lines resistant to 5-FU, oxaliplatin and SN38 and upon exposure of parental cells to the FGFR small-molecule inhibitor BGJ398. Our results indicate that FGFR4 is a targetable regulator of chemo-resistance in CRC, and hence inhibiting FGFR4 in combination with 5-FU and oxaliplatin is a potential therapeutic strategy for this disease.
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Abstract
The fibroblast growth factor receptors (FGFRs) regulate important biological processes including cell proliferation and differentiation during development and tissue repair. Over the past decades, numerous pathological conditions and developmental syndromes have emerged as a consequence of deregulation in the FGFRs signaling network. This review aims to provide an overview of FGFR family, their complex signaling pathways in tumorigenesis, and the current development and application of therapeutics targeting the FGFRs signaling for treatment of refractory human cancers.
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Affiliation(s)
- Kai Hung Tiong
- School of Postgraduate Studies and Research, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia
| | - Li Yen Mah
- School of Pharmacy, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia
- Center for Cancer and Stem Cell Research, International Medical University, 126 Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia
| | - Chee-Onn Leong
- School of Pharmacy, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia
- Center for Cancer and Stem Cell Research, International Medical University, 126 Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia
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Shen YY, Lu YC, Shen DP, Liu YJ, Su XY, Zhu GS, Yin XL, Ni XZ. Fibroblast growth factor receptor 4 Gly388Arg polymorphism in Chinese gastric cancer patients. World J Gastroenterol 2013; 19:4568-4575. [PMID: 23901234 PMCID: PMC3725383 DOI: 10.3748/wjg.v19.i28.4568] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 02/27/2013] [Accepted: 03/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the contribution of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism as a genetic risk factor for gastric cancer (GC) and to investigate any associations between this polymorphism and clinicopathological parameters and survival.
METHODS: Tumors and matched adjacent non-cancer tissues were collected from 304 GC patients, and 5 mL of venous blood was collected from 62 GC patients and 392 age- and sex-matched healthy controls without cancer history from the same ethnic population. DNA was extracted, and direct sequencing analyses were performed to genotype the FGFR4 Gly388Arg polymorphism in all the samples. Differences in the genotype frequencies of the FGFR4 Gly388Arg polymorphism between GC patients and healthy controls were estimated using the χ2 test. Binary logistic regression was used for all analysis variables to estimate risk as the ORs with 95%CIs. The relationships between the FGFR4 genotype and clinicopathological parameters were tested with the χ2 test. The Kaplan-Meier product-limit method, the log-rank test, and the Cox regression model were applied to evaluate the effect of the FGFR4 genotype on the overall survival of patients with GC.
RESULTS: In the present GC cohort, 118 patients (38.8%) were homozygous for the Gly388 allele, 124 patients (40.8%) were heterozygous, and 62 patients (20.4%) were homozygous for the Arg388 allele. The frequencies of the Gly/Gly, Gly/Arg, and Arg/Arg genotypes in the healthy controls were 33.6%, 48.0%, and 18.4%, respectively. The distributions of genotypes (χ2 = 3.589, P = 0.166) and alleles (χ2 = 0.342, P = 0.559) of the FGFR4 Gly388Arg polymorphism were not different between the GC patients and the healthy controls. Although we observed no correlation between the FGFR4 Gly388Arg polymorphism and clinicopathological parameters or survival in the total cohort of GC patients, the presence of the Arg388 allele was associated with shorter survival time in patients with GC if the tumor was small (log rank χ2 = 5.449, P = 0.020), well differentiated (log rank χ2 = 12.798, P = 0.000), T1 or T2 stage (log rank χ2 = 4.745, P = 0.029), without lymph node involvement (log rank χ2 = 6.647, P= 0.010), and at an early clinical stage (log rank χ2 = 4.615, P = 0.032).
CONCLUSION: Our results suggest that the FGFR4 Gly388Arg polymorphism is not a risk factor for GC cancer initiation but that it is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or at an early clinical stage.
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Park JY, Amankwah EK, Anic GM, Lin HY, Walls B, Park H, Krebs K, Madden M, Maddox K, Marzban S, Fang S, Chen W, Lee JE, Wei Q, Amos CI, Messina JL, Sondak VK, Sellers TA, Egan KM. Gene variants in angiogenesis and lymphangiogenesis and cutaneous melanoma progression. Cancer Epidemiol Biomarkers Prev 2013; 22:827-34. [PMID: 23462921 PMCID: PMC3708315 DOI: 10.1158/1055-9965.epi-12-1129] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Angiogenesis and lymphangiogenesis are important in the progression of melanoma. We investigated associations between genetic variants in these pathways with sentinel lymph node (SLN) metastasis and mortality in 2 independent series of patients with melanoma. METHODS Participants at Moffitt Cancer Center were 552 patients, all Caucasian, with primary cutaneous melanoma referred for SLN biopsy. A total of 177 patients had SLN metastasis, among whom 60 died from melanoma. Associations between 238 single-nucleotide polymorphisms (SNP) in 26 genes and SLN metastasis were estimated as ORs and 95% confidence intervals (CI) using logistic regression. Competing risk regression was used to estimate HRs and 95% CI for each SNP and melanoma-specific mortality. We attempted to replicate significant findings using data from a genome-wide association study comprising 1,115 patients with melanoma who were referred for SLN biopsy from MD Anderson Cancer Center (MDACC), among whom 189 patients had SLN metastasis and 92 patients died from melanoma. RESULTS In the Moffitt dataset, we observed significant associations in 18 SNPs with SLN metastasis and 17 SNPs with mortality. Multiple SNPs in COL18A1, EGF receptor (EGFR), FLT1, interleukin (IL)-10, platelet-derived growth factor D (PDGFD), PIK3CA, and toll-like receptor (TLR)-3 were associated with the risk of SLN metastasis and/or patient mortality. The MDACC data set replicated an association between mortality and rs2220377 in PDGFD. Furthermore, in a meta-analysis, 3 additional SNPs were significantly associated with SLN metastasis (EGFR rs723526 and TLR3 rs3775292) and melanoma-specific death (TLR3 rs7668666). CONCLUSIONS These findings suggest that genetic variation in angiogenesis and lymphangiogenesis contributes to regional nodal metastasis and progression of melanoma. IMPACT Additional research attempting to replicate these results is warranted.
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Affiliation(s)
- Jong Y Park
- Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
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Chen Z, Xie B, Zhu Q, Xia Q, Jiang S, Cao R, Shi L, Qi D, Li X, Cai L. FGFR4 and TGF-β1 expression in hepatocellular carcinoma: correlation with clinicopathological features and prognosis. Int J Med Sci 2013; 10:1868-75. [PMID: 24324363 PMCID: PMC3856377 DOI: 10.7150/ijms.6868] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Accepted: 10/17/2013] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To investigate the expression and correlation of transforming growth factor-β1 (TGF-β1) and fibroblast growth factor receptor 4 (FGFR4) in human hepatocellular carcinoma (HCC) and the relationship with clinicopathological features and prognosis. MATERIALS AND METHODS The expression of TGF-β1 and FGFR4 in 126 HCC samples was detected immunohistochemically. Combined with clinical postoperative follow-up data, the expression of TGF-β1 and FGFR4 in HCC and the relationship with the prognosis of patients were analyzed by statistically. RESULTS The positive expression rate of TGF-β1 was 84.1% (106/126) in tumors, and that in peritumoral liver tissues was 64.3% (81/126); the positive expression rate of FGFR4 in tumors was 74.6% (94/126) and that in peritumoral liver tissues was 57.1% (72/126). The expression of TGF-β1 and FGFR4 in the carcinoma tissues was significantly higher than that in peritumoral liver tissues (p < 0.05). Intratumoral TGF-β1 and FGFR4 expression was associated with TNM stage (p < 0.05). TGF-β1 and FGFR4 expression levels didn't significantly correlate with other clinicopathological parameters, including age, sex, tumor size, serum AFP level, tumor differentiation, lymph node metastasis, etc. (p > 0.05). TGF-β1 expression was positively correlated with FGFR4 expression (r = 0.595, p < 0.05). Patients with positive FGFR4 or TGF-β1 expression had shorter overall survival compared with negative expression (p < 0.05). CONCLUSIONS The expression of TGF-β1 and FGFR4 could make synergy on the occurrence and progression of HCC, and may be used as prognosis indicators for HCC patients.
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Affiliation(s)
- Zhixin Chen
- 1. Department of Biopharmaceutics, School of Pharmacy, Wenzhou Medical University, Zhejiang, Wenzhou (China)
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Dutra RL, de Carvalho MB, dos Santos M, Mercante AMDC, Gazito D, de Cicco R, Group GENCAPO, Tajara EH, Louro ID, da Silva AMÁ. FGFR4 profile as a prognostic marker in squamous cell carcinoma of the mouth and oropharynx. PLoS One 2012; 7:e50747. [PMID: 23226373 PMCID: PMC3511351 DOI: 10.1371/journal.pone.0050747] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 10/24/2012] [Indexed: 02/07/2023] Open
Abstract
Background Fibroblast growth factor receptor 4 (FGFR4) is a member of a receptor tyrosine kinase family of enzymes involved in cell cycle control and proliferation. A common single nucleotide polymorphism (SNP) Gly388Arg variant has been associated with increased tumor cell motility and progression of breast cancer, head and neck cancer and soft tissue sarcomas. The present study evaluated the prognostic significance of FGFR4 in oral and oropharynx carcinomas, finding an association of FGFR4 expression and Gly388Arg genotype with tumor onset and prognosis. Patients and Methods DNA from peripheral blood of 122 patients with oral and oropharyngeal squamous cell carcinomas was used to determine FGFR4 genotype by PCR-RFLP. Protein expression was assessed by immunohistochemistry (IHC) on paraffin-embedded tissue microarrays. Results Presence of allele Arg388 was associated with lymphatic embolization and with disease related premature death. In addition, FGFR4 low expression was related with lymph node positivity and premature relapse of disease, as well as disease related death. Conclusion Our results propose FGFR4 profile, measured by the Gly388Arg genotype and expression, as a novel marker of prognosis in squamous cell carcinoma of the mouth and oropharynx.
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Affiliation(s)
- Roberta Lelis Dutra
- Faculdade de Medicina, Universidade de São Paulo,São Paulo, São Paulo, Brazil
| | - Marcos Brasilino de Carvalho
- Laboratório de Biologia Molecular, Hospital Heliópolis, São Paulo, São Paulo, Brazil
- Serviço de Cirurgia Cabeça e Pescoço, Hospital Heliópolis, São Paulo, São Paulo, Brazil
| | - Marcelo dos Santos
- Programa de Pós Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | | | - Diana Gazito
- Laboratório de Sequenciamento, Associação Beneficente de Coleta de Sangue, São Paulo, São Paulo, Brazil
| | | | - GENCAPO Group
- Head and Neck Genome Project, GENCAPO, Ribeirão Preto, São Paulo, Brazil
| | - Eloiza Helena Tajara
- Departamento de Biologia Molecular, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, São Paulo, Brazil
| | - Iúri Drumond Louro
- Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
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Heinzle C, Gsur A, Hunjadi M, Erdem Z, Gauglhofer C, Stättner S, Karner J, Klimpfinger M, Wrba F, Reti A, Hegedus B, Baierl A, Grasl-Kraupp B, Holzmann K, Grusch M, Berger W, Marian B. Differential effects of polymorphic alleles of FGF receptor 4 on colon cancer growth and metastasis. Cancer Res 2012; 72:5767-77. [PMID: 22971346 DOI: 10.1158/0008-5472.can-11-3654] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A gly(388)arg polymorphism (rs351855) in the transmembrane domain of the fibroblast growth factor receptor (FGFR4) is associated with increased risk, staging, and metastasis in several different types of cancer. To specifically assess the impact of the polymorphic FGFR4 in colorectal cancer (CRC), we engineered CRC cell lines with distinct endogenous expression patterns to overexpress either the FGFR4(gly) or FGFR4(arg) alleles. The biologic analyses revealed an oncogenic importance for both polymorphic alleles, but FGFR4(gly) was the stronger inducer of tumor growth, whereas FGFR4(arg) was the stronger inducer of migration. An evaluation of clinical specimens revealed that FGFR4 was upregulated in 20/71 patients independent of gly(388)arg status. There was no correlation between the presence of an FGFR4(arg) allele and CRC or polyp risk in 3,471 participants of the CORSA study. However, among 182 patients with CRC, FGFR4(arg)-carriers had a fivefold higher risk of tumors that were stage II or greater. Together, our results established that both allelic forms of FGFR4 exert an oncogenic impact and may serve equally well as therapeutic targets in CRC. One important implication of our findings is that FGFR4(arg)-carriers are at a higher risk for more aggressive tumors and therefore may profit from early detection measures.
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Affiliation(s)
- Christine Heinzle
- Department of Medicine 1, Institute of Cancer Research, Clinical Institute of Pathology, University of Vienna, Vienna, Austria
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35
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Amankwah EK, Sellers TA, Park JY. Gene variants in the angiogenesis pathway and prostate cancer. Carcinogenesis 2012; 33:1259-69. [PMID: 22523086 PMCID: PMC3405650 DOI: 10.1093/carcin/bgs150] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Revised: 04/09/2012] [Accepted: 04/10/2012] [Indexed: 01/24/2023] Open
Abstract
Although the causes of prostate cancer are still unknown, numerous studies support the role of genetic factors in the development and progression of this disease. Single nucleotide polymorphisms (SNPs) in key angiogenesis genes have been studied in prostate cancer. In this review, we provide an overview of the current knowledge of the role of genetic variants in the angiogenesis pathway in prostate cancer risk and progression. Of the 17 prostate cancer genome-wide association studies (GWAS) conducted to date, only one identified disease-associated SNPs in a region of an angiogenesis pathway gene. An association was observed between aggressive disease and three intergenic SNPs (rs11199874, rs10749408 and rs10788165) in a region on chromosome 10q26 that encompasses FGFR2. The majority (27/32, 84.4%) of primary candidate gene studies reviewed had a small (n < 800, 20/32, 62.5%) to medium sample size (n = 800-2000, 7/32, 21.9%), whereas only five (15.6%) had a large sample size (n ≥ 2000). Results from the large studies revealed associations with risk and aggressive disease for SNPs in NOS2A, NOS3 and MMP-2 and risk for HIF1-α. Meta-analyses have so far been conducted on FGFR2, TGF-β, TNF-α, HIF1-α and IL10 and the results reveal an association with risk for SNPs in FGFR2 and TGF-β and aggressive disease for SNPs in IL-10. Thus, existing evidence from GWAS and large candidate gene studies indicates that SNPs from a limited number of angiogenesis pathway genes are associated with prostate cancer risk and progression.
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Affiliation(s)
| | | | - Jong Y. Park
- Department of Cancer Epidemiology, Division of Cancer Prevention and Control, Moffitt Cancer Center, Tampa, FL, USA
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36
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Hwang T, Atluri G, Xie M, Dey S, Hong C, Kumar V, Kuang R. Co-clustering phenome-genome for phenotype classification and disease gene discovery. Nucleic Acids Res 2012; 40:e146. [PMID: 22735708 PMCID: PMC3479160 DOI: 10.1093/nar/gks615] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Understanding the categorization of human diseases is critical for reliably identifying disease causal genes. Recently, genome-wide studies of abnormal chromosomal locations related to diseases have mapped >2000 phenotype–gene relations, which provide valuable information for classifying diseases and identifying candidate genes as drug targets. In this article, a regularized non-negative matrix tri-factorization (R-NMTF) algorithm is introduced to co-cluster phenotypes and genes, and simultaneously detect associations between the detected phenotype clusters and gene clusters. The R-NMTF algorithm factorizes the phenotype–gene association matrix under the prior knowledge from phenotype similarity network and protein–protein interaction network, supervised by the label information from known disease classes and biological pathways. In the experiments on disease phenotype–gene associations in OMIM and KEGG disease pathways, R-NMTF significantly improved the classification of disease phenotypes and disease pathway genes compared with support vector machines and Label Propagation in cross-validation on the annotated phenotypes and genes. The newly predicted phenotypes in each disease class are highly consistent with human phenotype ontology annotations. The roles of the new member genes in the disease pathways are examined and validated in the protein–protein interaction subnetworks. Extensive literature review also confirmed many new members of the disease classes and pathways as well as the predicted associations between disease phenotype classes and pathways.
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Affiliation(s)
- TaeHyun Hwang
- Bioinformatics core at Masonic Cancer Center, University of Minnesota Twin Cities, Minneapolis, MN 55455, USA
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37
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Eng L, Azad AK, Habbous S, Pang V, Xu W, Maitland-van der Zee AH, Savas S, Mackay HJ, Amir E, Liu G. Vascular endothelial growth factor pathway polymorphisms as prognostic and pharmacogenetic factors in cancer: a systematic review and meta-analysis. Clin Cancer Res 2012; 18:4526-37. [PMID: 22733538 DOI: 10.1158/1078-0432.ccr-12-1315] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Angiogenesis is an important host process that interacts with cancer cells to promote growth, invasion, and metastasis. Numerous therapeutic agents targeting the VEGF pathway have been developed. Host variability in VEGF pathway can influence angiogenesis-dependent signaling, altering sensitivity to antiangiogenic drugs and prognosis. A systematic review and meta-analysis was conducted (May 1990-July 2011). Eligible studies involved cancer patients and compared polymorphisms in the VEGF pathway [VEGF and molecules directly interacting with VEGF: KDR, FLT1, FGF, FGF2, FGFR, NRP1, endostatin (encoded by COL18A1)], and reported one of the following outcomes: overall survival, progression-free survival, time to recurrence, disease-free survival, response rate, or drug toxicity. We identified 48 cancer studies assessing prognosis and 12 cancer studies exploring pharmacogenetics of anti-VEGF therapy across various VEGF pathway polymorphisms. There was marked inter- and intradisease site heterogeneity in the effect of polymorphisms on both outcome and response to therapy. Meta-analyses of 5 VEGF polymorphisms (+936C>T, -460T>C, +405G>C, -1154G>A, and -2578C>A) identified a significant prognostic relationship: VEGF +405G>C variants showed a highly statistically significant improvement in overall survival [HR, 0.74; 95% confidence interval, 0.60-0.91; P = 0.004]. Variants (heterozygotes and/or homozygotes) of VEGF +405G>C were significantly associated with improved survival in a meta-analysis of multiple cancer sites.
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Affiliation(s)
- Lawson Eng
- Ontario Cancer Institute; Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital/University Health Network and University of Toronto, Toronto, CA
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38
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Marmé F, Hielscher T, Hug S, Bondong S, Zeillinger R, Castillo-Tong DC, Sehouli J, Braicu I, Vergote I, Isabella C, Mahner S, Ferschke I, Rom J, Sohn C, Schneeweiss A, Altevogt P. Fibroblast growth factor receptor 4 gene (FGFR4) 388Arg allele predicts prolonged survival and platinum sensitivity in advanced ovarian cancer. Int J Cancer 2012; 131:E586-91. [PMID: 22034009 DOI: 10.1002/ijc.27329] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Accepted: 10/05/2011] [Indexed: 01/04/2023]
Abstract
FGFR4 has been shown to play an important role in the etiology and progression of solid tumors. A single nucleotide polymorphism (SNP) within the FGFR4 gene has previously been linked to prognosis and response to chemotherapy in breast cancer and other malignancies. This study evaluates the relevance of this SNP in advanced ovarian cancer. FGFR4-genotype was analyzed in 236 patients recruited as part of the OVCAD project. Genotyping was performed on germ-line DNA using a TaqMan based genotyping assay. Results were correlated with clinicopathological variables and survival. The FGFR4 388Arg genotype was significantly associated with prolonged progression-free and overall survival (univariate: HR 0.68, p = 0.017; HR 0.49, p = 0.005; multivariate: HR 0.69, p = 0.025; HR 0.49, p = 0.006) though the positive prognostic value was restricted to patients without postoperative residual tumor. Indeed, there was a significant interaction between FGFR4 genotype and residual tumor for overall survival. Furthermore, the FGFR4 388Arg genotype significantly correlated with platinum sensitivity in the same subgroup (multivariate OR 3.81 p = 0.004). FGFR4 Arg388Gly genotype is an independent and strong context specific prognostic factor in patients with advanced ovarian cancer and could be used to predict platinum-sensitivity.
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Affiliation(s)
- Frederik Marmé
- Department of Obstetrics & Gynecology, University Hospital Heidelberg, Heidelberg, Germany.
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Abstract
Fibroblast growth factors (FGFs) and their cognate receptors, FGF receptors (FGFRs), play critical roles in a variety of normal developmental and physiological processes. Numerous reports support a role for deregulation of FGF-FGFR signaling, whether it is at the ligand and/or receptor level, in tumor development and progression. The FGF19-FGFR4 signaling axis has been implicated in the pathogenesis of several cancers, including hepatocellular carcinomas in mice and potentially in humans. This chapter focuses on recent progress in the understanding of the molecular mechanisms of FGF19 action and its potential involvement in cancer.
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40
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Prognostic parameters for the primary care of melanoma patients: what is really risky in melanoma? J Skin Cancer 2011; 2011:521947. [PMID: 22007305 PMCID: PMC3191731 DOI: 10.1155/2011/521947] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 07/21/2011] [Accepted: 07/21/2011] [Indexed: 12/18/2022] Open
Abstract
Due to intensified research in recent years, the understanding of the molecular mechanisms involved in the development of melanoma has dramatically improved. The discovery of specific, causal mutations such as BRAF or KIT oncogenes not only renders a targeted and thus more effective therapeutic approach possible, but also gives rise to a new genetic-based classification. Targeting just a few out of several potential mutations, BRAF-Inhibitors such as PLX 4032 achieved already tremendous results in the therapy of metastatic melanoma. Up to now, the correlation of clinical, histomorphologic, and genetic features is, however, not understood. Even more, is it not well known precisely what kind of molecular changes predispose the primary melanoma for metastasis. The identification of morphological surrogates and prognostic parameters in tumors with such genetic alteration seems therefore crucial when differentiating and classifying this heterogeneous tumor entity in more detail and thus facilitates the stratification of prognosis as well as therapy. This review summarizes the current understanding of carcinogenesis and gives a detailed overview of known morphologic and potentially future genetic prognostic parameters in malignant melanoma.
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Fibroblast growth factor receptors as therapeutic targets in human melanoma: synergism with BRAF inhibition. J Invest Dermatol 2011; 131:2087-95. [PMID: 21753785 DOI: 10.1038/jid.2011.177] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Cutaneous melanoma is a tumor with rising incidence and a very poor prognosis at the disseminated stage. Melanomas are characterized by frequent mutations in BRAF and also by overexpression of fibroblast growth factor 2 (FGF2), offering opportunities for therapeutic intervention. We investigated inhibition of FGF signaling and its combination with dacarbazine or BRAF inhibitors as an antitumor strategy in melanoma. The majority of melanoma cell lines displayed overexpression of FGF2 but also FGF5 and FGF18 together with different isoforms of FGF receptors (FGFRs) 1-4. Blockade of FGF signals with dominant-negative receptor constructs (dnFGFR1, 3, or 4) or small-molecule inhibitors (SU5402 and PD166866) reduced melanoma cell proliferation, colony formation, as well as anchorage-independent growth, and increased apoptosis. DnFGFR constructs also significantly inhibited tumor growth in vivo. Combination of FGF inhibitors with dacarbazine showed additive or antagonistic effects, whereas synergistic drug interaction was observed when combining FGFR inhibition with the multikinase/BRAF inhibitor sorafenib or the V600E mutant-specific BRAF inhibitor RG7204. In conclusion, FGFR inhibition has antitumor effects against melanoma cells in vitro and in vivo. Combination with BRAF inhibition offers a potential for synergistic antimelanoma effects and represents a promising therapeutic strategy against advanced melanoma.
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42
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Yu W, Feng S, Dakhova O, Creighton CJ, Cai Y, Wang J, Li R, Frolov A, Ayala G, Ittmann M. FGFR-4 Arg³⁸⁸ enhances prostate cancer progression via extracellular signal-related kinase and serum response factor signaling. Clin Cancer Res 2011; 17:4355-66. [PMID: 21622724 DOI: 10.1158/1078-0432.ccr-10-2858] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
PURPOSE Increased expression of FGFR-4 and its ligands have been linked to lethal prostate cancer (PCa). Furthermore, a germ line polymorphism in the FGFR-4 gene, resulting in arginine at codon 388 (Arg³⁸⁸) instead of glycine (Gly³⁸⁸), is associated with aggressive disease. The FGFR-4 Arg³⁸⁸ variant results in increased receptor stability, sustained receptor activation, and increased motility and invasion compared with Gly³⁸⁸. However, the impact of sustained signaling on cellular signal transduction pathways is unknown. EXPERIMENTAL DESIGN Expression microarray analysis of immortalized prostatic epithelial cells lines expressing FGFR-4 Arg³⁸⁸ or Gly³⁸⁸ was used to establish a gene signature associated with FGFR-4 Arg³⁸⁸ expression. Transient transfection of reporters and inhibitors was used to establish the pathways activated by FGFR-4 Arg³⁸⁸ expression. The impact of pathway knockdown in vitro and in an orthotopic model was assessed using inhibitors and/or short hairpin RNA (shRNA). RESULTS Expression of the FGFR-4 Arg³⁸⁸ protein leads to increased activity of the extracellular signal-related kinase (ERK) pathway, increased activity of serum response factor (SRF) and AP1, and transcription of multiple genes that are correlated with aggressive clinical behavior in PCa. Increased expression of SRF is associated with biochemical recurrence in men undergoing radical prostatectomy. Consistent with these observations, knockdown of FGFR-4 Arg³⁸⁸ in PCa cells decreases proliferation and invasion in vitro and primary tumor growth and metastasis in vivo. CONCLUSIONS These studies define a signal transduction pathway downstream of FGFR-4 Arg³⁸⁸ that acts via ERK and SRF to promote PCa progression.
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Affiliation(s)
- Wendong Yu
- Department of Pathology, Baylor College of Medicine, Houston, Texas, USA
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43
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Heinzle C, Sutterlüty H, Grusch M, Grasl-Kraupp B, Berger W, Marian B. Targeting fibroblast-growth-factor-receptor-dependent signaling for cancer therapy. Expert Opin Ther Targets 2011; 15:829-46. [PMID: 21375471 DOI: 10.1517/14728222.2011.566217] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Fibroblast growth factors (FGF) exert a combination of biological effects that contribute to four of the six essential hallmarks of cancer. It is no surprise that FGF-dependent signaling has increasingly moved to the center of cancer therapy research during the past decade. This is illustrated by the large number of publications focusing on various aspects of this theme that have been published in the past 5 years. AREAS COVERED Information from these sources as well as ongoing work from the authors' groups is used to outline the physiological functions of FGF signaling and to highlight how the high oncogenic effects of deregulated FGFs and FGFRs derive from their physiological functions. The biological effect of deregulated FGFR signaling in malignant diseases is described and the current state of therapeutic targeting of FGFR is summarized. EXPERT OPINION Strategies for targeting FGFR-signaling for cancer therapy are very promising, but need to be carefully developed based on the physiological roles of FGF signaling. Preventive measures may be necessary for protection from FGF-related side effects. Combined targeting of several receptor tyrosine kinases or combination with other therapies may be a useful way of avoiding or ameliorating side effects. FGF-related markers of prognosis and therapy response still need to be investigated.
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Affiliation(s)
- Christine Heinzle
- Medical University Vienna, Institute of Cancer Research, Department of Medicine 1, Vienna,Austria
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Frey UH, Fritz A, Rotterdam S, Schmid KW, Potthoff A, Altmeyer P, Siffert W, Brockmeyer NH. GNAS1 T393C polymorphism and disease progression in patients with malignant melanoma. Eur J Med Res 2011; 15:422-7. [PMID: 21156401 PMCID: PMC3352186 DOI: 10.1186/2047-783x-15-10-422] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Background Once metastasized, despite a variety of therapeutic options, the prognosis of patients with malignant melanoma (MM) is still poor. Therefore, the search for reliable markers to identify patients with high risk of disease progression is of high clinical importance. We have recently shown that TT genotypes of the single-nucleotide polymorphism (SNP) T393C in the gene GNAS1 are significantly associated with better outcome in a variety of carcinomas. Patients In the present study we assessed whether the T393C SNP is also related to the clinical course in MM. 328 patients with MM were retrospectively genotyped and genotypes were correlated with clinical outcome. Results While the allele frequency in the MM group (fC 0.52) did not significantly differ from that of healthy blood donors, the T393C SNP was associated with tumor progression of MM. Carriers of the C-allele showed a significantly more severe tumor progression as estimated from the time period to develop metastasis (HR 2.2, 95% CI 1.1-3.2, p = 0.017). Proportions of 5-year metastasis-free intervals were 87.1% for TT genotypes and 66.0% for C-allele carriers. Moreover, multivariable Cox regression analysis including tumor stage and melanoma subtype proved the T393C polymorphism to be an independent factor for metastasis (p = 0.012). Conclusions In summary, the GNAS1 T393C SNP represents a genetic host factor for predicting tumor progression also in patients with MM; genotyping of this SNP may contribute to better define patients who could benefit from an early individualized therapy.
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Affiliation(s)
- U H Frey
- Institut für Pharmakogenetik, Universität Duisburg-Essen, Germany
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45
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Haugsten EM, Wiedlocha A, Olsnes S, Wesche J. Roles of fibroblast growth factor receptors in carcinogenesis. Mol Cancer Res 2010; 8:1439-52. [PMID: 21047773 DOI: 10.1158/1541-7786.mcr-10-0168] [Citation(s) in RCA: 229] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The fibroblast growth factor receptors (FGFR) play essential roles both during development and in the adult. Upon ligand binding, FGFRs induce intracellular signaling networks that tightly regulate key biological processes, such as cell proliferation, survival, migration, and differentiation. Deregulation of FGFR signaling can thus alter tissue homeostasis and has been associated with several developmental syndromes as well as with many types of cancer. In human cancer, FGFRs have been found to be deregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications. In this review, we will give an overview of the main FGFR alterations described in human cancer to date and discuss their contribution to cancer progression.
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Affiliation(s)
- Ellen Margrethe Haugsten
- Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway.
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46
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Sugiyama N, Varjosalo M, Meller P, Lohi J, Hyytiäinen M, Kilpinen S, Kallioniemi O, Ingvarsen S, Engelholm LH, Taipale J, Alitalo K, Keski-Oja J, Lehti K. Fibroblast growth factor receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to extracellular matrix degradation. Cancer Res 2010; 70:7851-61. [PMID: 20876804 DOI: 10.1158/0008-5472.can-10-1223] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aberrant expression and polymorphism of fibroblast growth factor receptor 4 (FGFR4) has been linked to tumor progression and anticancer drug resistance. We describe here a novel mechanism of tumor progression by matrix degradation involving epithelial-to-mesenchymal transition in response to membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14) induction at the edge of tumors expressing the FGFR4-R388 risk variant. Both FGFR4 and MT1-MMP were upregulated in tissue biopsies from several human cancer types including breast adenocarcinomas, where they were partially coexpressed at the tumor/stroma border and tumor invasion front. The strongest overall coexpression was found in prostate carcinoma. Studies with cultured prostate carcinoma cell lines showed that the FGFR4-R388 variant, which has previously been associated with poor cancer prognosis, increased MT1-MMP-dependent collagen invasion. In this experimental model, knockdown of FGFR4-R388 or MT1-MMP by RNA interference blocked tumor cell invasion and growth in collagen. This was coupled with impaired phosphorylation of FGFR substrate 2 and Src, upregulation of E-cadherin, and suppression of cadherin-11 and N-cadherin. These in vitro results were substantiated by reduced MT1-MMP content and in vivo growth of prostate carcinoma cells after the FGFR4-R388 gene silencing. In contrast, knockdown of the alternative FGFR4-G388 allele enhanced MT1-MMP and invasive tumor cell growth in vivo and within three-dimensional collagen. These results will help to explain the reported association of the FGFR4-R388 variant with the progression and poor prognosis of certain types of tumors.
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Affiliation(s)
- Nami Sugiyama
- Molecular Cancer Biology Research Program, Departments of Pathology and Virology, Haartman Institute, Helsinki, Finland
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Xu W, Li Y, Wang X, Chen B, Wang Y, Liu S, Xu J, Zhao W, Wu J. FGFR4 transmembrane domain polymorphism and cancer risk: a meta-analysis including 8555 subjects. Eur J Cancer 2010; 46:3332-8. [PMID: 20638838 DOI: 10.1016/j.ejca.2010.06.017] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Accepted: 06/14/2010] [Indexed: 12/22/2022]
Abstract
Fibroblast growth factor receptor 4 (FGFR4), belonging to the receptor tyrosine kinase family, is involved in cancer initiation and progression. The FGFR4 Gly388Arg polymorphism in the transmembrane domain of the receptor was shown to contribute to genetic susceptibility to cancer but the results were inconsistent. We performed a meta-analysis using 12 eligible case-control studies with a total of 4892 patients and 3663 controls to summarise the data on the association between the FGFR4 Gly388Arg polymorphism and cancer risks. The overall odds ratio (OR) with a 95% confidence interval (CI) showed statistical association between the FGFR4 Gly388Arg polymorphism and cancer risks under homozygote comparison, allele contrast and the recessive genetic model. In the subgroup analysis by ethnicity, statistically significantly increased cancer risks were found among Asians for homozygote comparison (OR = 1.43, 95% CI = 1.13-1.80, P(heterogeneity)=0.24), allele contrast (OR = 1.16, 95% CI = 1.04-1.29, P(heterogeneity) = 0.25) and the recessive genetic model (OR = 1.47, 95% CI = 1.19-1.81, P(heterogeneity) = 0.15). In the subgroup analysis for different tumour types, Arg(388) allele had an effect of increasing the risks of breast (homozygote comparison OR = 1.57, 95% CI = 1.04-2.37, P(heterogeneity) = 0.83 and the recessive model OR = 1.51, 95% CI = 1.02-2.24, P(heterogeneity) = 0.80) and prostate cancer (Gly/Arg versus Gly/Gly: OR = 1.16, 95% CI = 1.02-1.32, P(heterogeneity)=0.74; Arg versus Gly: OR = 1.17, 95% CI = 1.07-1.29, P(heterogeneity) = 0.18 and the dominant model: OR = 1.20, 95% CI = 1.06-1.35, P(heterogeneity) = 0.89). Our meta-analysis suggests that the FGFR4 Gly388Arg polymorphism most likely contributes to susceptibility to cancer, especially in Asians. Besides, the Arg(388) allele might be associated with increased risks of breast and prostate cancer.
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Affiliation(s)
- Wei Xu
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu, People's Republic of China
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An extended antibody microarray for surface profiling metastatic melanoma. J Immunol Methods 2010; 358:23-34. [PMID: 20363224 DOI: 10.1016/j.jim.2010.03.017] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2010] [Revised: 03/24/2010] [Accepted: 03/25/2010] [Indexed: 11/24/2022]
Abstract
An antibody microarray was developed for profiling the surface proteome of melanoma cells, which may facilitate melanoma sub-classification and provide important prognostic information useful in predicting the clinical behavior of the melanoma (e.g., likely sites of metastatic spread), patient outcome and treatment response. Forty-eight antibodies were selected based on their correlation with melanoma development, progression and/or prognosis and printed on nitrocellulose slides. The immobilised antibodies capture live cells expressing corresponding antigens to produce a cell binding dot pattern representing the surface antigen profile (immunophenotype) of the melanoma. Surface antigen signatures were determined for a normal melanocyte and 6 melanoma cell lines and cell suspensions prepared from 10 surgically excised melanoma lymph node metastases. A procedure for obtaining separate surface antigen profiles for melanoma cells and leukocytes from clinical lymph node samples was also developed using anti-CD45 magnetic beads. The capture of live, bead-bound leukocytes on these antibody microarrays provides a significant enhancement of this microarray technology. The antibody microarray will be used to profile panels of surgically excised melanoma lymph node metastases (melanoma and leukocyte fractions) to determine whether the immunophenotypes correlate with clinicopathological characteristics, disease progression and clinical outcome.
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49
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Sonvilla G, Allerstorfer S, Heinzle C, Stättner S, Karner J, Klimpfinger M, Wrba F, Fischer H, Gauglhofer C, Spiegl-Kreinecker S, Grasl-Kraupp B, Holzmann K, Grusch M, Berger W, Marian B. Fibroblast growth factor receptor 3-IIIc mediates colorectal cancer growth and migration. Br J Cancer 2010; 102:1145-56. [PMID: 20234367 PMCID: PMC2853090 DOI: 10.1038/sj.bjc.6605596] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background: Deregulation of fibroblast growth factor receptor 3 (FGFR3) is involved in several malignancies. Its role in colorectal cancer has not been assessed before. Methods: Expression of FGFR3 in human colorectal tumour specimens was analysed using splice variant-specific real-time reverse transcriptase PCR assays. To analyse the impact of FGFR3-IIIc expression on tumour cell biology, colon cancer cell models overexpressing wild-type (WT-3b and WT3c) or dominant-negative FGFR3 variants (KD3c and KD3b) were generated by either plasmid transfection or adenoviral transduction. Results: Although FGFR3 mRNA expression is downregulated in colorectal cancer, alterations mainly affected the FGFR3-IIIb splice variant, resulting in an increased IIIc/IIIb ratio predominantly in a subgroup of advanced tumours. Overexpression of WT3c increased proliferation, survival and colony formation in all colon cancer cell models tested, whereas WT3b had little activity. In addition, it conferred sensitivity to autocrine FGF18-mediated growth and migration signals in SW480 cells with low endogenous FGFR3-IIIc expression. Disruption of FGFR3-IIIc-dependent signalling by dominant-negative FGFR3-IIIc or small interfering RNA-mediated FGFR3-IIIc knockdown resulted in inhibition of cell growth and induction of apoptosis, which could not be observed when FGFR3-IIIb was blocked. In addition, KD3c expression blocked colony formation and migration and distinctly attenuated tumour growth in SCID mouse xenograft models. Conclusion: Our data show that FGFR3-IIIc exerts oncogenic functions by mediating FGF18 effects in colorectal cancer and may constitute a promising new target for therapeutic interventions.
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Affiliation(s)
- G Sonvilla
- Department of Medicine 1, Institute of Cancer Research, Medical University Vienna, Vienna, Austria
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Ribatti D, Annese T, Longo V. Angiogenesis and melanoma. Cancers (Basel) 2010; 2:114-32. [PMID: 24281035 PMCID: PMC3827594 DOI: 10.3390/cancers2010114] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2010] [Revised: 02/10/2010] [Accepted: 02/24/2010] [Indexed: 11/16/2022] Open
Abstract
Angiogenesis occurs in pathological conditions, such as tumors, where a specific critical point in tumor progression is the transition from the avascular to the vascular phase. Tumor angiogenesis depends mainly on the release by neoplastic cells of growth factors specific for endothelial cells, which are able to stimulate the growth of the host's blood vessels. This article summarizes the literature concerning the relationship between angiogenesis and human melanoma progression. The recent applications of antiangiogenic agents which interfere with melanoma progression are also described.
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Affiliation(s)
- Domenico Ribatti
- Department of Human Anatomy and Histology, University of Bari Medical School, Piazza G. Cesare, 11, Policlinico 70124, Bari, Italy.
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