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1
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Wang Y, Wu Y, Li L, Gao J, Gao DS, Sun S. GDNF triggers proliferation of rat C6 glioma cells via the NF-κB/CXCL1 signaling pathway. PLoS One 2023; 18:e0289071. [PMID: 37594930 PMCID: PMC10437914 DOI: 10.1371/journal.pone.0289071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 07/10/2023] [Indexed: 08/20/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor that is characterized by its high proliferative and migratory potential, leading to a high invasiveness of this tumor type. However, the underlying mechanism of GBM proliferation and migration has not been fully elucidated. In this study, at first, we used RNA-seq together with bioinformatics technology to screen for C-X-C motif ligand 1 (CXCL1) as a proliferation-related gene. And exogenous glial cell line-derived neurotrophic factor (GDNF) induced proliferation and up-regulated the level of CXCL1 in rat C6 glioma cells determined by sqPCR and ELISA. Then, we manipulated the CXCL1 expression by using a lentiviral vector (CXCL1-RNAi) approach. By this, the proliferation of C6 cells was decreased, suggesting that CXCL1 plays a key role in proliferation in these cells. We hypothesized that exogenous GDNF promoted NF-κB nuclear translocation and therefore, analyzed the interaction of CXCL1 with NF-κB by Western Blot and immunofluorescence. Additionally, we used BAY 11-7082, a phosphorylation inhibitor of NF-κB, to elucidate NF-κB mediated the effect of GDNF on CXCL1. These results demonstrated that GDNF enhanced the proliferation of rat C6 glioma cells through activating the NF-κB/CXCL1 signaling pathway. In summary, these studies not only revealed the mechanism of action of exogenous GDNF in promoting the proliferation of C6 glioma cells but may also provide a new biological target for the treatment of malignant glioma.
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Affiliation(s)
- Yue Wang
- National Demonstration Center for Experimental Basic Medical Science Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yue Wu
- Department of Neurobiology and Anatomy, Xuzhou Key Laboratory of Neurobiology, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Li Li
- Department of Pathophysiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jin Gao
- Department of Cell Biology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Dian Shuai Gao
- Department of Neurobiology and Anatomy, Xuzhou Key Laboratory of Neurobiology, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Shen Sun
- National Demonstration Center for Experimental Basic Medical Science Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Histology and Embryology, Xuzhou Medical University, Xuzhou, Jiangsu, China
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2
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Chen Z, Fang Y, Jiang W. Important Cells and Factors from Tumor Microenvironment Participated in Perineural Invasion. Cancers (Basel) 2023; 15:1360. [PMID: 36900158 PMCID: PMC10000249 DOI: 10.3390/cancers15051360] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/09/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
Perineural invasion (PNI) as the fourth way for solid tumors metastasis and invasion has attracted a lot of attention, recent research reported a new point that PNI starts to include axon growth and possible nerve "invasion" to tumors as the component. More and more tumor-nerve crosstalk has been explored to explain the internal mechanism for tumor microenvironment (TME) of some types of tumors tends to observe nerve infiltration. As is well known, the interaction of tumor cells, peripheral blood vessels, extracellular matrix, other non-malignant cells, and signal molecules in TME plays a key role in the occurrence, development, and metastasis of cancer, as to the occurrence and development of PNI. We aim to summarize the current theories on the molecular mediators and pathogenesis of PNI, add the latest scientific research progress, and explore the use of single-cell spatial transcriptomics in this invasion way. A better understanding of PNI may help to understand tumor metastasis and recurrence and will be beneficial for improving staging strategies, new treatment methods, and even paradigm shifts in our treatment of patients.
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Affiliation(s)
- Zirong Chen
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- Anatomy Laboratory of Division of Nose and Cranial Base, Clinical Anatomy Center of Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yan Fang
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- Anatomy Laboratory of Division of Nose and Cranial Base, Clinical Anatomy Center of Xiangya Hospital, Central South University, Changsha 410008, China
| | - Weihong Jiang
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- Anatomy Laboratory of Division of Nose and Cranial Base, Clinical Anatomy Center of Xiangya Hospital, Central South University, Changsha 410008, China
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Hurník P, Chyra Z, Ševčíková T, Štembírek J, Trtková KS, Gaykalova DA, Buchtová M, Hrubá E. Epigenetic Regulations of Perineural Invasion in Head and Neck Squamous Cell Carcinoma. Front Genet 2022; 13:848557. [PMID: 35571032 PMCID: PMC9091179 DOI: 10.3389/fgene.2022.848557] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/09/2022] [Indexed: 11/13/2022] Open
Abstract
Carcinomas of the oral cavity and oropharynx belong among the ten most common malignancies in the human population. The prognosis of head and neck squamous cell carcinoma (HNSCC) is determined by the degree of invasiveness of the primary tumor and by the extent of metastatic spread into regional and distant lymph nodes. Moreover, the level of the perineural invasion itself associates with tumor localization, invasion's extent, and the presence of nodal metastases. Here, we summarize the current knowledge about different aspects of epigenetic changes, which can be associated with HNSCC while focusing on perineural invasion (PNI). We review epigenetic modifications of the genes involved in the PNI process in HNSCC from the omics perspective and specific epigenetic modifications in OSCC or other neurotropic cancers associated with perineural invasion. Moreover, we summarize DNA methylation status of tumor-suppressor genes, methylation and demethylation enzymes and histone post-translational modifications associated with PNI. The influence of other epigenetic factors on the HNSCC incidence and perineural invasion such as tobacco, alcohol and oral microbiome is overviewed and HPV infection is discussed as an epigenetic factor associated with OSCC and related perineural invasion. Understanding epigenetic regulations of axon growth that lead to tumorous spread or uncovering the molecular control of axon interaction with cancer tissue can help to discover new therapeutic targets for these tumors.
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Affiliation(s)
- Pavel Hurník
- Department of Clinical and Molecular Pathology and Medical Genetics, Faculty of Medicine and University Hospital Ostrava, Ostrava, Czechia
- Department of Histology and Embryology, Medical Faculty, Masaryk University, Brno, Czechia
| | - Zuzana Chyra
- Department of Hematooncology, University Hospital Ostrava, Ostrava, Czechia
| | - Tereza Ševčíková
- Department of Hematooncology, University Hospital Ostrava, Ostrava, Czechia
| | - Jan Štembírek
- Department of Maxillofacial Surgery, University Hospital Ostrava, Ostrava, Czechia
- Laboratory of Molecular Morphogenesis, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czechia
| | - Kateřina Smešný Trtková
- Department of Clinical and Molecular Pathology and Medical Genetics, Faculty of Medicine and University Hospital Ostrava, Ostrava, Czechia
- Department of Clinical and Molecular Pathology, Faculty of Medicine and University Hospital Olomouc, Olomouc, Czechia
| | - Daria A. Gaykalova
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland Medical Center, Baltimore, MD, United States
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, MD, United States
- Institute for Genome Sciences, University of Maryland Medical Center, Baltimore, MD, United States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States
| | - Marcela Buchtová
- Laboratory of Molecular Morphogenesis, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czechia
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
| | - Eva Hrubá
- Laboratory of Molecular Morphogenesis, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czechia
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
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Roda N, Blandano G, Pelicci PG. Blood Vessels and Peripheral Nerves as Key Players in Cancer Progression and Therapy Resistance. Cancers (Basel) 2021; 13:cancers13174471. [PMID: 34503281 PMCID: PMC8431382 DOI: 10.3390/cancers13174471] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The interactions between cancer cells and the surrounding blood vessels and peripheral nerves are critical in all the phases of tumor development. Accordingly, therapies that specifically target vessels and nerves represent promising anticancer approaches. The first aim of this review is to document the importance of blood vessels and peripheral nerves in both cancer onset and local or distant growth of tumoral cells. We then focus on the state-of-the-art therapies that limit cancer progression through the impairment of blood vessels and peripheral nerves. The mentioned literature is helpful for the scientific community to appreciate the recent advances in these two fundamental components of tumors. Abstract Cancer cells continuously interact with the tumor microenvironment (TME), a heterogeneous milieu that surrounds the tumor mass and impinges on its phenotype. Among the components of the TME, blood vessels and peripheral nerves have been extensively studied in recent years for their prominent role in tumor development from tumor initiation. Cancer cells were shown to actively promote their own vascularization and innervation through the processes of angiogenesis and axonogenesis. Indeed, sprouting vessels and axons deliver several factors needed by cancer cells to survive and proliferate, including nutrients, oxygen, and growth signals, to the expanding tumor mass. Nerves and vessels are also fundamental for the process of metastatic spreading, as they provide both the pro-metastatic signals to the tumor and the scaffold through which cancer cells can reach distant organs. Not surprisingly, continuously growing attention is devoted to the development of therapies specifically targeting these structures, with promising initial results. In this review, we summarize the latest evidence that supports the importance of blood vessels and peripheral nerves in cancer pathogenesis, therapy resistance, and innovative treatments.
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Affiliation(s)
- Niccolò Roda
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; (N.R.); (G.B.)
| | - Giada Blandano
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; (N.R.); (G.B.)
| | - Pier Giuseppe Pelicci
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; (N.R.); (G.B.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
- Correspondence:
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5
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Unveiling the pathogenesis of perineural invasion from the perspective of neuroactive molecules. Biochem Pharmacol 2021; 188:114547. [PMID: 33838132 DOI: 10.1016/j.bcp.2021.114547] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/13/2022]
Abstract
Perineural invasion (PNI) is characterized by an encounter between the cancer cells and neuronal fibers and holds an extremely poor prognosis for malignant tumors. The exact molecular mechanism behind PNI yet remains to be explored. However, it is worth-noting that an involvement of the neuroactive molecules plays a major part in this process. A complex signaling network comprising the interplay between immunological cascades and neurogenic molecules such as tumor-derived neurotrophins, neuromodulators, and growth factors constitutes an active microenvironment for PNI associated with malignancy. The present review aims at discussing the following points in relation to PNI: a) Communication between PNI and neuroplasticity mechanisms can explain the pathophysiology of poor, short and long-term outcomes in cancer patients; b) Neuroactive molecules can significantly alter the neurons and cancer cells so as to sustain PNI progression; c) Finally, careful manipulation of neurogenic pathways and/or their crosstalk with the immunological molecules implicated in PNI could provide a potential breakthrough in cancer therapeutics.
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6
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Hunt PJ, Andújar FN, Silverman DA, Amit M. Mini-review: Trophic interactions between cancer cells and primary afferent neurons. Neurosci Lett 2021; 746:135658. [PMID: 33482305 PMCID: PMC7899767 DOI: 10.1016/j.neulet.2021.135658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 01/05/2021] [Accepted: 01/11/2021] [Indexed: 10/22/2022]
Abstract
Cancer neurobiology is an emerging discipline that inevitably unfurls new perspectives in oncology. The role that nerves play in cancer progression resonates with the long-reported dependency of tumors on neuro-molecular mechanisms that remain insufficiently elucidated. Whereas interactions between neurotrophic growth factors and receptors have been heavily studied in the nervous system, their expression in cancers and their impact on tumor cell growth and metastasis through their corresponding signaling pathways has been undervalued. Accumulating evidence suggests that trophic factors released by nerves strongly influence tumor development and that this neural contribution appears to not only play a stimulatory role but also function as an essential part of the tumor's microenvironment. This bidirectional communication between proliferating cells and tumor-infiltrating nerves drives axonogenesis and tumor growth and migration. Acquiring a better understanding of the trophic interactions between primary afferent neurons and invading tumors will guide clinically actionable strategies to prevent tumor-associated axonogenesis, disrupting the chemical crosstalk between neurons and tumors and ultimately decreasing tumor growth and spread.
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Affiliation(s)
- Patrick J Hunt
- Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, United States; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United States.
| | - Fabiola N Andújar
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United States; Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Deborah A Silverman
- University of Texas Medical Scientist Training Program at Houston, Houston, TX, United States; Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Moran Amit
- Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
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7
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Liu L, Zhao L, Zhang J, Song G, Shields CL, Wei R. Aberrantly expressed GFRα-1/RET in patients with lacrimal adenoid cystic carcinoma is associated with high recurrence risk: a retrospective study of 51 LACC cases. Cancer Biol Med 2021; 18:199-205. [PMID: 33628594 PMCID: PMC7877180 DOI: 10.20892/j.issn.2095-3941.2020.0271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/16/2020] [Indexed: 12/19/2022] Open
Abstract
Objective: Because of the poor prognosis of lacrimal adenoid cystic carcinoma (LACC), we aimed to investigate the effects of perineural invasion (PNI) and consequent aberrations in GDNF/GFRα-1/RET protein expression on LACC recurrence. Methods: Clinicopathological data for 51 histologically confirmed patients with LACC enrolled between 2001 and 2017 were retrospectively analyzed. Hematoxylin and eosin staining was applied to assess PNI. Tissue-based immunohistochemistry (IHC) detection of GDNF, GFRα-1, and RET proteins was performed on LACC formalin-fixed, paraffin-embedded specimens. We generated semi-quantitative data of the IHC results and compared them with the clinicopathological data for the 51 patients. Results: Of the 51 patients, 19 (37.3%) were PNI positive. Recurrence was more common for LACC with than without PNI (73.7% vs. 37.5%, P = 0.01). GDNF, GFRα-1, and RET proteins were expressed in 62.7%, 62.7%, and 54.9% of the 51 patients with LACC, respectively. The expression of all 3 proteins was more common in patients with than without PNI. In agreement with previous findings, PNI-associated GFRα-1 and RET positivity, as detected by IHC, remained significantly associated with recurrence, whereas GDNF expression, as detected by IHC, was not correlated with LACC recurrence. Specifically, patients with concurrent GFRα-1 and RET expression may have a high risk of PNI (89.5% positivity rate) and recurrence (84.2% positivity rate). Conclusions: PNI may contribute to LACC recurrence. The concurrent expression of GFRα-1 and RET proteins, as detected by IHC, may potentially be associated with LACC PNI and recurrence.
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Affiliation(s)
- Lin Liu
- Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China
| | - Liqiong Zhao
- Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China
| | - Jie Zhang
- Tianjin Orbit Institute, Ophthalmology Department, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Guoxiang Song
- Tianjin Orbit Institute, Ophthalmology Department, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Carol L Shields
- Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia 19107, PA, USA
| | - Ruihua Wei
- Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China
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Choi YD, Jung JY, Baek M, Khan S, Song PI, Ryu S, Koo JY, Chauhan SC, Tsin A, Choi C, Kim WJ, Kim M. APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF. Int J Mol Sci 2020; 21:E3586. [PMID: 32438692 PMCID: PMC7279477 DOI: 10.3390/ijms21103586] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/15/2020] [Accepted: 05/17/2020] [Indexed: 12/21/2022] Open
Abstract
Pancreatic cancer is the worst exocrine gastrointestinal cancer leading to the highest mortality. Recent studies reported that aberrant expression of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is involved in uncontrolled cell growth. However, the molecular mechanism of APE1 biological role remains unrevealed in pancreatic cancer progression. Here, we demonstrate that APE1 accelerates pancreatic cancer cell proliferation through glial cell line-derived neurotrophic factor (GDNF)/glial factor receptor α1 (GFRα1)/Src/ERK axis-cascade signaling. The proliferation of endogenous APE1 expressed-MIA PaCa-2, a human pancreatic carcinoma cell line, was increased by treatment with GDNF, a ligand of GFRα1. Either of downregulated APE1 or GFRα1 expression using small interference RNA (siRNA) inhibited GDNF-induced cancer cell proliferation. The MEK-1 inhibitor PD98059 decreased GDNF-induced MIA PaCa-2 cell proliferation. Src inactivation by either its siRNA or Src inhibitor decreased ERK-phosphorylation in response to GDNF in MIA PaCa-2 cells. Overexpression of GFRα1 in APE1-deficient MIA PaCa-2 cells activated the phosphorylation of Src and ERK. The expression of both APE1 and GFRα1 was gradually increased as progressing pancreatic cancer grades. Our results highlight a critical role for APE1 in GDNF-induced pancreatic cancer cell proliferation through APE1/GFRα1/Src/ERK axis-cascade signaling and provide evidence for future potential therapeutic drug targets for the treatment of pancreatic cancer.
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Affiliation(s)
- Yoo-Duk Choi
- Department of Pathology, Chonnam National University Medical School, Gwangju 61186, Korea; (Y.-D.C.); (J.-Y.K.)
| | - Ji-Yeon Jung
- Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 61186, Korea;
| | - Minwoo Baek
- Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, MN 55812, USA;
| | - Sheema Khan
- Department of Immunology & Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; (S.K.); (S.C.C.)
| | - Peter I. Song
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; (P.I.S.); (A.T.)
| | - Sunhyo Ryu
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University Medical Campus, Boston, MA 02118, USA;
| | - Joo-Yeon Koo
- Department of Pathology, Chonnam National University Medical School, Gwangju 61186, Korea; (Y.-D.C.); (J.-Y.K.)
| | - Subhash C. Chauhan
- Department of Immunology & Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; (S.K.); (S.C.C.)
| | - Andrew Tsin
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; (P.I.S.); (A.T.)
| | - Chan Choi
- Department of Pathology, Chonnam National University Hwasun Hospital, Hwasun 58128, Korea;
| | - Won Jae Kim
- Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 61186, Korea;
| | - Mihwa Kim
- Department of Pathology, Chonnam National University Medical School, Gwangju 61186, Korea; (Y.-D.C.); (J.-Y.K.)
- Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 61186, Korea;
- Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA; (P.I.S.); (A.T.)
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Ma WR, Xu P, Liu ZJ, Zhou J, Gu LK, Zhang J, Deng DJ. Impact of GFRA1 gene reactivation by DNA demethylation on prognosis of patients with metastatic colon cancer. World J Gastroenterol 2020; 26:184-198. [PMID: 31988584 PMCID: PMC6962434 DOI: 10.3748/wjg.v26.i2.184] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 12/14/2019] [Accepted: 12/23/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The expression of the membrane receptor protein GFRA1 is frequently upregulated in many cancers, which can promote cancer development by activating the classic RET-RAS-ERK and RET-RAS-PI3K-AKT pathways. Several therapeutic anti-GFRA1 antibody-drug conjugates are under development. Demethylation (or hypomethylation) of GFRA1 CpG islands (dmGFRA1) is associated with increased gene expression and metastasis risk of gastric cancer. However, it is unknown whether dmGFRA1 affects the metastasis of other cancers, including colon cancer (CC).
AIM To study whether dmGFRA1 is a driver for CC metastasis and GFRA1 is a potential therapeutic target.
METHODS CC and paired surgical margin tissue samples from 144 inpatients and normal colon mucosal biopsies from 21 noncancer patients were included in this study. The methylation status of GFRA1 islands was determined by MethyLight and denaturing high-performance liquid chromatography and bisulfite-sequencing. Kaplan-Meier analysis was used to explore the effect of dmGFRA1 on the survival of CC patients. Impacts of GFRA1 on CC cell proliferation and migration were evaluated by a battery of biological assays in vitro and in vivo. The phosphorylation of AKT and ERK proteins was examined by Western blot analysis.
RESULTS The proportion of dmGFRA1 in CC, surgical margin, and normal colon tissues by MethyLight was 68.4%, 73.4%, and 35.9% (median; nonparametric test, P = 0.001 and < 0.001), respectively. Using the median value of dmGFRA1 peak area proportion as the cutoff, the proportion of dmGFRA1-high samples was much higher in poorly differentiated CC samples than in moderately or well-differentiated samples (92.3%% vs 55.8%, Chi-square test, P = 0.002) and significantly higher in CC samples with distant metastasis than in samples without (77.8% vs 46.0%, P = 0.021). The overall survival of patients with dmGFRA1-low CC was significantly longer than that of patients with dmGFRA1-high CC (adjusted hazard ratio = 0.49, 95% confidence interval: 0.24-0.98), especially for 89 CC patients with metastatic CC (adjusted hazard ratio = 0.41, 95% confidence interval: 0.18-0.91). These data were confirmed by the mining results from TCGA datasets. Furthermore, GFRA1 overexpression significantly promoted the proliferation/invasion of RKO and HCT116 cells and the growth of RKO cells in nude mice but did not affect their migration. GFRA1 overexpression markedly increased the phosphorylation levels of AKT and ERK proteins, two key molecules in two classic GFRA1 downstream pathways.
CONCLUSION GFRA1 expression is frequently reactivated by DNA demethylation in CC tissues and is significantly associated with a poor prognosis in patients with CC, especially those with metastatic CC. GFRA1 can promote the proliferation/growth of CC cells, probably by the activation of AKT and ERK pathways. GFRA1 might be a therapeutic target for CC patients, especially those with metastatic potential.
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Affiliation(s)
- Wan-Ru Ma
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100143, China
| | - Peng Xu
- Shihezi University School of Medicine, Shihezi 832000, Xinjiang Uygur Autonomous Region, China
- Morphological Center of Basic Medical School of Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China
| | - Zhao-Jun Liu
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100143, China
| | - Jing Zhou
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100143, China
| | - Lian-Kun Gu
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100143, China
| | - Jun Zhang
- Shihezi University School of Medicine, Shihezi 832000, Xinjiang Uygur Autonomous Region, China
| | - Da-Jun Deng
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100143, China
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10
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Ayanlaja AA, Zhang B, Ji G, Gao Y, Wang J, Kanwore K, Gao D. The reversible effects of glial cell line-derived neurotrophic factor (GDNF) in the human brain. Semin Cancer Biol 2018; 53:212-222. [PMID: 30059726 DOI: 10.1016/j.semcancer.2018.07.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 07/10/2018] [Accepted: 07/18/2018] [Indexed: 12/20/2022]
Abstract
Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor, and a member of the transforming growth factor β (TGF-β) superfamily acting on different neuronal activities. GDNF was originally identified as a neurotrophic factor crucially involved in the survival of dopaminergic neurons of the nigrostriatal pathway and is currently an established therapeutic target in Parkinson's disease. However, GDNF was later reported to be highly expressed in gliomas, especially in glioblastomas, and was demonstrated as a potent proliferation factor involved in the development and migration of gliomas. Here, we review our current understanding and progress made so far by researchers in our laboratories with references to relevant articles to support our discoveries. We present past and recent discoveries on the mechanisms involved in the protection of neurons by GDNF and examine its emerging roles in gliomas, as well as reasons for the abnormal expression in Glioblastoma Multiforme (GBM). Collectively, our work establishes a paradigm by which the ability of GDNF to protect dopaminergic neurons from degradation and its corresponding effects on glioma cells points to an underlying biological vulnerability in the effects of GDNF in the normal brain which can be subverted for use by cancer cells. Hence, presenting novel opportunities for intervention in glioma therapies.
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Affiliation(s)
- Abiola Abdulrahman Ayanlaja
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Baole Zhang
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - GuangQuan Ji
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Yue Gao
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Jie Wang
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Kouminin Kanwore
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - DianShuai Gao
- Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
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Abstract
Recent studies have demonstrated a critical role for nerves in enabling tumor progression. The association of nerves with cancer cells is well established for a variety of malignant tumors, including pancreatic, prostate and the head and neck cancers. This association is often correlated with poor prognosis. A strong partnership between cancer cells and nerve cells leads to both cancer progression and expansion of the nerve network. This relationship is supported by molecular pathways related to nerve growth and repair. Peripheral nerves form complex tumor microenvironments, which are made of several cell types including Schwann cells. Recent studies have revealed that Schwann cells enable cancer progression by adopting a de-differentiated phenotype, similar to the Schwann cell response to nerve trauma. A detailed understanding of the molecular and cellular mechanisms involved in the regulation of cancer progression by the nerves is essential to design strategies to inhibit tumor progression.
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12
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Baspinar S, Bircan S, Ciris M, Karahan N, Bozkurt KK. Expression of NGF, GDNF and MMP-9 in prostate carcinoma. Pathol Res Pract 2017; 213:483-489. [PMID: 28237042 DOI: 10.1016/j.prp.2017.02.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 02/05/2017] [Accepted: 02/06/2017] [Indexed: 12/23/2022]
Abstract
The aim of the present study was to investigate the immunohistochemical expression of NGF, GDNF and MMP-9 in benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN) and prostate cancer (PC), and to analyse their association with the clinicopathological parameters in PC cases. Immunohistochemistry was performed on the tissue microarray (TMA) sections of 30 BPH, 40 HGPIN and 121 primary PC tissues. There was a significant difference regarding the expression of NGF and GDNF between PC and HGPIN (p<0.0001; p<0.0001), and PC and BPH (p=0.001; p<0.0001), but not between HGPIN and BPH (p>0.05). Furthermore MMP-9 expression was significantly different among all groups (PC vs. HGPIN, p<0.0001; PC vs. BPH, p<0.0001; HGPIN vs. BPH, p=0.001). NGF, GDNF and MMP-9 expression was significantly stronger in cases with high Gleason score (p<0.0001, p=0.004, p<0.0001 respectively) and pT stage (p=0.046, p=0.004, p=0.001, respectively) in PC cases. All these markers were also associated with perineural, lymphovascular and extraprostatic invasion (p <0.05). In addition, a positive correlation was found between NGF and MMP-9 (p<0.0001, r=0.435), NGF and GDNF (p<0.0001, r=0.634), and GDNF and MMP-9 (p<0.0001, r=0.670) in PC cases. According to our results we suggest an interaction between NGF, GDNF and MMP-9 during the transition to malignancy in PC. Also this interaction may involve in regulating PC cell differentiation, tumor invasion, progression, and the agressiveness of PC.
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Affiliation(s)
- Sirin Baspinar
- Suleyman Demirel University School of Medicine, Department of Pathology, Isparta, Turkey.
| | - Sema Bircan
- Suleyman Demirel University School of Medicine, Department of Pathology, Isparta, Turkey
| | - Metin Ciris
- Suleyman Demirel University School of Medicine, Department of Pathology, Isparta, Turkey
| | - Nermin Karahan
- Suleyman Demirel University School of Medicine, Department of Pathology, Isparta, Turkey
| | - Kemal Kursat Bozkurt
- Suleyman Demirel University School of Medicine, Department of Pathology, Isparta, Turkey
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13
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Abstract
The local extension of cancer cells along nerves is a frequent clinical finding for various tumours. Traditionally, nerve invasion was assumed to occur via the path of least resistance; however, recent animal models and human studies have revealed that cancer cells have an innate ability to actively migrate along axons in a mechanism called neural tracking. The tendency of cancer cells to track along nerves is supported by various cell types in the perineural niche that secrete multiple growth factors and chemokines. We propose that the perineural niche should be considered part of the tumour microenvironment, describe the molecular cues that facilitate neural tracking and suggest methods for its inhibition.
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Affiliation(s)
- Moran Amit
- Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion-Israel Institute of Technology, Haalia Street No. 8, Haifa, Israel
| | - Shorook Na'ara
- Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion-Israel Institute of Technology, Haalia Street No. 8, Haifa, Israel
| | - Ziv Gil
- Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion-Israel Institute of Technology, Haalia Street No. 8, Haifa, Israel
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14
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Kessler ER, Eckhardt SG, Pitts TM, Bradshaw-Pierce EL, O'byrant CL, Messersmith WA, Nallapreddy S, Weekes C, Spratlin J, Lieu CH, Kane MA, Eppers S, Freas E, Leong S. Phase I trial of vandetanib in combination with gemcitabine and capecitabine in patients with advanced solid tumors with an expanded cohort in pancreatic and biliary cancers. Invest New Drugs 2015; 34:176-83. [PMID: 26715573 DOI: 10.1007/s10637-015-0316-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 12/14/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Vandetanib is a multitargeted tyrosine kinase inhibitor that affects vascular endothelial growth factor receptor (VEGF), epidermal growth factor (EGF), and rearranged during transfection (RET) mediated receptors which are important for growth and invasion of biliary and pancreatic cancers. This phase I study evaluated the safety profile of vandetanib in combination with standard doses of gemcitabine and capecitabine in order to determine the maximum tolerated dose (MTD). METHODS In this single center phase I trial, patients received gemcitabine intravenously (i.v.) at 1000 mg/m2 days 1, 8, 15 in a 28 day cycle, capecitabine orally at 850 mg/m2 twice daily on days 1-21, and escalating doses of vandetanib (200 or 300 mg orally daily). Once the MTD was defined, an expansion cohort of patients with advanced biliary cancers and locally advanced or metastatic pancreatic cancer was enrolled. Blood samples were also collected at predetermined time points for biomarker analysis. RESULTS Twenty-three patients were enrolled: 9 in the dose escalation and 14 in the dose expansion cohort. One dose limiting toxicity (DLT), of grade 4 neutropenia, occurred in the 200 mg vandetanib cohort. The most common adverse effects were diarrhea (39 %), nausea and vomiting (34%), and rash (33%). There were 3 partial responses and stable disease of >2 months (range 2-45, median 5) was observed in 15/23 patients. There was no association between changes in biomarker analytes and disease response. CONCLUSION The combination of gemcitabine, capecitabine and vandetanib is well tolerated at the recommended phase II dose of gemcitabine 1000 mg/m2 weekly for three consecutive weeks, capecitabine 850 mg/m2 BID days 1-21, and vandetanib 300 mg daily, every 28 days. This combination demonstrated promising activity in pancreaticobiliary cancers and further evaluation is warranted in these diseases. NCT00551096.
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Affiliation(s)
- Elizabeth R Kessler
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.,University of Colorado Cancer Center, Aurora, Colorado, USA
| | - S Gail Eckhardt
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.,University of Colorado Cancer Center, Aurora, Colorado, USA
| | - Todd M Pitts
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.,University of Colorado Cancer Center, Aurora, Colorado, USA
| | - Erica L Bradshaw-Pierce
- University of Colorado Cancer Center, Aurora, Colorado, USA.,Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, Aurora, CO, USA
| | - Cindy L O'byrant
- Department of Clinical Pharmacy, Skaggs School of Pharmacy, Aurora, CO, USA
| | - Wells A Messersmith
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.,University of Colorado Cancer Center, Aurora, Colorado, USA
| | - Sujatha Nallapreddy
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.,University of Colorado Cancer Center, Aurora, Colorado, USA
| | - Colin Weekes
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.,University of Colorado Cancer Center, Aurora, Colorado, USA
| | | | - Christopher H Lieu
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.,University of Colorado Cancer Center, Aurora, Colorado, USA
| | - Madeleine A Kane
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.,University of Colorado Cancer Center, Aurora, Colorado, USA
| | - Sarah Eppers
- University of Colorado Cancer Center, Aurora, Colorado, USA
| | | | - Stephen Leong
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA. .,University of Colorado Cancer Center, Aurora, Colorado, USA.
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15
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Perineural growth in head and neck squamous cell carcinoma: a review. Oral Oncol 2014; 51:16-23. [PMID: 25456006 DOI: 10.1016/j.oraloncology.2014.10.004] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Revised: 09/30/2014] [Accepted: 10/06/2014] [Indexed: 02/07/2023]
Abstract
Perineural growth is a unique route of tumor metastasis that is associated with poor prognosis in several solid malignancies. It is diagnosed by the presence of tumor cells inside the neural space seen on histological or imaging evaluations. Little is known about molecular mechanisms involved in the growth and spread of tumor cells in neural spaces. The poor prognosis associated with perineural growth and lack of targeted approaches necessitates the study of molecular factors involved in communication between tumor and neural cells. Perineural growth rates, shown to be as high as 63% in head and neck squamous cell carcinoma (HNSCC), correlate with increased local recurrence and decreased disease-free survival. Here we describe the literature on perineural growth in HNSCC. In addition, we discuss factors implicated in perineural growth of cancer. These factors include brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 and -4, glial cell-line derived neurotrophic factor (GDNF), the neural cell adhesion molecule (NCAM), substance P (SP), and chemokines. We also explore the literature on membrane receptors, including the Trk family and the low-affinity nerve growth factor receptor. This review highlights areas for further study of the mechanisms of perineural invasion which may facilitate the identification of therapeutic targets in HNSCC.
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16
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Liu Z, Zhang J, Gao Y, Pei L, Zhou J, Gu L, Zhang L, Zhu B, Hattori N, Ji J, Yuasa Y, Kim W, Ushijima T, Shi H, Deng D. Large-scale characterization of DNA methylation changes in human gastric carcinomas with and without metastasis. Clin Cancer Res 2014; 20:4598-612. [PMID: 25009298 PMCID: PMC4309661 DOI: 10.1158/1078-0432.ccr-13-3380] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE Metastasis is the leading cause of death for gastric carcinoma. An epigenetic biomarker panel for predicting gastric carcinoma metastasis could have significant clinical impact on the care of patients with gastric carcinoma. The main purpose of this study is to characterize the methylation differences between gastric carcinomas with and without metastasis. EXPERIMENTAL DESIGN Genome-wide DNA methylation profiles between 4 metastatic and 4 nonmetastatic gastric carcinomas and their surgical margins (SM) were analyzed using methylated-CpG island amplification with microarray. The methylation states of 73 candidate genes were further analyzed in patients with gastric carcinoma in a discovery cohort (n=108) using denatured high performance liquid chromatography, bisulfite-sequencing, and MethyLight. The predictive values of potential metastasis-methylation biomarkers were validated in cohorts of patients with gastric carcinoma in China (n=330), Japan (n=129), and Korea (n=153). RESULTS The gastric carcinoma genome showed significantly higher proportions of hypomethylation in the promoter and exon-1 regions, as well as increased hypermethylation of intragenic fragments when compared with SMs. Significant differential methylation was validated in the CpG islands of 15 genes (P<0.05) and confirmed using bisulfite sequencing. These genes included BMP3, BNIP3, CDKN2A, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, and ZNF382. Methylation changes of GFRA1, SRF, and ZNF382 resulted in up- or downregulation of their transcription. Most importantly, the prevalence of GFRA1, SRF, and ZNF382 methylation alterations was consistently and coordinately associated with gastric carcinoma metastasis and the patients' overall survival throughout discovery and validation cohorts in China, Japan, and Korea. CONCLUSION Methylation changes of GFRA1, SRF, and ZNF382 may be a potential biomarker set for prediction of gastric carcinoma metastasis.
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Affiliation(s)
- Zhaojun Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Etiology, Peking University Cancer Hospital and Institute, Fu-Cheng-Lu, Beijing, China
| | - Jun Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Etiology, Peking University Cancer Hospital and Institute, Fu-Cheng-Lu, Beijing, China. Shihezi University School of Medicine, Shihezi, China
| | - Yanhong Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Etiology, Peking University Cancer Hospital and Institute, Fu-Cheng-Lu, Beijing, China
| | - Lirong Pei
- GRU Cancer Center, Georgia Regents University, Augusta, Georgia
| | - Jing Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Etiology, Peking University Cancer Hospital and Institute, Fu-Cheng-Lu, Beijing, China
| | - Liankun Gu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Etiology, Peking University Cancer Hospital and Institute, Fu-Cheng-Lu, Beijing, China
| | - Lianhai Zhang
- Department of Surgery, Peking University Cancer Hospital and Institute, Fu-Cheng-Lu, Beijing, China
| | - Budong Zhu
- Department of Oncology, Peking University Cancer Hospital and Institute, Fu-Cheng-Lu, Beijing, China
| | - Naoko Hattori
- Division of Epigenetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Jiafu Ji
- Department of Surgery, Peking University Cancer Hospital and Institute, Fu-Cheng-Lu, Beijing, China
| | - Yasuhito Yuasa
- Department of Molecular Oncology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Wooho Kim
- Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea
| | - Toshikazu Ushijima
- Division of Epigenetics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Huidong Shi
- GRU Cancer Center, Georgia Regents University, Augusta, Georgia.
| | - Dajun Deng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Etiology, Peking University Cancer Hospital and Institute, Fu-Cheng-Lu, Beijing, China.
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17
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Li S, Sun Y, Gao D. Role of the nervous system in cancer metastasis. Oncol Lett 2013; 5:1101-1111. [PMID: 23599747 PMCID: PMC3629128 DOI: 10.3892/ol.2013.1168] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Accepted: 10/17/2012] [Indexed: 12/17/2022] Open
Abstract
The notion that tumors lack innervation was proposed several years ago. However, nerve fibers are irregulatedly found in some tumor tissues. Their terminals interaction with cancer cells are considered to be neuro-neoplastic synapses. Moreover, neural-related factors, which are important players in the development and activity of the nervous system, have been found in cancer cells. Thus, they establish a direct connection between the nervous system and tumor cells. They modulate the process of metastasis, including degradation of base membranes, cancer cell invasion, migration, extravasation and colonization. Peripheral nerve invasion provides another pathway for the spread of cancer cells when blood and lymphatic metastases are absent, which is based on the interactions between the microenvironments of nerve fibers and tumor cells. The nervous system also modulates angiogenesis, the tumor microenvironment, bone marrow, immune functions and inflammatory pathways to influence metastases. Denervation of the tumor has been reported to enhance cancer metastasis. Stress, social isolation and other emotional factors may increase distant metastasis through releasing hormones from the brain, the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Disruption of circadian rhythms will also promote cancer metastasis through direct and indirect actions of the nervous system. Therefore, the nervous system plays an important role in cancer metastasis.
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Affiliation(s)
- Sha Li
- Department of Radiation Oncology, Lanzhou General Hospital of PLA, Lanzhou, Gansu 730050
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18
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Urie BK, Russell DS, Kisseberth WC, London CA. Evaluation of expression and function of vascular endothelial growth factor receptor 2, platelet derived growth factor receptors-alpha and -beta, KIT, and RET in canine apocrine gland anal sac adenocarcinoma and thyroid carcinoma. BMC Vet Res 2012; 8:67. [PMID: 22630170 PMCID: PMC3542001 DOI: 10.1186/1746-6148-8-67] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Accepted: 05/08/2012] [Indexed: 12/17/2022] Open
Abstract
Background Toceranib phosphate (Palladia) has a reported objective response rate of 25% in both canine apocrine gland anal sac adenocarcinoma (AGASACA) and thyroid carcinoma (TC), with stable disease occurring in an additional 50-60% of dogs. The basis for the observed responses to toceranib is not known. The purpose of this study was to evaluate AGASACA and TC samples for the expression and activation of VEGFR2, PDGFRα, PDGFRβ, KIT and RET to assess whether dysregulation of these receptor tyrosine kinases (RTKs) may contribute to the biologic activity of toceranib. Results mRNA for VEGFR2, PDGFRα/β, KIT and RET was detected in all AGASACA samples. mRNA for VEGFR2, PDGFRα/β, and KIT was detected in all TC samples, while mRNA for RET was amplified in 10/15 samples. No phosphorylation of VEGFR2, PDGFRα/β, or KIT was observed on the arrays. However, phosphorylation of RET was detected in 54% of the primary AGASACA and 20% of TC. VEGFR2 was expressed in 19/24 primary and 6/10 metastatic AGASACA and 6/15 TC samples. KIT was present in 8/24 primary and 3/10 metastatic AGASACA and 9/15 TC samples. PDGFRα expression was noted in all tumor samples. In contrast PDGFRβ expression was found in only a few tumor samples but was evident in the stroma of all tumor specimens. Conclusions Known targets of toceranib are expressed in both AGASAC and TC. Given the observed expression of VEGFR and PDGFRα/β and phosphorylation of RET, these RTKs merit investigation as to their roles in the biology of AGSACA and TC and their contribution to toceranib’s activity.
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Affiliation(s)
- Bridget K Urie
- Department of Veterinary Clinical Sciences, The Ohio State University College of Veterinary Medicine, 601 Vernon L Tharp Street, Columbus, OH 43210, USA
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Morandi A, Plaza-Menacho I, Isacke CM. RET in breast cancer: functional and therapeutic implications. Trends Mol Med 2011; 17:149-57. [PMID: 21251878 DOI: 10.1016/j.molmed.2010.12.007] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2010] [Revised: 12/13/2010] [Accepted: 12/14/2010] [Indexed: 02/07/2023]
Abstract
Recent studies demonstrate that the receptor tyrosine kinase RET is overexpressed in a subset of ER-positive breast cancers and that crosstalk between RET and ER is important in responses to endocrine therapy. The development of small molecular inhibitors that target RET allows the opportunity to consider combination therapies as a strategy to improve response to treatment and to prevent and combat endocrine resistance. This review discusses: (i) the current knowledge about RET, its co-receptors and ligands in breast cancer; (ii) the breast cancer clinical trials involving agents that target RET; and (iii) the challenges that remain in terms of specificity of available inhibitors and in understanding the complex molecular mechanisms that underlie the resistance to endocrine therapy.
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Affiliation(s)
- Andrea Morandi
- Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK
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20
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Kato M, Takeda K, Hossain K, Thang ND, Kaneko Y, Kumasaka M, Yamanoshita O, Uemura N, Takahashi M, Ohgami N, Kawamoto Y. A redox-linked novel pathway for arsenic-mediated RET tyrosine kinase activation. J Cell Biochem 2010; 110:399-407. [PMID: 20235151 DOI: 10.1002/jcb.22550] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
We examined the biochemical effects of arsenic on the activities of RET proto-oncogene (c-RET protein tyrosine kinases) and RET oncogene (RET-MEN2A and RET-PTC1 protein tyrosine kinases) products. Arsenic activated c-RET kinase with promotion of disulfide bond-mediated dimerization of c-RET protein. Arsenic further activated RET-MEN2A kinase, which was already 3- to 10-fold augmented by genetic mutation compared with c-RET kinase activity, with promotion of disulfide bond-mediated dimerization of RET-MEN2A protein (superactivation). Arsenic also increased extracellular domain-deleted RET-PTC1 kinase activity with promotion of disulfide bond-mediated dimerization of RET-PTC1 protein. Arsenic increased RET-PTC1 kinase activity with cysteine 365 (C365) replaced by alanine with promotion of dimer formation but not with cysteine 376 (C376) replaced by alanine. Our results suggest that arsenic-mediated regulation of RET kinase activity is dependent on conformational change of RET protein through modulation of a special cysteine sited at the intracellular domain in RET protein (relevant cysteine of C376 in RET-PTC1 protein). Moreover, arsenic enhanced the activity of immunoprecipitated RET protein with increase in thiol-dependent dimer formation. As arsenic (14.2 microM) was detected in the cells cultured with arsenic (100 microM), direct association between arsenic and RET in the cells might modulate dimer formation. Thus, we demonstrated a novel redox-linked mechanism of activation of arsenic-mediated RET proto-oncogene and oncogene products.
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Affiliation(s)
- Masashi Kato
- Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan.
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21
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Ohshima Y, Yajima I, Takeda K, Iida M, Kumasaka M, Matsumoto Y, Kato M. c-RET molecule in malignant melanoma from oncogenic RET-carrying transgenic mice and human cell lines. PLoS One 2010; 5:e10279. [PMID: 20422010 PMCID: PMC2858158 DOI: 10.1371/journal.pone.0010279] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2009] [Accepted: 03/19/2010] [Indexed: 12/19/2022] Open
Abstract
Malignant melanoma is one of the most aggressive cancers and its incidence worldwide has been increasing at a greater rate than that of any other cancer. We previously reported that constitutively activated RFP-RET-carrying transgenic mice (RET-mice) spontaneously develop malignant melanoma. In this study, we showed that expression levels of intrinsic c-Ret, glial cell line-derived neurotrophic factor (Gdnf) and Gdnf receptor alpha 1 (Gfra1) transcripts in malignant melanomas from RET-transgenic mice were significantly upregulated compared with those in benign melanocytic tumors. These results suggest that not only introduced oncogenic RET but also intrinsic c-Ret/Gdnf are involved in murine melanomagenesis in RET-mice. We then showed that c-RET and GDNF transcript expression levels in human malignant melanoma cell lines (HM3KO and MNT-1) were higher than those in primary cultured normal human epithelial melanocytes (NHEM), while GFRa1 transcript expression levels were comparable among NHEM, HM3KO and MNT-1. We next showed c-RET and GFRa1 protein expression in HM3KO cells and GDNF-mediated increased levels of their phosphorylated c-RET tyrosine kinase and signal transduction molecules (ERK and AKT) sited potentially downstream of c-RET. Taken together with the finding of augmented proliferation of HM3KO cells after GDNF stimulation, our results suggest that GDNF-mediated c-RET kinase activation is associated with the pathogenesis of malignant melanoma.
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Affiliation(s)
- Yuichiro Ohshima
- Units of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan
- Department of Dermatology, Aichi Medical University School of Medicine, Nagakute-cho, Aichi-gun, Aichi, Japan
| | - Ichiro Yajima
- Units of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan
| | - Kozue Takeda
- Units of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan
| | - Machiko Iida
- Units of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan
| | - Mayuko Kumasaka
- Units of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan
| | - Yoshinari Matsumoto
- Department of Dermatology, Aichi Medical University School of Medicine, Nagakute-cho, Aichi-gun, Aichi, Japan
| | - Masashi Kato
- Units of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi, Japan
- * E-mail:
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22
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Ben QW, Wang JC, Liu J, Zhu Y, Yuan F, Yao WY, Yuan YZ. Positive expression of L1-CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma. Ann Surg Oncol 2010; 17:2213-21. [PMID: 20162456 DOI: 10.1245/s10434-010-0955-x] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Indexed: 12/18/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) frequently invades and migrates along neural tissue, which results in local tumor recurrences, distant metastases, and poor prognosis. We evaluated whether L1 cell adhesion molecule (L1-CAM) and glial cell line-derived neurotrophic factor (GDNF) expression in PDAC correlated with neural invasion and overall survival on a large cohort of previously untreated patients. METHODS L1-CAM and GDNF were examined by immunohistochemistry in pancreatic cancer tissue samples of 94 cases with PDAC on a tissue microarray. The molecular findings were correlated with pain, clinicopathologic characteristics, and overall survival in these patients. RESULTS L1-CAM and GDNF were overexpressed in pancreatic cancer tissues compared with the adjacent normal tissues of pancreas. Positive L1-CAM expression was associated with node involvement (P = 0.007), vascular invasion (P = 0.012), perineural invasion (P = 0.001), and higher degree of pain (P = 0.005). In univariate analysis, tissue expression of L1-CAM was associated with poor survival (hazard ratio, 2.508; 95% confidence interval, 1.551-4.053; P < 0.001), and this was also significant in multivariate analysis (hazard ratio, 2.046; 95% confidence interval, 1.200-3.488; P = 0.009). Positive staining of GDNF, neural invasion, and vascular invasion were all statistically significantly related to unfavorable prognosis. CONCLUSIONS Enhanced expression of L1-CAM may contribute to the pain syndrome and perineural invasion and may correlate with poor overall survival in human pancreatic cancer.
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Affiliation(s)
- Qi-Wen Ben
- Department of Gastroenterology, School of Medicine, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China
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23
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Gil Z, Cavel O, Kelly K, Brader P, Rein A, Gao SP, Carlson DL, Shah JP, Fong Y, Wong RJ. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J Natl Cancer Inst 2010; 102:107-18. [PMID: 20068194 DOI: 10.1093/jnci/djp456] [Citation(s) in RCA: 186] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The ability of cancer to infiltrate along nerves is a common clinical observation in pancreas, head and neck, prostate, breast, and gastrointestinal carcinomas. For these tumors, nerves may provide a conduit for local cancer progression into the central nervous system. Although neural invasion is associated with poor outcome, the mechanism that triggers it is unknown. METHODS We used an in vitro Matrigel dorsal root ganglion and pancreatic cancer cell coculture model to assess the dynamic interactions between nerves and cancer cell migration and the role of glial cell-derived neurotrophic factor (GDNF). An in vivo murine sciatic nerve model was used to study how nerve invasion affects sciatic nerve function. RESULTS Nerves induced a polarized neurotrophic migration of cancer cells (PNMCs) along their axons, which was more efficient than in the absence of nerves (migration distance: mean = 187.1 microm, 95% confidence interval [CI] = 148 to 226 microm vs 14.4 microm, 95% CI = 9.58 to 19.22 microm, difference = 143 microm; P < .001; n = 20). PNMC was induced by secretion of GDNF, via phosphorylation of the RET-Ras-mitogen-activated protein kinase pathway. Nerves from mice deficient in GDNF had reduced ability to attract cancer cells (nerve invasion index: wild type vs gdnf+/-, mean = 0.76, 95% CI = 0.75 to 0.77 vs 0.43, 95% CI = 0.42 to 0.44; P < .001; n = 60-66). Tumor specimens excised from patients with neuroinvasive pancreatic carcinoma had higher expression of the GDNF receptors RET and GRFalpha1 as compared with normal tissue. Finally, systemic therapy with pyrazolopyrimidine-1, a tyrosine kinase inhibitor targeting the RET pathway, suppressed nerve invasion toward the spinal cord and prevented paralysis in mice. CONCLUSION These data provide evidence for paracrine regulation of pancreatic cancer invasion by nerves, which may have important implications for potential therapy directed against nerve invasion by cancer.
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Affiliation(s)
- Ziv Gil
- Department of Otolaryngology, Head and Neck Surgery, Tel Aviv Sourasky Medical Center, 6 Weizmann St, Tel Aviv, 64239, Israel.
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24
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Ape1/Ref-1 induces glial cell-derived neurotropic factor (GDNF) responsiveness by upregulating GDNF receptor alpha1 expression. Mol Cell Biol 2009; 29:2264-77. [PMID: 19188437 DOI: 10.1128/mcb.01484-08] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) dysregulation has been identified in several human tumors and in patients with a variety of neurodegenerative diseases. However, the function of Ape1/Ref-1 is unclear. We show here that Ape1/Ref-1 increases the expression of glial cell-derived neurotropic factor (GDNF) receptor alpha1 (GFRalpha1), a key receptor for GDNF. Expression of Ape1/Ref-1 led to an increase in the GDNF responsiveness in human fibroblast. Ape1/Ref-1 induced GFRalpha1 transcription through enhanced binding of NF-kappaB complexes to the GFRalpha1 promoter. GFRalpha1 levels correlate proportionally with Ape1/Ref-1 in cancer cells. The knockdown of endogenous Ape1/Ref-1 in pancreatic cancer cells markedly suppressed GFRalpha1 expression and invasion in response to GNDF, while overexpression of GFRalpha1 restored invasion. In neuronal cells, the Ape1/Ref-1-mediated increase in GDNF responsiveness not only stimulated neurite outgrowth but also protected the cells from beta-amyloid peptide and oxidative stress. Our results show that Ape1/Ref-1 is a novel physiological regulator of GDNF responsiveness, and they also suggest that Ape1/Ref-1-induced GFRalpha1 expression may play important roles in pancreatic cancer progression and neuronal cell survival.
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25
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Ng WH, Wan GQ, Peng ZN, Too HP. Glial cell-line derived neurotrophic factor (GDNF) family of ligands confer chemoresistance in a ligand-specific fashion in malignant gliomas. J Clin Neurosci 2009; 16:427-36. [PMID: 19138852 DOI: 10.1016/j.jocn.2008.06.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2008] [Revised: 05/28/2008] [Accepted: 06/01/2008] [Indexed: 01/15/2023]
Abstract
Glial cell-line derived neurotrophic factor (GDNF) is a neurotrophic factor known to promote neuronal survival of dopaminergic neurons in the embryonic midbrain as well as contribute to carcinogenesis in many cancers. Its ubiquitous presence in the central nervous system suggests a role in the mitogenesis of high-grade astrocytoma. GDNF is overexpressed in glioblastoma cell lines and human gliomas. GFRalpha1b is the predominant spliced receptor isoform in human gliomas and RET9 is the predominant co-receptor. Significantly there is differential overexpression of the GFRalpha1b spliced isoform compared to the GFRalpha1a spliced variant. Pre-treatment of glioblastoma cell lines with GDNF but not the alternative ligand neurturin, promoted mitogenic behaviour and conferred chemoresistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Signaling mapping of BCNU and GDNF suggest that the ability of GDNF to promote Akt activity and inhibit JNK activity may contribute to the increased cellular survival after BCNU chemotherapy.
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Affiliation(s)
- Wai Hoe Ng
- Department of Biochemistry, Faculty of Medicine, National University of Singapore.
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26
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Sabo E, Meitner PA, Tavares R, Corless CL, Lauwers GY, Moss SF, Resnick MB. Expression analysis of Barrett's esophagus-associated high-grade dysplasia in laser capture microdissected archival tissue. Clin Cancer Res 2008; 14:6440-8. [PMID: 18927283 DOI: 10.1158/1078-0432.ccr-08-0302] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
PURPOSE Identifying genes differentially expressed in nondysplastic BE (NDBE) from those expressed in high-grade dysplasia (HGD) should be of value in improving our understanding of this transition and may yield new diagnostic and/or prognostic markers. The aim of this study was to determine the differential transcriptome of HGD compared with NDBE through gene microarray analysis of epithelial cells microdissected from archival tissue specimens. EXPERIMENTAL DESIGN Laser capture microdissection was used to isolate epithelial cells from adjacent inflammatory and stromal cells. Epithelial mRNA was extracted from areas of NDBE and HGD in matched biopsies from 11 patients. mRNA was reverse transcribed and applied on Affymetrix cDNA microarray chips customized for formalin-exposed tissue. For a subset of these genes, differential gene expression was confirmed by real-time PCR and immunohistochemistry. RESULTS There were 131 genes overexpressed by at least 2.5-fold in HGD versus NDBE and 16 genes that were underexpressed by at least 2.5-fold. Among the overexpressed genes are several previously shown to be increased in the neoplastic progression of BE, as well as novel genes such as lipocalin-2, S100A9, matrix metallopeptidase 12, secernin 1, and topoisomerase IIalpha. Genes decreased in dysplastic epithelium include MUC5AC, trefoil factor 1 (TFF1), meprin A, and CD13. Real-time PCR validated the changes in expression in 24 of 28 selected genes. Immunohistochemistry confirmed increased protein expression for topoisomerase IIalpha, S100A9, and lipocalin-2 and decreased expression of TFF1 across the spectrum of BE-associated dysplasia from NDBE through adenocarcinoma. CONCLUSIONS This is the first study to identify epithelial genes differentially expressed in HGD versus NDBE in matched patient samples. The genes identified include several previously implicated in the pathogenesis of BE-associated dysplasia and new candidates for further investigation.
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Affiliation(s)
- Edmond Sabo
- Department of Pathology and Medicine, Rhode Island Hospital, Providence, Rhode Island 02903, USA
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27
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Wang W, Zhao H, Zhang S, Kang E, Chen Y, Ni C, Zhang S, Zhu M. Patterns of expression and function of the p75(NGFR) protein in pancreatic cancer cells and tumours. Eur J Surg Oncol 2008; 35:826-32. [PMID: 19041213 DOI: 10.1016/j.ejso.2008.10.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2008] [Revised: 10/21/2008] [Accepted: 10/23/2008] [Indexed: 02/06/2023] Open
Abstract
BACKGROUNDS/AIMS Pancreatic carcinoma is one of the most aggressive human malignancies. The aggressive and highly metastatic behaviour of pancreatic carcinoma may partly be attributable to the autocrine and/or paracrine interactions involving altered expression of neurotrophin growth factors and their corresponding receptors. The aim of the present study is to investigate the expression pattern and function of the p75(NGFR) protein in pancreatic cancer cell lines and tumours to explain the phenomenon of perineural invasion in pancreatic cancer. METHODS The expression of p75(NGFR) in 137 pancreatic adenocarcinoma samples and the corresponding adjacent pancreatic samples was examined immunohistochemically using the EnVision Plus System. Then we examined the in vitro chemotaxis behaviour of cancer cells transfected with p75(NGFR) plasmid to nerve growth factor (NGF). RESULTS Immunostaining for p75(NGFR) was weak or absent in both normal pancreata and pancreatic carcinoma tissues; however, the immunostaining was relatively weaker in the pancreatic carcinoma tissues than in the normal pancreata. It is interesting to note that p75(NGFR) expression in the cancer tissues was positively correlated with the degree of perineural invasion (chi(2)=32.94, P<0.01). The chemotaxis ability of the p75(NGFR)-transfected pancreatic cancer cells to NGF was significantly stronger than that of the non-transfected or vacant vector transfected cells (P<0.01). CONCLUSIONS Our findings indicate that p75(NGFR) expression may be involved in the perineural invasion of pancreatic cancer cells, and the mechanism might be through mediating the chemoattraction of cancer cells for neural tissues.
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Affiliation(s)
- W Wang
- Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, PR China
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Zeng Q, Cheng Y, Zhu Q, Yu Z, Wu X, Huang K, Zhou M, Han S, Zhang Q. The relationship between overexpression of glial cell-derived neurotrophic factor and its RET receptor with progression and prognosis of human pancreatic cancer. J Int Med Res 2008; 36:656-64. [PMID: 18652760 DOI: 10.1177/147323000803600406] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
We used immunohistochemical staining to assess protein over-expression of glial cell-derived neurotrophic factor (GDNF) and its RET receptor tyrosine kinase in patients with pancreatic cancer and benign pancreatic neoplasm, and assessed correlations with clinicopathological features and prognosis. Surgically resected pancreatic cancer patients (40/58, 68.9%) showed positive GDNF immunostaining, a significantly higher frequency than in patients with benign pancreatic tumour (3/11, 27.3%). Intrapancreatic neural invasion by cancer cells was significantly related to over-expression of GDNF. Strongly positive expression of GDNF was significantly more frequent than lesser grades of expression in patients with severe back pain before and 12 months after surgery. Expression of RET was significantly related to lymphatic invasion, survival rate after tumour resection and degree of tumour cell differentiation. We conclude that GDNF may be important in pancreatic cancer proliferation and metastasis, especially in patients with perineural invasion. Strongly positive expression of GDNF may be an indication for early intensified radiotherapy. RET expression in pancreatic cancer tissues may be a useful prognostic marker.
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Affiliation(s)
- Q Zeng
- Department of General Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang Province, China
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Li CG, Huang ZQ, Wei LX, Dong JH, Liu JG, Wang YS. Clinical pathology of perineural invasion in hilar cholangiocarcinoma. Shijie Huaren Xiaohua Zazhi 2008; 16:379-384. [DOI: 10.11569/wcjd.v16.i4.379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate the characteristics and mechanism of perineural invasion in hilar cholangiocarcinoma.
METHODS: A clinicopathologic study was conducted on tissue sections from 73 patients with hilar cholangiocarcinoma to observe the incidence and modes of perineural invasion. Clinicopathologic factors, such as tumor differentiation and pathologic stage, were analyzed when perineural invasion was observed in the sections. Immunohistochemical staining for CD34 and D2-40 in cancer tissue samples was performed to clarify the association of perineural invasion with vessels.
RESULTS: The overall incidence of perineural invasion was 91.78% (67 of 73 patients). However, the incidence of perineural invasion did not show any remarkable difference in various differentiated adenocarcinomas. Logistic regression analysis identified that penetration of bile duct was significantly correlated with perineural invasion (P < 0.01). The microvessel density (MVD) was significantly lower in well-differentiated adenocarcinomas than in moderately- and poorly- differentiated adenocarcinomas (P < 0.05). Five patterns were observed as the tumor cells invaded nerve fibers. Although tumor cells were found to invade microvessels and microlymphatics, immunohistochemical staining for CD34 and D2-40 respectively showed no association between perineural invasion and lymphatic or vascular invasion.
CONCLUSION: Perineural invasion is common in hilar cholangiocarcinoma and does not develop via the lymphatic or vascular network, but is a continuous extension from the primary tumor. Nerve plexus around the membrana adventitia should be completely divested during radical excision of hilar cholangiocarcinoma.
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Koide N, Yamada T, Shibata R, Mori T, Fukuma M, Yamazaki K, Aiura K, Shimazu M, Hirohashi S, Nimura Y, Sakamoto M. Establishment of perineural invasion models and analysis of gene expression revealed an invariant chain (CD74) as a possible molecule involved in perineural invasion in pancreatic cancer. Clin Cancer Res 2006; 12:2419-26. [PMID: 16638847 DOI: 10.1158/1078-0432.ccr-05-1852] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
PURPOSE Perineural invasion causes frequent local recurrence even after resection and a poor prognosis for pancreatic cancer. We established perineural invasion models and analyzed the molecular mechanism of perineural invasion in pancreatic cancer. EXPERIMENTAL DESIGN Seven pancreatic cancer cell lines with or without human peripheral nerves were s.c. implanted in nonobese diabetes/severe combined immunodeficient mice. We compared expression profiles among high and low perineural invasion cell lines by using an oligonucleotide microarray. We examined up-regulation of the invariant chain (CD74) in high perineural invasion cell lines in mRNA and protein levels and surgical cases immunohistochemically. RESULTS Four of seven pancreatic cancer cell lines (CaPan1, CaPan2, CFPAC, and MPanc96) showed perineural invasion to s.c. transplanted human peripheral nerves. Moreover, CaPan1 and CaPan2 (high perineural invasion group) also resulted in a high frequency of perineural invasion to mouse s.c. peripheral nerves, whereas three pancreatic cancer cell lines HPAFII, AsPC1, and Panc1 (low perineural invasion group) did not show perineural invasion to either human or mouse nerves. We identified 37 up-regulated genes and 12 down-regulated genes in the high perineural invasion group compared with the low perineural invasion group. Among them, CD74 was up-regulated in the high perineural invasion group in mRNA and protein levels. Furthermore, immunohistochemical expression of CD74 in clinical cases revealed its significant overexpression in pancreatic cancer with perineural invasion (P < 0.008). CONCLUSIONS This is the first report of perineural invasion models using human pancreatic cancer cell lines. In combination with gene expression profiling, it was indicated that CD74 could be a candidate molecule involved in perineural invasion. These models provide new approaches for study of perineural invasion in pancreatic cancer.
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MESH Headings
- Aged
- Animals
- Antigens, Differentiation, B-Lymphocyte/analysis
- Antigens, Differentiation, B-Lymphocyte/genetics
- Blotting, Western
- Cell Line, Tumor
- Cluster Analysis
- Disease Models, Animal
- Female
- Gene Expression Regulation, Neoplastic/genetics
- Histocompatibility Antigens Class II/analysis
- Histocompatibility Antigens Class II/genetics
- Humans
- Immunohistochemistry
- Male
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Middle Aged
- Neoplasm Invasiveness
- Neoplasms, Experimental/genetics
- Neoplasms, Experimental/pathology
- Oligonucleotide Array Sequence Analysis
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Peripheral Nerves/metabolism
- Peripheral Nerves/pathology
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
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Affiliation(s)
- Norimasa Koide
- Departments of Pathology and Surgery, School of Medicine, Keio University, USA
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Ito Y, Okada Y, Sato M, Sawai H, Funahashi H, Murase T, Hayakawa T, Manabe T. Expression of glial cell line-derived neurotrophic factor family members and their receptors in pancreatic cancers. Surgery 2005; 138:788-94. [PMID: 16269310 DOI: 10.1016/j.surg.2005.07.007] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2005] [Revised: 07/14/2005] [Accepted: 07/15/2005] [Indexed: 12/11/2022]
Abstract
BACKGROUND The glial cell line-derived neurotrophic factor (GDNF) is a member of neurotrophic polypeptide family, which promotes survival and rescue of various neural cells in the central and peripheral nerve systems. We previously reported that GDNF promotes tumor cell invasion in pancreatic cancer cell lines. The purpose of this study was to investigate GDNF family expression and the status of related receptors in actual cancer tissues, and assess correlations with clinicopathologic behavior. METHODS Immunohistochemical assessment of GDNF, neurturin, persephin, artemin, GDNF family receptor alpha-1 and alpha-2, and RET was performed for 51 cases of surgically resected pancreatic cancer. RESULTS In all intrapancreatic nerves, GDNF and artermin were expressed strongly. In pancreatic cancer tissues. The expression of RET was stronger than that seen in normal ductal cells and was significantly related to the survival rate after resection (P = .026) and lymphatic invasion (P = .014). Intrapancreatic neural invasion was significantly related to the expression of GDNF (P = .047). CONCLUSIONS We conclude that the expression of RET in pancreatic cancer tissues may be a useful prognostic marker and GDNF may play an important role in neural invasion.
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Affiliation(s)
- Yoshinori Ito
- Department of Gastroenterological Surgery, Nagoya City University, Graduate School of Medical Sciences, Kawasumi, Japan
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Murakawa K, Tada M, Takada M, Tamoto E, Shindoh G, Teramoto KI, Matsunaga A, Komuro K, Kanai M, Kawakami A, Fujiwara Y, Kobayashi N, Shirata K, Nishimura N, Okushiba SI, Kondo S, Hamada JI, Katoh H, Yoshiki T, Moriuchi T. Prediction of lymph node metastasis and perineural invasion of biliary tract cancer by selected features from cDNA array data. J Surg Res 2004; 122:184-94. [PMID: 15555617 DOI: 10.1016/j.jss.2004.06.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2004] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To better understand the nature of the malignancy of biliary tract carcinoma and evaluate the feasibility of its prediction by gene expression profiles. METHODS AND RESULTS We explored the gene expression profiles characteristic of progression and invasiveness in the cDNA array data obtained from 37 biliary tract carcinomas (15 bile duct, 11 gallbladder, 11 of ampulla of Vater). We pre-selected 51 and 100 genes for the presence versus absence of lymph node metastasis and perineural invasion on the basis of statistical difference. To search optimized sets of genes for prediction, we applied a sequential forward feature selection, minimizing leave-one-out error rates on a k-nearest neighbor classifier. We could predict lymph node metastasis and perineural invasion with an accuracy of 94 and 100%, respectively. When the 6-stage IA cancers without perineural invasion were precluded, a marked difference in gene expression (147 gene), discriminable with 100% accuracy, was noted between positive versus negative perineural invasion, suggesting that the acquisition of invasive character is rather a later molecular pathological event in biliary tract cancer. CONCLUSION The present method provides a powerful means of classifying biliary tract carcinomas. We also suggest that perineural invasion is an important target of array databased pattern classification, which may predict patient outcomes and facilitate the determination of the extent of surgery to minimize the risk of recurrence.
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Affiliation(s)
- Katsuhiko Murakawa
- Department of Surgical Oncology, Division of Cancer Diagnostics and Therapeutics, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
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