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1
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Jayabal P, Zhou F, Ma X, Bondra KM, Blackman B, Weintraub ST, Chen Y, Chévez-Barrios P, Houghton PJ, Gallie B, Shiio Y. Nitric oxide suppression by secreted frizzled-related protein 2 drives retinoblastoma. Cell Rep 2023; 42:112103. [PMID: 36773293 PMCID: PMC10412738 DOI: 10.1016/j.celrep.2023.112103] [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: 01/28/2021] [Revised: 12/15/2022] [Accepted: 01/27/2023] [Indexed: 02/12/2023] Open
Abstract
Retinoblastoma is a cancer of the infant retina primarily driven by loss of the Rb tumor suppressor gene, which is undruggable. Here, we report an autocrine signaling, mediated by secreted frizzled-related protein 2 (SFRP2), which suppresses nitric oxide and enables retinoblastoma growth. We show that coxsackievirus and adenovirus receptor (CXADR) is the cell-surface receptor for SFRP2 in retinoblastoma cells; that CXADR functions as a "dependence receptor," transmitting a growth-inhibitory signal in the absence of SFRP2; and that the balance between SFRP2 and CXADR determines nitric oxide production. Accordingly, high SFRP2 RNA expression correlates with high-risk histopathologic features in retinoblastoma. Targeting SFRP2 signaling by SFRP2-binding peptides or by a pharmacological inhibitor rapidly induces nitric oxide and profoundly inhibits retinoblastoma growth in orthotopic xenograft models. These results reveal a cytokine signaling pathway that regulates nitric oxide production and retinoblastoma cell proliferation and is amenable to therapeutic intervention.
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Affiliation(s)
- Panneerselvam Jayabal
- Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Fuchun Zhou
- Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Xiuye Ma
- Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Kathryn M Bondra
- Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Barron Blackman
- Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Susan T Weintraub
- Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Yidong Chen
- Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Population Health Sciences, The University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Patricia Chévez-Barrios
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Peter J Houghton
- Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Brenda Gallie
- The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada
| | - Yuzuru Shiio
- Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
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2
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Li YP, Wang YT, Wang W, Zhang X, Shen RJ, Jin K, Jin LW, Jin ZB. Second hit impels oncogenesis of retinoblastoma in patient-induced pluripotent stem cell-derived retinal organoids: direct evidence for Knudson's theory. PNAS NEXUS 2022; 1:pgac162. [PMID: 36714839 PMCID: PMC9802398 DOI: 10.1093/pnasnexus/pgac162] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/13/2022] [Indexed: 02/01/2023]
Abstract
Retinoblastoma (Rb) is a type of malignant tumor due to abnormal retinogenesis with biallelic mutations of the RB1 gene. Its pathogenesis has been proposed as a "two-mutation hypothesis" by Knudson since 1971; however, there remain some debates on disease onset sufficiency of the biallelic RB1 mutations. To obtain straightforward evidence for this hypothesis, we investigated whether two-hit mutations of the RB1 gene drive tumorigenesis in patient-induced pluripotent stem cell (hiPSC)-derived human retinal organoids (hROs) and whether single allelic mutation hiPSC-derived hROs exhibit molecular and cellular defects. We generated hiPSCs with a heterozygous germline mutation (RB1m1/ wt ) from a Rb patient. A second-allele RB1 gene mutation was knocked in to produce compound heterozygous mutations (RB1m1/m2 ) in the hiPSCs. These two hiPSC lines were independently developed into hROs through a stepwise differentiation. The hiPSC-RB1m1/m2 derived organoids demonstrated tumorigenesis in dishes, consistent with Rb profiles in spatiotemporal transcriptomes, in which developmentally photoreceptor fate-determining markers, CRX and OTX2, were highly expressed in hiPSC-RB1m1/m2 derived hROs. Additionally, ARR3+ maturing cone precursors were co-labeled with proliferative markers Ki67 or PCNA, in agreement with the consensus that human Rb is originated from maturing cone precursors. Finally, we demonstrated that retinal cells of hROs with monoallelic RB1 mutation were abnormal in molecular aspects due to its haploinsufficiency. In conclusion, this study provides straightforward supporting evidence in a way of reverse genetics for "two-hit hypothesis" in the Rb tumorigenesis and opens new avenues for development of early intervention and treatment of Rb.
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Affiliation(s)
- Yan-Ping Li
- Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Ya-Ting Wang
- Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Wen Wang
- Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Xiao Zhang
- Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Ren-Juan Shen
- Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Kangxin Jin
- Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Li-Wen Jin
- Quanzhou Aier Eye Hospital, Quanzhou 362017, China
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3
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Yao Y, Gu X, Xu X, Ge S, Jia R. Novel insights into RB1 mutation. Cancer Lett 2022; 547:215870. [PMID: 35964818 DOI: 10.1016/j.canlet.2022.215870] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 08/05/2022] [Accepted: 08/05/2022] [Indexed: 01/09/2023]
Abstract
Since the discovery of the retinoblastoma susceptibility gene (RB1) decades ago, RB1 has been regarded as a prototype tumor suppressor gene providing a paradigm for tumor genetic research. Constant research has updated the understanding of RB1-related pathways and their impact on tumor and nontumor diseases. Mutation of RB1 gene has been observed in multiple types of malignant tumors including prostate cancer, lung cancer, breast cancer, and almost every familial and sporadic case of retinoblastoma. Even if well-known and long-investigated, the application potential of RB1 mutation has not been fully tapped. In this review, we focus on the mechanism underlying RB1 mutation during oncogenesis. Therapeutically, we have further discussed potential clinical strategies by targeting RB1-mutated cancers. The unsolved problems and prospects of RB1 mutation are also discussed.
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Affiliation(s)
- Yiran Yao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
| | - Xiang Gu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
| | - Xiaofang Xu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
| | - Shengfang Ge
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
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4
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Rozanska A, Cerna-Chavez R, Queen R, Collin J, Zerti D, Dorgau B, Beh CS, Davey T, Coxhead J, Hussain R, Al-Aama J, Steel DH, Benvenisty N, Armstrong L, Parulekar M, Lako M. pRB-Depleted Pluripotent Stem Cell Retinal Organoids Recapitulate Cell State Transitions of Retinoblastoma Development and Suggest an Important Role for pRB in Retinal Cell Differentiation. Stem Cells Transl Med 2022; 11:415-433. [PMID: 35325233 PMCID: PMC9052432 DOI: 10.1093/stcltm/szac008] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 12/19/2021] [Indexed: 11/12/2022] Open
Abstract
Retinoblastoma (Rb) is a childhood cancer of the developing retina, accounting for up to 17% of all tumors in infancy. To gain insights into the transcriptional events of cell state transitions during Rb development, we established 2 disease models via retinal organoid differentiation of a pRB (retinoblastoma protein)-depleted human embryonic stem cell line (RB1-null hESCs) and a pRB patient-specific induced pluripotent (iPSC) line harboring a RB1 biallelic mutation (c.2082delC). Both models were characterized by pRB depletion and accumulation of retinal progenitor cells at the expense of amacrine, horizontal and retinal ganglion cells, which suggests an important role for pRB in differentiation of these cell lineages. Importantly, a significant increase in the fraction of proliferating cone precursors (RXRγ+Ki67+) was observed in both pRB-depleted organoid models, which were defined as Rb-like clusters by single-cell RNA-Seq analysis. The pRB-depleted retinal organoids displayed similar features to Rb tumors, including mitochondrial cristae aberrations and rosette-like structures, and were able to undergo cell growth in an anchorage-independent manner, indicative of cell transformation in vitro. In both models, the Rb cones expressed retinal ganglion and horizontal cell markers, a novel finding, which could help to better characterize these tumors with possible therapeutic implications. Application of Melphalan, Topotecan, and TW-37 led to a significant reduction in the fraction of Rb proliferating cone precursors, validating the suitability of these in vitro models for testing novel therapeutics for Rb.
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Affiliation(s)
- Agata Rozanska
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | | | - Rachel Queen
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Joseph Collin
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Darin Zerti
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Birthe Dorgau
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Chia Shyan Beh
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Tracey Davey
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Jonathan Coxhead
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Rafiqul Hussain
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Jumana Al-Aama
- Faculty of Medicine, King Abdulaziz University, Riyadh, Saudi Arabia
| | - David H Steel
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Nissim Benvenisty
- The Azrieli Center for Stem Cells and Genetic Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Lyle Armstrong
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Manoj Parulekar
- Birmingham Women's and Children NHS Foundation Trust, Birmingham, UK
| | - Majlinda Lako
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
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5
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Yang J, Li Y, Han Y, Feng Y, Zhou M, Zong C, He X, Jia R, Xu X, Fan J. Single-cell transcriptome profiling reveals intratumoural heterogeneity and malignant progression in retinoblastoma. Cell Death Dis 2021; 12:1100. [PMID: 34815392 PMCID: PMC8611004 DOI: 10.1038/s41419-021-04390-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 10/18/2021] [Accepted: 10/29/2021] [Indexed: 12/23/2022]
Abstract
Retinoblastoma is a childhood retinal tumour that is the most common primary malignant intraocular tumour. However, it has been challenging to identify the cell types associated with genetic complexity. Here, we performed single-cell RNA sequencing on 14,739 cells from two retinoblastoma samples to delineate the heterogeneity and the underlying mechanism of retinoblastoma progression. Using a multiresolution network-based analysis, we identified two major cell types in human retinoblastoma. Cell trajectory analysis yielded a total of 5 cell states organized into two main branches, and the cell cycle-associated cone precursors were the cells of origin of retinoblastoma that were required for initiating the differentiation and malignancy process of retinoblastoma. Tumour cells differentiation reprogramming trajectory analysis revealed that cell-type components of multiple tumour-related pathways and predominantly expressed UBE2C were associated with an activation state in the malignant progression of the tumour, providing a potential novel "switch gene" marker during early critical stages in human retinoblastoma development. Thus, our findings improve our current understanding of the mechanism of retinoblastoma progression and are potentially valuable in providing novel prognostic markers for retinoblastoma.
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Affiliation(s)
- Jie Yang
- grid.16821.3c0000 0004 0368 8293Department of Ophthalmology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China ,grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P. R. China
| | - Yongyun Li
- grid.16821.3c0000 0004 0368 8293Department of Ophthalmology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China ,grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P. R. China
| | - Yanping Han
- grid.16821.3c0000 0004 0368 8293Department of Ophthalmology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China ,grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P. R. China
| | - Yiyi Feng
- grid.16821.3c0000 0004 0368 8293Department of Ophthalmology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China ,grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P. R. China
| | - Min Zhou
- grid.16821.3c0000 0004 0368 8293Department of Ophthalmology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China ,grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P. R. China
| | - Chunyan Zong
- grid.16821.3c0000 0004 0368 8293Department of Ophthalmology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China ,grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P. R. China
| | - Xiaoyu He
- grid.16821.3c0000 0004 0368 8293Department of Ophthalmology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China ,grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P. R. China
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P. R. China.
| | - Xiaofang Xu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P. R. China.
| | - Jiayan Fan
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P. R. China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P. R. China.
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6
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Torres-Montaner A. The telomere complex and the origin of the cancer stem cell. Biomark Res 2021; 9:81. [PMID: 34736527 PMCID: PMC8567692 DOI: 10.1186/s40364-021-00339-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 10/21/2021] [Indexed: 11/15/2022] Open
Abstract
Exquisite regulation of telomere length is essential for the preservation of the lifetime function and self-renewal of stem cells. However, multiple oncogenic pathways converge on induction of telomere attrition or telomerase overexpression and these events can by themselves trigger malignant transformation. Activation of NFκB, the outcome of telomere complex damage, is present in leukemia stem cells but absent in normal stem cells and can activate DOT1L which has been linked to MLL-fusion leukemias. Tumors that arise from cells of early and late developmental stages appear to follow two different oncogenic routes in which the role of telomere and telomerase signaling might be differentially involved. In contrast, direct malignant transformation of stem cells appears to be extremely rare. This suggests an inherent resistance of stem cells to cancer transformation which could be linked to a stem cell’specific mechanism of telomere maintenance. However, tumor protection of normal stem cells could also be conferred by cell extrinsic mechanisms.
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Affiliation(s)
- A Torres-Montaner
- Department of Pathology, Queen's Hospital, Rom Valley Way, London, Romford, RM7 OAG, UK. .,Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Cádiz, 11510 Puerto Real, Cádiz, Spain.
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7
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Giant Y79 retinoblastoma cells contain functionally active T-type calcium channels. Pflugers Arch 2021; 473:1631-1639. [PMID: 34392423 DOI: 10.1007/s00424-021-02612-4] [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: 05/04/2021] [Revised: 07/26/2021] [Accepted: 08/05/2021] [Indexed: 10/20/2022]
Abstract
Retinoblastoma is the most common malignant intraocular tumor in children. Y79 human retinoblastoma cells are in vitro models of retinal tumors used for drug screening. Undifferentiated Y79 cells originate from a primitive multi-potential neuroectodermal cell and express neuronal and glial properties. However, the nature of cellular heterogeneity in Y79 cells is unclear because functional methods to characterize neurons or glial cells have not been employed to Y79 cells. Here, we perform patch-clamp recordings to characterize electrophysiological properties in retinoblastoma cells. We identified a population of large-sized Y79 cells (i.e., giant cells, ~ 40-µm diameter), hyperpolarized resting membrane potential (-54 mV), and low input resistance (~ 600 MΩ), indicating electrically mature cells. We also found that giant Y79 cells contain increased density of T-type calcium channels. Finally, we found that T-type calcium channels are active only in giant cells suggesting that cancer treatments aimed to prevent calcium influx in retinoblastomas should be tested in giant cells.
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8
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Retinoblastoma from human stem cell-derived retinal organoids. Nat Commun 2021; 12:4535. [PMID: 34315877 PMCID: PMC8316454 DOI: 10.1038/s41467-021-24781-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 06/30/2021] [Indexed: 12/13/2022] Open
Abstract
Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. Children with germline mutations in RB1 have a high likelihood of developing retinoblastoma and other malignancies later in life. Genetically engineered mouse models of retinoblastoma share some similarities with human retinoblastoma but there are differences in their cellular differentiation. To develop a laboratory model of human retinoblastoma formation, we make induced pluripotent stem cells (iPSCs) from 15 participants with germline RB1 mutations. Each of the stem cell lines is validated, characterized and then differentiated into retina using a 3-dimensional organoid culture system. After 45 days in culture, the retinal organoids are dissociated and injected into the vitreous of eyes of immunocompromised mice to support retinoblastoma tumor growth. Retinoblastomas formed from retinal organoids made from patient-derived iPSCs have molecular, cellular and genomic features indistinguishable from human retinoblastomas. This model of human cancer based on patient-derived iPSCs with germline cancer predisposing mutations provides valuable insights into the cellular origins of this debilitating childhood disease as well as the mechanism of tumorigenesis following RB1 gene inactivation. Retinoblastoma is a heritable pediatric cancer driven by mutations in RB1. Here, the authors demonstrate the first patient derived model of retinoblastoma using iPSCs from patients with germline mutations in RB1.
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Wang L, Yi S, Wang R, Wang J. Long non-coding RNA KCNQ1OT1 promotes proliferation, migration and invasion via targeting miR-134 in retinoblastoma. J Gene Med 2021; 23:e3336. [PMID: 33818859 DOI: 10.1002/jgm.3336] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 03/30/2021] [Accepted: 03/30/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) exert a significant role in carcinogenesis. lncRNA KCNQ1OT1 is detected in many tumors and is considered as an oncogene. The expression and mechanism of KCNQ1OT1 in retinoblastoma (Rb) are not clearly elucidated. METHODS KCNQ1OT1, miR-134 and TRIM44 mRNA expression were examined by a quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Proliferation, migration and invasion of Weri-Rb1 and Y79 cells were tested by cell counting kit-8, colony formation, scratch and transwell assays. Meanwhile, the regulatory relationships among KCNQ1OT1, miR-134 and TRIM44 were clarified by several biological experiments, including dual-luciferase reporter assay, RNA immunoprecipitation, subcellular distribution, qRT-PCR and western blotting. RESULTS lncRNA KCNQ1OT1 was up-regulated in Rb tissues and Rb cell lines. In addition, the expression of KCNQ1OT1 was negatively correlated with the disease-free survival rate of RB patients. Silencing KCNQ1OT1 could significantly inhibit the RB progression in vivo and in vitro. The analysis of the mechanism of KCNQ1OT1 showed that KCNQ1OT1 can sponge miR-134, and miR-134 may inhibit TRIM44 expression. Moreover, the rescue assays showed that KCNQ1OT1 promoted RB progression by regulating the miR-134/TRIM44 pathway. CONCLUSIONS The present study indicates that a new KCNQ1OT1/miR-134/TRIM44 pathway regulates Rb progression. It may be used as a potential prognostic marker for Rb.
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Affiliation(s)
- Lei Wang
- The 2nd Ward of Ophthalmological, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Sisi Yi
- The 2nd Ward of Ophthalmological, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Runze Wang
- The 2nd Ward of Ophthalmological, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jianwen Wang
- The 2nd Ward of Ophthalmological, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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10
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Human embryonic stem cell-derived organoid retinoblastoma reveals a cancerous origin. Proc Natl Acad Sci U S A 2020; 117:33628-33638. [PMID: 33318192 PMCID: PMC7776986 DOI: 10.1073/pnas.2011780117] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
As a genetic malignancy, retinoblastoma (Rb) is caused by RB1 mutations; however, its developmental origin and drug agents for human Rb remain largely unexplored. Here we describe an innovative Rb organoid model derived from human embryonic stem cells with a biallelic mutagenesis of the RB1 gene. We identify tumorigenic growth in the Rb organoids, as well as properties consistent with human primary Rb. We confirm that the Rb cell of origin stemmed from ARR3+ maturing cone precursor cells and SYK inhibitors displaying a significant therapeutic response. Our elegant in-dish Rb organoid model can be used to efficiently and effectively dissect the origin of Rb and mechanisms of Rb tumorigenesis, as well as screen novel therapies. Retinoblastoma (Rb) is the most prevalent intraocular malignancy in children, with a worldwide survival rate <30%. We have developed a cancerous model of Rb in retinal organoids derived from genetically engineered human embryonic stem cells (hESCs) with a biallelic mutagenesis of the RB1 gene. These organoid Rbs exhibit properties highly consistent with Rb tumorigenesis, transcriptome, and genome-wide methylation. Single-cell sequencing analysis suggests that Rb originated from ARR3-positive maturing cone precursors during development, which was further validated by immunostaining. Notably, we found that the PI3K-Akt pathway was aberrantly deregulated and its activator spleen tyrosine kinase (SYK) was significantly up-regulated. In addition, SYK inhibitors led to remarkable cell apoptosis in cancerous organoids. In conclusion, we have established an organoid Rb model derived from genetically engineered hESCs in a dish that has enabled us to trace the cell of origin and to test novel candidate therapeutic agents for human Rb, shedding light on the development and therapeutics of other malignancies.
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11
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Zluhan-Martínez E, Pérez-Koldenkova V, Ponce-Castañeda MV, Sánchez MDLP, García-Ponce B, Miguel-Hernández S, Álvarez-Buylla ER, Garay-Arroyo A. Beyond What Your Retina Can See: Similarities of Retinoblastoma Function between Plants and Animals, from Developmental Processes to Epigenetic Regulation. Int J Mol Sci 2020; 21:E4925. [PMID: 32664691 PMCID: PMC7404004 DOI: 10.3390/ijms21144925] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/29/2020] [Accepted: 07/07/2020] [Indexed: 12/15/2022] Open
Abstract
The Retinoblastoma protein (pRb) is a key cell cycle regulator conserved in a wide variety of organisms. Experimental analysis of pRb's functions in animals and plants has revealed that this protein participates in cell proliferation and differentiation processes. In addition, pRb in animals and its orthologs in plants (RBR), are part of highly conserved protein complexes which suggest the possibility that analogies exist not only between functions carried out by pRb orthologs themselves, but also in the structure and roles of the protein networks where these proteins are involved. Here, we present examples of pRb/RBR participation in cell cycle control, cell differentiation, and in the regulation of epigenetic changes and chromatin remodeling machinery, highlighting the similarities that exist between the composition of such networks in plants and animals.
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Affiliation(s)
- Estephania Zluhan-Martínez
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de Mexico, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM 04510, Mexico; (E.Z.-M.); (M.d.l.P.S.); (B.G.-P.)
- Posgrado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Av. Universidad 3000, Coyoacán 04510, Mexico
| | - Vadim Pérez-Koldenkova
- Laboratorio Nacional de Microscopía Avanzada, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc, 330. Col. Doctores, Alc. Cuauhtémoc 06720, Mexico;
| | - Martha Verónica Ponce-Castañeda
- Unidad de Investigación Médica en Enfermedades Infecciosas, Centro Médico Nacional SXXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico;
| | - María de la Paz Sánchez
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de Mexico, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM 04510, Mexico; (E.Z.-M.); (M.d.l.P.S.); (B.G.-P.)
| | - Berenice García-Ponce
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de Mexico, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM 04510, Mexico; (E.Z.-M.); (M.d.l.P.S.); (B.G.-P.)
| | - Sergio Miguel-Hernández
- Laboratorio de Citopatología Ambiental, Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Campus Zacatenco, Calle Wilfrido Massieu Esquina Cda, Manuel Stampa 07738, Mexico;
| | - Elena R. Álvarez-Buylla
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de Mexico, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM 04510, Mexico; (E.Z.-M.); (M.d.l.P.S.); (B.G.-P.)
| | - Adriana Garay-Arroyo
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de Mexico, 3er Circuito Ext. Junto a J. Botánico, Ciudad Universitaria, UNAM 04510, Mexico; (E.Z.-M.); (M.d.l.P.S.); (B.G.-P.)
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12
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Forrer Charlier C, Martins RAP. Protective Mechanisms Against DNA Replication Stress in the Nervous System. Genes (Basel) 2020; 11:E730. [PMID: 32630049 PMCID: PMC7397197 DOI: 10.3390/genes11070730] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/25/2020] [Accepted: 06/25/2020] [Indexed: 02/06/2023] Open
Abstract
The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage and, consequently, mutations and chromosomal rearrangements. Extensive research has revealed that DNA replication stress drives genome instability during tumorigenesis. Over decades, genetic studies of inherited syndromes have established a connection between the mutations in genes required for proper DNA repair/DNA damage responses and neurological diseases. It is becoming clear that both the prevention and the responses to replication stress are particularly important for nervous system development and function. The accurate regulation of cell proliferation is key for the expansion of progenitor pools during central nervous system (CNS) development, adult neurogenesis, and regeneration. Moreover, DNA replication stress in glial cells regulates CNS tumorigenesis and plays a role in neurodegenerative diseases such as ataxia telangiectasia (A-T). Here, we review how replication stress generation and replication stress response (RSR) contribute to the CNS development, homeostasis, and disease. Both cell-autonomous mechanisms, as well as the evidence of RSR-mediated alterations of the cellular microenvironment in the nervous system, were discussed.
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Affiliation(s)
| | - Rodrigo A. P. Martins
- Programa de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil;
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13
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Abstract
Retinoblastoma, an intraocular cancer primarily affecting children, interacts with surrounding intraocular and extraocular structures in the development and progression. Subretinal and vitreous seeds are characteristic features of retinoblastoma, which result from the interaction between the tumor and its environment at the levels of tissue and microenvironment. The retina and vitreous affect the disease course and responses to treatment options. Also, neighboring cells in the retina and physicochemical properties of the tumor microenvironment are related to the biological activities of retinoblastoma tumors. Researches focusing on the tumor environment of retinoblastoma will lead to the development of more effective treatment options, which can revolutionize the prognosis of patients with retinoblastoma.
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14
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Chen ZR, Liu G. Fecal calprotectin and colorectal cancer. Shijie Huaren Xiaohua Zazhi 2019; 27:1436-1440. [DOI: 10.11569/wcjd.v27.i23.1436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Fecal calprotectin (FC) is a bioactive protein secreted by inflammatory cells in the intestine, having anti-microbial and anti-infection activities. The content of FC reflects the inflammatory state of the intestine, and its role in inflammatory bowel disease has been translated into clinical practice. In recent years, the application of FC in colorectal cancer (CRC) has been increasing. Previous research results show that FC can be used to screen colorectal cancer and differentiate it from other intestinal diseases, and the concentration of FC may be related to the stage, location, and resectability of CRC. However, its role still needs to be further clarified through high-quality, large-sample research. This paper reviews the application of FC in colorectal cancer.
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Affiliation(s)
- Zong-Ran Chen
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Gang Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
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15
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He Z, Gharaibeh RZ, Newsome RC, Pope JL, Dougherty MW, Tomkovich S, Pons B, Mirey G, Vignard J, Hendrixson DR, Jobin C. Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut 2019; 68:289-300. [PMID: 30377189 PMCID: PMC6352414 DOI: 10.1136/gutjnl-2018-317200] [Citation(s) in RCA: 253] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 09/12/2018] [Accepted: 10/04/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Campylobacter jejuni produces a genotoxin, cytolethal distending toxin (CDT), which has DNAse activity and causes DNA double-strand breaks. Although C. jejuni infection has been shown to promote intestinal inflammation, the impact of this bacterium on carcinogenesis has never been examined. DESIGN Germ-free (GF) ApcMin/+ mice, fed with 1% dextran sulfate sodium, were used to test tumorigenesis potential of CDT-producing C. jejuni. Cells and enteroids were exposed to bacterial lysates to determine DNA damage capacity via γH2AX immunofluorescence, comet assay and cell cycle assay. To examine the interplay of CDT-producing C. jejuni, gut microbiome and host in tumorigenesis, colonic RNA-sequencing and faecal 16S rDNA sequencing were performed. Rapamycin was administrated to investigate the prevention of CDT-producing C. jejuni-induced tumorigenesis. RESULTS GF ApcMin/+ mice colonised with human clinical isolate C. jejuni81-176 developed significantly more and larger tumours when compared with uninfected mice. C. jejuni with a mutated cdtB subunit, mutcdtB, attenuated C. jejuni-induced tumorigenesis in vivo and decreased DNA damage response in cells and enteroids. C. jejuni infection induced expression of hundreds of colonic genes, with 22 genes dependent on the presence of cdtB. The C. jejuni-infected group had a significantly different microbial gene expression profile compared with the mutcdtB group as shown by metatranscriptomic data, and different microbial communities as measured by 16S rDNA sequencing. Finally, rapamycin could diminish the tumorigenic capability of C. jejuni. CONCLUSION Human clinical isolate C. jejuni 81-176 promotes colorectal cancer and induces changes in microbial composition and transcriptomic responses, a process dependent on CDT production.
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Affiliation(s)
- Zhen He
- Department of Medicine, University of Florida, Gainesville, Florida, USA,Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Raad Z Gharaibeh
- Department of Medicine, University of Florida, Gainesville, Florida, USA
| | - Rachel C Newsome
- Department of Medicine, University of Florida, Gainesville, Florida, USA
| | - Jllian L Pope
- Department of Medicine, University of Florida, Gainesville, Florida, USA
| | | | - Sarah Tomkovich
- Department of Medicine, University of Florida, Gainesville, Florida, USA
| | - Benoit Pons
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, ENVT, INP- Purpan, UPS, Toulouse, France
| | - Gladys Mirey
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, ENVT, INP- Purpan, UPS, Toulouse, France
| | - Julien Vignard
- Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, ENVT, INP- Purpan, UPS, Toulouse, France
| | - David R Hendrixson
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Christian Jobin
- Department of Medicine, University of Florida, Gainesville, Florida, USA,Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida, USA,Department of Infectious Diseases and Immunology, University of Florida, Gainesville, Florida, USA
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16
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Koso H, Tsuhako A, Matsubara D, Fujita Y, Watanabe S. Ras activation in retinal progenitor cells induces tumor formation in the eye. Exp Eye Res 2018; 180:39-42. [PMID: 30500365 DOI: 10.1016/j.exer.2018.11.025] [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: 08/22/2018] [Revised: 11/15/2018] [Accepted: 11/26/2018] [Indexed: 11/25/2022]
Abstract
The RAS gene family members, H-RAS, K-RAS, and N-RAS, are frequently mutated in human cancer. A subset of retinal tumors displays K-RAS mutations; however, the specific role of RAS activation on retinal tumor formation is unclear. To examine the role of RAS in retinal development, we overexpressed the mutant H-RAS gene (G12V) in retinal progenitor cells (RPCs), a multipotent progenitor cell population that gives rise to all six neuron types in the retina and to the Muller glia. The Msi1CreER mouse strain was used to induce mosaic activation of Ras (RasV12) in the RPCs of the postnatal retina. RAS-activated RPCs translocated to the basal part of the retina, differentiated into cells with glial characteristics, and underwent apoptosis. We next induced RAS activation in a large population of RPCs in the embryonic retina using the Pax6Cre mouse strain. In contrast to the phenotype observed in Msi1CreER;RasV12 mice, Ras-activated cells retained their apical attachment. Basal translocation was partially suppressed in the retina of Pax6Cre;RasV12 mice, indicating that basal translocation of Ras-activated cells was not cell autonomous. Notably, RAS-activated retinal cells were highly proliferative and promoted the formation of eye tumors in Pax6Cre;RasV12 mice. Together, our data indicate that the tumorigenicity of RAS activation in RPCs is context dependent, with tumor formation occurring when RAS activity is present in a large cluster of embryonic RPCs.
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Affiliation(s)
- Hideto Koso
- Division of Molecular and Developmental Biology, Institute of Medical Science, The University of Tokyo, Japan
| | - Asano Tsuhako
- Division of Molecular and Developmental Biology, Institute of Medical Science, The University of Tokyo, Japan
| | - Daisuke Matsubara
- Department of Integrative Pathology, Jichi Medical University, Japan
| | - Yasuyuki Fujita
- Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Japan
| | - Sumiko Watanabe
- Division of Molecular and Developmental Biology, Institute of Medical Science, The University of Tokyo, Japan.
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17
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Jo DH, Kim JH, Kim JH. Targeting tyrosine kinases for treatment of ocular tumors. Arch Pharm Res 2018; 42:305-318. [PMID: 30470974 DOI: 10.1007/s12272-018-1094-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Accepted: 11/19/2018] [Indexed: 01/09/2023]
Abstract
Uveal melanoma is the most common intraocular primary malignant tumor in adults, and retinoblastoma is the one in children. Current mainstay treatment options include chemotherapy using conventional drugs and enucleation, the total removal of the eyeball. Targeted therapies based on profound understanding of molecular mechanisms of ocular tumors may increase the possibility of preserving the eyeball and the vision. Tyrosine kinases, which modulate signaling pathways regarding various cellular functions including proliferation, differentiation, and attachment, are one of the attractive targets for targeted therapies against uveal melanoma and retinoblastoma. In this review, the roles of both types of tyrosine kinases, receptor tyrosine kinases and non-receptor tyrosine kinases, were summarized in relation with ocular tumors. Although the conventional treatment options for uveal melanoma and retinoblastoma are radiotherapy and chemotherapy, respectively, specific tyrosine kinase inhibitors will enhance our armamentarium against them by controlling cancer-associated signaling pathways related to tyrosine kinases. This review can be a stepping stone for widening treatment options and realizing targeted therapies against uveal melanoma and retinoblastoma.
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Affiliation(s)
- Dong Hyun Jo
- Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.,Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jin Hyoung Kim
- Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.,Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jeong Hun Kim
- Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. .,Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, 08826, Republic of Korea. .,Department of Ophthalmology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea. .,Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
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18
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Abstract
Orbital tumors in children are characterised by a wide histological diversity due to the architectural complexity of the orbit. Several classifications may be proposed according to their location, histologic type and malignant or benign character. The most common clinical manifestation is the leukocoria. Diagnostic delay of these tumors, even if they are benign, may affect prognosis and lead to a loss of vision and/or a morphological deformation. Imaging plays an important role in positive diagnosis, in the differentiation between benign processes and potentially malignant processes, in the assessment of local and loco-regional staging and in follow-up monitoring under treatment. This study aimed to highlight the radiological features of primary intra-orbital tumors in children which are, in general, different from those of adults, by conducting a retrospective study of 40 medical records whose data were collected in the Division of Pediatric Radiology at the Mohammed VI University Hospital in Marrakech, Morocco over a period of 4 years (2014-2017).
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Affiliation(s)
- Dounia Basraoui
- Département de Radiologie, Hôpital Mère et Enfant, Centre d'Enseignement Mohammed VI, Faculté de Médecine de Marrakech, Université Cadi Ayad, Marrakech, Maroc
| | - Fadwa Jaafari
- Département de Radiologie, Hôpital Mère et Enfant, Centre d'Enseignement Mohammed VI, Faculté de Médecine de Marrakech, Université Cadi Ayad, Marrakech, Maroc
| | - Hicham Jalal
- Département de Radiologie, Hôpital Mère et Enfant, Centre d'Enseignement Mohammed VI, Faculté de Médecine de Marrakech, Université Cadi Ayad, Marrakech, Maroc
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19
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Asnaghi L, Tripathy A, Yang Q, Kaur H, Hanaford A, Yu W, Eberhart CG. Targeting Notch signaling as a novel therapy for retinoblastoma. Oncotarget 2018; 7:70028-70044. [PMID: 27661116 PMCID: PMC5342532 DOI: 10.18632/oncotarget.12142] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Accepted: 09/14/2016] [Indexed: 01/15/2023] Open
Abstract
Retinoblastoma is the most common intraocular malignancy of childhood. Notch plays a key role in retinal cells from which retinoblastomas arise, and we therefore studied the role of Notch signaling in promoting retinoblastoma proliferation. Moderate or strong nuclear expression of Hes1 was found in 10 of 11 human retinoblastoma samples analyzed immunohistochemically, supporting a role for Notch in retinoblastoma growth. Notch pathway components were present in WERI Rb1 and Y79 retinoblastoma lines, with Jag2 and DLL4 more highly expressed than other ligands, and Notch1 and Notch2 more abundant than Notch3. The cleaved/active form of Notch1 was detectable in both lines. Inhibition of the pathway, achieved using a γ-secretase inhibitor (GSI) or by downregulating Jag2, DLL4 or CBF1 using short hairpin RNA, potently reduced growth, proliferation and clonogenicity in both lines. Upregulation of CXCR4 and CXCR7 and downregulation of PI3KC2β were identified by microarray upon Jag2 suppression. The functional importance of PI3KC2β was confirmed using shRNA. Synergy was found by combining GSI with Melphalan at their IC50. These findings indicate that Notch pathway is active in WERI Rb1 and Y79, and in most human retinoblastoma samples, and suggest that Notch antagonists may represent a new approach to more effectively treat retinoblastoma.
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Affiliation(s)
- Laura Asnaghi
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Arushi Tripathy
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Qian Yang
- Department of Ophthalmology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Harpreet Kaur
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Allison Hanaford
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Wayne Yu
- Microarray Core Facility, Sidney Kimmel Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Charles G Eberhart
- Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.,Department of Ophthalmology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.,Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
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20
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Rickman DS, Schulte JH, Eilers M. The Expanding World of N-MYC–Driven Tumors. Cancer Discov 2018; 8:150-163. [DOI: 10.1158/2159-8290.cd-17-0273] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 08/04/2017] [Accepted: 10/18/2017] [Indexed: 11/16/2022]
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21
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Stenfelt S, Blixt MKE, All-Ericsson C, Hallböök F, Boije H. Heterogeneity in retinoblastoma: a tale of molecules and models. Clin Transl Med 2017; 6:42. [PMID: 29124525 PMCID: PMC5680409 DOI: 10.1186/s40169-017-0173-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 10/26/2017] [Indexed: 12/13/2022] Open
Abstract
Retinoblastoma, an intraocular pediatric cancer, develops in the embryonic retina following biallelic loss of RB1. However, there is a wide range of genetic and epigenetic changes that can affect RB1 resulting in different clinical outcomes. In addition, other transformations, such as MYCN amplification, generate particularly aggressive tumors, which may or may not be RB1 independent. Recognizing the cellular characteristics required for tumor development, by identifying the elusive cell-of-origin for retinoblastoma, would help us understand the development of these tumors. In this review we summarize the heterogeneity reported in retinoblastoma on a molecular, cellular and tissue level. We also discuss the challenging heterogeneity in current retinoblastoma models and suggest future platforms that could contribute to improved understanding of tumor initiation, progression and metastasis in retinoblastoma, which may ultimately lead to more patient-specific treatments.
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Affiliation(s)
- Sonya Stenfelt
- Department of Neuroscience, Uppsala University, 75124, Uppsala, Sweden
| | - Maria K E Blixt
- Department of Neuroscience, Uppsala University, 75124, Uppsala, Sweden
| | | | - Finn Hallböök
- Department of Neuroscience, Uppsala University, 75124, Uppsala, Sweden
| | - Henrik Boije
- Department of Neuroscience, Uppsala University, 75124, Uppsala, Sweden.
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22
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Olmedillas-López S, Lévano-Linares DC, Alexandre CLA, Vega-Clemente L, Sánchez EL, Villagrasa A, Ruíz-Tovar J, García-Arranz M, García-Olmo D. Detection of KRAS G12D in colorectal cancer stool by droplet digital PCR. World J Gastroenterol 2017; 23:7087-7097. [PMID: 29093617 PMCID: PMC5656456 DOI: 10.3748/wjg.v23.i39.7087] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 09/15/2017] [Accepted: 09/26/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To assess KRAS G12D mutation detection by droplet digital PCR (ddPCR) in stool-derived DNA from colorectal cancer (CRC) patients.
METHODS In this study, tumor tissue and stool samples were collected from 70 patients with stage I-IV CRC diagnosed by preoperative biopsy. KRAS mutational status was determined by pyrosequencing analysis of DNA obtained from formalin-fixed paraffin-embedded (FFPE) tumor tissues. The KRAS G12D mutation was then analyzed by ddPCR in FFPE tumors and stool-derived DNA from patients with this point mutation. Wild-type (WT) tumors, as determined by pyrosequencing, were included as controls; analysis of FFPE tissue and stool-derived DNA by ddPCR was performed for these patients as well.
RESULTS Among the total 70 patients included, KRAS mutations were detected by pyrosequencing in 32 (45.71%), whereas 38 (54.29%) had WT tumors. The frequency of KRAS mutations was higher in left-sided tumors (11 located in the right colon, 15 in the left, and 6 in the rectum). The predominant point mutation was KRAS G12D (14.29%, n = 10), which was more frequent in early-stage tumors (I-IIA, n = 7). In agreement with pyrosequencing results, the KRAS G12D mutation was detected by ddPCR in FFPE tumor-derived DNA, and only a residual number of mutated copies was found in WT controls. The KRAS G12D mutation was also detected in stool-derived DNA in 80% of all fecal samples from CRC patients with this point mutation.
CONCLUSION ddPCR is a reliable and sensitive method to analyze KRAS G12D mutation in stool-derived DNA from CRC patients, especially at early stages. This non-invasive approach is potentially applicable to other relevant biomarkers for CRC management.
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Affiliation(s)
- Susana Olmedillas-López
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
| | - Dennis César Lévano-Linares
- Department of Surgery, School of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
- Department of Surgery, Rey Juan Carlos University Hospital, Madrid 28933, Spain
| | | | - Luz Vega-Clemente
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
| | - Edurne León Sánchez
- Department of Biomedicine and Biotechnology, Universidad de Alcalá, Madrid 28805, Spain
| | - Alejandro Villagrasa
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
| | - Jaime Ruíz-Tovar
- Department of Surgery, Rey Juan Carlos University Hospital, Madrid 28933, Spain
| | - Mariano García-Arranz
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
- Department of Surgery, School of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
| | - Damián García-Olmo
- Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
- Department of Surgery, School of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid 28040, Spain
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23
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Jo DH, Lee K, Kim JH, Jun HO, Kim Y, Cho YL, Yu YS, Min JK, Kim JH. L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma. Oncotarget 2017; 8:15441-15452. [PMID: 28061460 PMCID: PMC5362498 DOI: 10.18632/oncotarget.14487] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 12/13/2016] [Indexed: 01/07/2023] Open
Abstract
Retinoblastoma is the most common intraocular cancer in children, affecting 1/20,000 live births. Currently, children with retinoblastoma were treated with chemotherapy using drugs such as carboplatin, vincristine, and etoposide. Unfortunately, if conventional treatment fails, the affected eyes should be removed to prevent extension into adjacent tissues and metastasis. This study is to investigate the roles of L1 in adhesion-mediated proliferation and chemoresistance of retinoblastoma. L1 was differentially expressed in 30 retinoblastoma tissues and 2 retinoblastoma cell lines. Furthermore, the proportions of L1-positive cells in retinoblastoma tumors were negatively linked with the number of Flexner-Wintersteiner rosettes, a characteristic of differentiated retinoblastoma tumors, in each tumor sample. Following in vitro experiments using L1-deleted and -overexpressing cells showed that L1 increased adhesion-mediated proliferation of retinoblastoma cells via regulation of cell cycle-associated proteins with modulation of Akt, extracellular signal-regulated kinase, and p38 pathways. In addition, L1 increased resistance against carboplatin, vincristine, and esoposide through up-regulation of apoptosis- and multidrug resistance-related genes. In vivo tumor formation and chemoresistance were also positively linked with the levels of L1 in an orthotopic transplantation model in mice. In this manner, L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma. Targeted therapy to L1 might be effective in the treatment of retinoblastoma tumors, especially which rapidly proliferate and demonstrate resistance to conventional chemotherapeutic drugs.
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Affiliation(s)
- Dong Hyun Jo
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.,Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea
| | - Kyungmin Lee
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.,Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea
| | - Jin Hyoung Kim
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea
| | - Hyoung Oh Jun
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea
| | - Younghoon Kim
- Department of Pathology, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Young-Lai Cho
- Department of Chemistry, Dongguk University, Seoul, Republic of Korea
| | - Young Suk Yu
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Ki Min
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.,Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea
| | - Jeong Hun Kim
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.,Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea.,Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
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24
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Abstract
In this review, Dyson summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients? The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?
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Aldiri I, Ajioka I, Xu B, Zhang J, Chen X, Benavente C, Finkelstein D, Johnson D, Akiyama J, Pennacchio LA, Dyer MA. Brg1 coordinates multiple processes during retinogenesis and is a tumor suppressor in retinoblastoma. Development 2016; 142:4092-106. [PMID: 26628093 PMCID: PMC4712833 DOI: 10.1242/dev.124800] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 (Smarca4) in retinal development and retinoblastoma in mice using molecular and cellular approaches. Brg1 was found to regulate retinal size by controlling cell cycle length, cell cycle exit and cell survival during development. Brg1 was not required for cell fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, making them more susceptible to retinoblastoma. ChIP-Seq analysis suggests that Brg1 might regulate gene expression through multiple mechanisms. Summary: The SWI/SNF protein Brg1 controls cell cycle length, cell cycle exit and cell survival, and is required for cell differentiation and retinal lamination, in the developing mouse retina.
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Affiliation(s)
- Issam Aldiri
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Itsuki Ajioka
- Center for Brain Integration Research (CBIR), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan
| | - Beisi Xu
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Jiakun Zhang
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Xiang Chen
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Claudia Benavente
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - David Finkelstein
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Dianna Johnson
- Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Jennifer Akiyama
- Lawrence Berkeley National Laboratory, Genomics Division, Berkeley, CA 94701, USA Department of Energy, Joint Genome Institute, Walnut Creek, CA 94598, USA
| | - Len A Pennacchio
- Lawrence Berkeley National Laboratory, Genomics Division, Berkeley, CA 94701, USA Department of Energy, Joint Genome Institute, Walnut Creek, CA 94598, USA
| | - Michael A Dyer
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
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Rennoll S, Yochum G. Regulation of MYC gene expression by aberrant Wnt/β-catenin signaling in colorectal cancer. World J Biol Chem 2015; 6:290-300. [PMID: 26629312 PMCID: PMC4657124 DOI: 10.4331/wjbc.v6.i4.290] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 08/26/2015] [Accepted: 10/13/2015] [Indexed: 02/05/2023] Open
Abstract
The Wnt/β-catenin signaling pathway controls intestinal homeostasis and mutations in components of this pathway are prevalent in human colorectal cancers (CRCs). These mutations lead to inappropriate expression of genes controlled by Wnt responsive DNA elements (WREs). T-cell factor/Lymphoid enhancer factor transcription factors bind WREs and recruit the β-catenin transcriptional co-activator to activate target gene expression. Deregulated expression of the c-MYC proto-oncogene (MYC) by aberrant Wnt/β-catenin signaling drives colorectal carcinogenesis. In this review, we discuss the current literature pertaining to the identification and characterization of WREs that control oncogenic MYC expression in CRCs. A common theme has emerged whereby these WREs often map distally to the MYC genomic locus and control MYC gene expression through long-range chromatin loops with the MYC proximal promoter. We propose that by determining which of these WREs is critical for CRC pathogenesis, novel strategies can be developed to treat individuals suffering from this disease.
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Abstract
Diffuse anterior retinoblastoma is a rare variant of retinoblastoma seeding in the area of the vitreous base and anterior chamber. Patients with diffuse anterior retinoblastoma are older than those with the classical types, with the mean age being 6.1 years. The original cells of diffuse anterior retinoblastoma are supposed to be cone precursor. Patients most commonly present with pseudouveitis, pseudohypopyon, and increased intraocular pressure. The retina under fundus examination is likely to be normal, and the clinical features mimic the inflammation progress, which can often lead to misdiagnosis. The published diffuse anterior retinoblastoma cases were diagnosed after fine-needle aspiration biopsy running the potential risk of inducing metastasis. The most common treatment for diffuse anterior retinoblastoma is enucleation followed by systematic chemotherapy according to the patient’s presentation and clinical course. This review summarizes the recent advances in etiology (including tumorigenesis and cell origin), pathology, diagnosis, differential diagnosis, and new treatment. The challenges of early diagnosis and prospects are also discussed.
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Affiliation(s)
- Jing Yang
- Department of Ophthalmology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou City, Henan Province, People's Republic of China ; Department of Ophthalmology, Peking University Third Hospital, Beijing, People's Republic of China ; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, People's Republic of China
| | - Yalong Dang
- Department of Ophthalmology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou City, Henan Province, People's Republic of China ; Department of Ophthalmology, Peking University Third Hospital, Beijing, People's Republic of China ; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, People's Republic of China
| | - Yu Zhu
- Department of Ophthalmology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou City, Henan Province, People's Republic of China
| | - Chun Zhang
- Department of Ophthalmology, Peking University Third Hospital, Beijing, People's Republic of China ; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, People's Republic of China
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Sethi MK, Kim H, Park CK, Baker MS, Paik YK, Packer NH, Hancock WS, Fanayan S, Thaysen-Andersen M. In-depth N-glycome profiling of paired colorectal cancer and non-tumorigenic tissues reveals cancer-, stage- and EGFR-specific protein N-glycosylation. Glycobiology 2015; 25:1064-78. [PMID: 26085185 DOI: 10.1093/glycob/cwv042] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 06/11/2015] [Indexed: 01/01/2023] Open
Abstract
Glycomics may assist in uncovering the structure-function relationships of protein glycosylation and identify glycoprotein markers in colorectal cancer (CRC) research. Herein, we performed label-free quantitative glycomics on a carbon-liquid chromatography-tandem mass spectrometry-based analytical platform to accurately profile the N-glycosylation changes associated with CRC malignancy. N-Glycome profiling was performed on isolated membrane proteomes of paired tumorigenic and adjacent non-tumorigenic colon tissues from a cohort of five males (62.6 ± 13.1 y.o.) suffering from colorectal adenocarcinoma. The CRC tissues were typed according to their epidermal growth factor receptor (EGFR) status by western blotting and immunohistochemistry. Detailed N-glycan characterization and relative quantitation identified an extensive structural heterogeneity with a total of 91 N-glycans. CRC-specific N-glycosylation phenotypes were observed including an overrepresentation of high mannose, hybrid and paucimannosidic type N-glycans and an under-representation of complex N-glycans (P < 0.05). Sialylation, in particular α2,6-sialylation, was significantly higher in CRC tumors relative to non-tumorigenic tissues, whereas α2,3-sialylation was down-regulated (P < 0.05). CRC stage-specific N-glycosylation was detected by high α2,3-sialylation and low bisecting β1,4-GlcNAcylation and Lewis-type fucosylation in mid-late relative to early stage CRC. Interestingly, a novel link between the EGFR status and the N-glycosylation was identified using hierarchical clustering of the N-glycome profiles. EGFR-specific N-glycan signatures included high bisecting β1,4-GlcNAcylation and low α2,3-sialylation (both P < 0.05) relative to EGFR-negative CRC tissues. This is the first study to correlate CRC stage and EGFR status with specific N-glycan features, thus advancing our understanding of the mechanisms causing the biomolecular deregulation associated with CRC.
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Affiliation(s)
| | - Hoguen Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Korea
| | - Cheol Keun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Korea
| | - Mark S Baker
- Department of Biomedical Sciences, Macquarie University, North Ryde NSW 2109, Australia
| | - Young-Ki Paik
- Yonsei Proteome Research Center, Yonsei University, Seoul 120-749, Korea
| | | | - William S Hancock
- Department of Biomedical Sciences, Macquarie University, North Ryde NSW 2109, Australia Barnett Institute and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA
| | - Susan Fanayan
- Department of Biomedical Sciences, Macquarie University, North Ryde NSW 2109, Australia
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Cerman E, Çekiç O. Clinical use of photodynamic therapy in ocular tumors. Surv Ophthalmol 2015; 60:557-74. [PMID: 26079736 DOI: 10.1016/j.survophthal.2015.05.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 05/15/2015] [Accepted: 05/18/2015] [Indexed: 01/10/2023]
Abstract
Although the introduction of intravitreal anti-vascular endothelial growth factor drugs reduced the indications for photodynamic therapy in ophthalmology, it may still be used in various ocular tumors. Although many studies have shown that photodynamic therapy is effective in ocular tumors, the literature consists of case reports and series. In this review, we systematically performed a meta-analysis for the use of photodynamic therapy in circumscribed choroidal hemangioma, diffuse choroidal hemangioma, retinal capillary hemangioma, von Hippel-Lindau angiomatosis, choroidal melanoma, retinal astrocytoma, retinoblastoma, eyelid tumors, conjunctival tumors, and choroidal metastasis.
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Affiliation(s)
- Eren Cerman
- Department of Ophthalmology, Marmara University School of Medicine, Istanbul, Turkey
| | - Osman Çekiç
- Department of Ophthalmology, Marmara University School of Medicine, Istanbul, Turkey.
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30
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Stewart E, Federico S, Karlstrom A, Shelat A, Sablauer A, Pappo A, Dyer MA. The Childhood Solid Tumor Network: A new resource for the developmental biology and oncology research communities. Dev Biol 2015; 411:287-293. [PMID: 26068307 DOI: 10.1016/j.ydbio.2015.03.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Significant advances have been made over the past 25 years in our understanding of the most common adult solid tumors such as breast, colon, lung and prostate cancer. Much less is known about childhood solid tumors because they are rare and because they originate in developing organs during fetal development, childhood and adolescence. It can be very difficult to study the cellular origins of pediatric solid tumors in developing organs characterized by rapid proliferative expansion, growth factor signaling, developmental angiogenesis, programmed cell death, tissue reorganization and cell migration. Not only has the etiology of pediatric cancer remained elusive because of their developmental origins, but it also makes it more difficult to treat. Molecular targeted therapeutics that alter developmental pathway signaling may have devastating effects on normal organ development. Therefore, basic research focused on the mechanisms of development provides an essential foundation for pediatric solid tumor translational research. In this article, we describe new resources available for the developmental biology and oncology research communities. In a companion paper, we present the detailed characterization of an orthotopic xenograft of a pediatric solid tumor derived from sympathoadrenal lineage during development.
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Affiliation(s)
- Elizabeth Stewart
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Sara Federico
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Asa Karlstrom
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Anang Shelat
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Andras Sablauer
- Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Alberto Pappo
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Michael A Dyer
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
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31
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Chen X, Pappo A, Dyer MA. Pediatric solid tumor genomics and developmental pliancy. Oncogene 2015; 34:5207-15. [PMID: 25639868 PMCID: PMC4522402 DOI: 10.1038/onc.2014.474] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 12/09/2014] [Accepted: 12/09/2014] [Indexed: 12/13/2022]
Abstract
Pediatric solid tumors are remarkably diverse in their cellular origins, developmental timing and clinical features. Over the last 5 years, there have been significant advances in our understanding of the genetic lesions that contribute to the initiation and progression of pediatric solid tumors. To date, over 1000 pediatric solid tumors have been analyzed by Next-Generation Sequencing. These genomic data provide the foundation to launch new research efforts to address one of the fundamental questions in cancer biology—why are some cells more susceptible to malignant transformation by particular genetic lesions at discrete developmental stages than others? Because of their developmental, molecular, cellular and genetic diversity, pediatric solid tumors provide an ideal platform to begin to answer this question. In this review, we highlight the diversity of pediatric solid tumors and provide a new framework for studying the cellular and developmental origins of pediatric cancer. We also introduce a new unifying concept called cellular pliancy as a possible explanation for susceptibility to cancer and the developmental origins of pediatric solid tumors.
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Affiliation(s)
- X Chen
- Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - A Pappo
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - M A Dyer
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.,Howard Hughes Medical Institute, Chevy Chase, MD, USA
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Abstract
Heritable germline mutations in major cancer genes generally lead to a restricted pattern of tissue-specific malignancies, yet many of the same mutations frequently occur somatically in a broad range of spontaneous neoplasms affecting different organs. Might this reflect a difference in tumorigenesis in children and adults?
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33
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34
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Zhang H, Zhu YQ, Wu YQ, Zhang P, Qi J. Detection of promoter hypermethylation of Wnt antagonist genes in fecal samples for diagnosis of early colorectal cancer. World J Gastroenterol 2014; 20:6329-6335. [PMID: 24876755 PMCID: PMC4033472 DOI: 10.3748/wjg.v20.i20.6329] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the feasibility of detecting aberrantly hypermethylated Wnt-antagonist gene promoters (SFRP2 and WIF-1) in fecal DNA as non-invasive biomarkers for early colorectal cancer (CRC).
METHODS: The methylation-specific polymerase chain reaction assay was performed to blindly analyze the methylation status of SFRP2 and WIF-1 gene promoters in fecal samples from 48 subjects with CRC, 35 with adenomas, 32 with hyperplastic polyps and 30 endoscopically normal subjects. Additionally, we compared the diagnostic efficiency of measuring the hypermethylated SFRP2 and WIF-1 genes in the feces to the fecal occult blood test (FOBT) for the early detection of CRC.
RESULTS: Hypermethylated SFRP2 was detected in the feces of 56.3% (27/48) of CRC cases, 51.4% (18/35) of adenoma cases and 12.5% (4/32) of patients with hyperplastic polyps. The hypermethylation of WIF-1 was detected in 60.4% (29/48), 45.7% (16/35) and 18.7% (6/32) of fecal samples from CRC, adenoma and hyperplastic polyp patients, respectively. At least one hypermethylated gene was detected in 81.3% (39/48) of CRC and 65.7% (23/35) of adenoma samples. In contrast, only a hypermethylated WIF-1 gene was detected in one case of normal fecal samples. Moreover, no significant associations were observed between SFPR2 and WIF-1 hypermethylation and clinicopathological features. Additionally, 81.8% of CRC cases diagnosed as Dukes A stage or advanced adenomas had at least one hypermethylated gene detected, while the detection rate with the FOBT was only 31.8% (P < 0.001).
CONCLUSION: Hypermethylated SFRP2 and WIF-1 genes in fecal DNA are novel and promising molecular biomarkers that have great diagnostic potential for early CRC.
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Xiao W, Chen X, He M. Inhibition of the Jagged/Notch pathway inhibits retinoblastoma cell proliferation via suppressing the PI3K/Akt, Src, p38MAPK and Wnt/β‑catenin signaling pathways. Mol Med Rep 2014; 10:453-8. [PMID: 24805975 DOI: 10.3892/mmr.2014.2213] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 03/28/2014] [Indexed: 11/06/2022] Open
Abstract
The Notch signaling pathway is a highly conserved developmental pathway, which is important in the regulation of cellular proliferation, differentiation and apoptosis. The aberrant expression of the Notch pathway has been associated with carcinogenesis in various types of cancer. In order to investigate the expression profiles and biological functions of Notch receptors and ligands in retinoblastoma, the expression levels of their proteins in the human retinoblastoma cell line SO‑Rb50 using western blot analysis was assessed. The present study revealed that Notch1 and Jagged2 were highly expressed compared with human retinal pigment epithelial cells. When treated with DAPT, a specific inhibitor of Notch receptor cleavage, expression of Notch1 and Jagged2 were downregulated in a dose‑dependent manner, which was accompanied by substantial cell growth arrest, as indicated by the Cell Counting kit‑8 assay. In addition, phosphorylation of Akt, p38 mitogen‑activated protein kinase and Src, together with the expression of phosphoinositide 3‑kinase and β‑catenin, was abated in a dose‑dependent manner. However, expression of either total extracellular signal‑regulated kinase (Erk)1/2 or phospho‑Erk1/2 was not changed in SO‑Rb50 cells. These findings demonstrated that the Jagged2/Notch1 pathway can promote oncogenesis in retinoblastoma in co‑operation with multiple signaling pathways. The inhibition of the Notch signaling pathway by DAPT represents a potentially attractive strategy for the therapy of retinoblastoma.
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Affiliation(s)
- Wei Xiao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Xiaoyun Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Mingguang He
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510060, P.R. China
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Walther J, Schastak S, Dukic-Stefanovic S, Wiedemann P, Neuhaus J, Claudepierre T. Efficient photodynamic therapy on human retinoblastoma cell lines. PLoS One 2014; 9:e87453. [PMID: 24498108 PMCID: PMC3909110 DOI: 10.1371/journal.pone.0087453] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 12/29/2013] [Indexed: 01/10/2023] Open
Abstract
Photodynamic therapy (PDT) has shown to be a promising technique to treat various forms of malignant neoplasia. The photodynamic eradication of the tumor cells is achieved by applying a photosensitizer either locally or systemically and following local activation through irradiation of the tumor mass with light of a specific wavelength after a certain time of incubation. Due to preferential accumulation of the photosensitizer in tumor cells, this procedure allows a selective inactivation of the malignant tumor while sparing the surrounding tissue to the greatest extent. These features and requirements make the PDT an attractive therapeutic option for the treatment of retinoblastoma, especially when surgical enucleation is a curative option. This extreme solution is still in use in case of tumours that are resistant to conventional chemotherapy or handled too late due to poor access to medical care in less advanced country. In this study we initially conducted in-vitro investigations of the new cationic water-soluble photo sensitizer tetrahydroporphyrin-tetratosylat (THPTS) regarding its photodynamic effect on human Rb-1 and Y79 retinoblastoma cells. We were able to show, that neither the incubation with THPTS without following illumination, nor the sole illumination showed a considerable effect on the proliferation of the retinoblastoma cells, whereas the incubation with THPTS combined with following illumination led to a maximal cytotoxic effect on the tumor cells. Moreover the phototoxicity was lower in normal primary cells from retinal pigmented epithelium demonstrating a higher phototoxic effect of THPTS in cancer cells than in this normal retinal cell type. The results at hand form an encouraging foundation for further in-vivo studies on the therapeutic potential of this promising photosensitizer for the eyeball and vision preserving as well as potentially curative therapy of retinoblastoma.
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Affiliation(s)
- Jan Walther
- Department of Ophthalmology, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Stanislas Schastak
- Department of Ophthalmology, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | | | - Peter Wiedemann
- Department of Ophthalmology, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Jochen Neuhaus
- Department of Urology, University of Leipzig, Leipzig, Germany
| | - Thomas Claudepierre
- Department of Ophthalmology, Faculty of Medicine, University of Leipzig, Leipzig, Germany
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Maio GD, Rengucci C, Zoli W, Calistri D. Circulating and stool nucleic acid analysis for colorectal cancer diagnosis. World J Gastroenterol 2014; 20:957-67. [PMID: 24574768 PMCID: PMC3921547 DOI: 10.3748/wjg.v20.i4.957] [Citation(s) in RCA: 26] [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: 09/26/2013] [Revised: 12/05/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
In recent years, the need to identify molecular markers characterized by high sensitivity and specificity in detecting and monitoring early and colorectal cancer lesions has increased. Up to now, none of the markers or panels of markers analyzed have met the rigorous standards required of a screening program. The important discovery of circulating nucleic acids in biological fluids has aroused intense scientific interest because of their usefulness in malignant and non malignant diseases. Over time, their yield and stability have been identified and compared with other "standard" biomarkers. The analysis of circulating DNA from blood and stool is a relatively simple and non-invasive procedure, representing a very attractive marker to detect genetic and epigenetic mutations and to monitor disease progression. A correlation between blood and stool biomarkers could also help to enhance currently available diagnostic approaches. However, various processing and analytic problems need to be resolved before such an approach can be applied in clinical practice.
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38
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Pentimalli F, Indovina P, Giordano A. Retinoblastoma beyondRB1: recent advances in genetic biomarkers. EXPERT REVIEW OF OPHTHALMOLOGY 2014. [DOI: 10.1586/eop.10.75] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Jo DH, Son D, Na Y, Jang M, Choi JH, Kim JH, Yu YS, Seok SH, Kim JH. Orthotopic transplantation of retinoblastoma cells into vitreous cavity of zebrafish for screening of anticancer drugs. Mol Cancer 2013; 12:71. [PMID: 23835085 PMCID: PMC3707771 DOI: 10.1186/1476-4598-12-71] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Accepted: 07/03/2013] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND With high throughput screening, novel therapeutic agents can be efficiently identified. Unfortunately, researchers only resort to in vitro cell viability assays for screening of anticancer drugs for retinoblastoma, the most common intraocular cancer in the childhood. Current available animal models of retinoblastoma require more than 2 weeks for tumour formation and the investigation of the efficacy of therapeutic agents. In this study, we established a novel orthotopic transplantation model of retinoblastoma in zebrafish as an in vivo animal model for screening of anticancer drugs. METHODS We injected retinoblastoma cells into the vitreous cavity of zebrafish at 48 hours after fertilization. Eyeballs of zebrafish were scanned daily under the confocal laser microscope, and the tumor population was quantitatively analyzed by measuring the mean intensity of green fluorescent protein (GFP). Transplanted retinoblastoma cells were isolated to perform further analyses including Western blotting and reverse transcriptase-polymerase chain reaction to confirm that retinoblastoma cells maintained their characteristics as tumor cells even after transplantation and further isolation. To figure out the potential of this model for screening of anticancer drugs, zebrafish were cultured in Ringer's solution containing carboplatin and melphalan after the injection of retinoblastoma cells. RESULTS The degree of the tumor population was dependent on the number of retinoblastoma cells injected and maintained stably for at least 4 days. Transplanted retinoblastoma cells maintain their proliferative potential and characteristics as retinoblastoma cells after isolation. Interestingly, systemic application of carboplatin and melphalan demonstrated significant reduction in the tumor population, which could be quantitatively analyzed by the estimation of the mean intensity of GFP. CONCLUSIONS This orthotopic retinoblastoma model in zebrafish is expected to be utilized for the screening of anticancer drugs for the treatment of retinoblastoma.
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Affiliation(s)
- Dong Hyun Jo
- Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
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40
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Luo C, Deng YP. Retinoblastoma: concerning its initiation and treatment. Int J Ophthalmol 2013; 6:397-401. [PMID: 23826540 DOI: 10.3980/j.issn.2222-3959.2013.03.26] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 03/22/2013] [Indexed: 02/05/2023] Open
Abstract
Retinoblastoma (RB) is the most common intraocular cancer of infancy and childhood. This cancer is initiated by mutation on RB1, the tumor suppressor gene that is responsible for the regulation of both cell cycle and gnome stability in retinal cells. Patients with a constitutional mutation on RB1 can be inherited. RB occurs approximately 1 in every 15 000-20 000 live births. The worldwide mortality for this cancer is about 5%-11%. However, this rate rises to about 40%-70% in developing countries due to a delay in diagnosis. A wide variety of options are available for the treatment, but often a combination of therapies is adopted to optimize individualized care.
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Affiliation(s)
- Chang Luo
- Department of Ophthalmology, West China Hospital, Sichuan University, 37# Guo Xue Xiang, Chengdu 610041, Sichuan Province, China
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Kapatai G, Brundler MA, Jenkinson H, Kearns P, Parulekar M, Peet AC, McConville CM. Gene expression profiling identifies different sub-types of retinoblastoma. Br J Cancer 2013; 109:512-25. [PMID: 23756868 PMCID: PMC3721394 DOI: 10.1038/bjc.2013.283] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 05/16/2013] [Accepted: 05/16/2013] [Indexed: 02/06/2023] Open
Abstract
Background: Mutation of the RB1 gene is necessary but not sufficient for the development of retinoblastoma. The nature of events occurring subsequent to RB1 mutation is unclear, as is the retinal cell-of-origin of this tumour. Methods: Gene expression profiling of 21 retinoblastomas was carried out to identify genetic events that contribute to tumorigenesis and to obtain information about tumour histogenesis. Results: Expression analysis showed a clear separation of retinoblastomas into two groups. Group 1 retinoblastomas express genes associated with a range of different retinal cell types, suggesting derivation from a retinal progenitor cell type. Recurrent chromosomal alterations typical of retinoblastoma, for example, chromosome 1q and 6p gain and 16q loss were also a feature of this group, and clinically they were characterised by an invasive pattern of tumour growth. In contrast, group 2 retinoblastomas were found to retain many characteristics of cone photoreceptor cells and appear to exploit the high metabolic capacity of this cell type in order to promote tumour proliferation. Conclusion: Retinoblastoma is a heterogeneous tumour with variable biology and clinical characteristics.
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Affiliation(s)
- G Kapatai
- School of Cancer Sciences, Vincent Drive, University of Birmingham, Birmingham, UK
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A clinical update and radiologic review of pediatric orbital and ocular tumors. JOURNAL OF ONCOLOGY 2013; 2013:975908. [PMID: 23577029 PMCID: PMC3610355 DOI: 10.1155/2013/975908] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Revised: 01/14/2013] [Accepted: 01/20/2013] [Indexed: 12/15/2022]
Abstract
While pediatric orbital tumors are most often managed in tertiary care centers, clinicians should be aware of the signs of intraocular and orbital neoplasms. In the pediatric population, a delay in diagnosis of orbital and intraocular lesions, even if benign, can lead to vision loss and deformity. Intraocular lesions reviewed are retinoblastoma, medulloepithelioma, and retinal astrocytic hamartoma. Orbital neoplasms reviewed are rhabdomyosarcoma, neuroblastoma metastases, optic pathway glioma, plexiform neurofibroma, leukemia, lymphoprolipherative disease, orbital inflammatory syndrome, dermoid and epidermoid inclusion cysts, and Langerhans' cell histiocytosis. Vascular lesions reviewed are infantile hemangioma and venous lymphatic malformation. In conjunction with clinical examination, high-resolution ophthalmic imaging and radiologic imaging play an important role in making a diagnosis and differentiating between benign and likely malignant processes. The radiologic imaging characteristics of these lesions will be discussed to facilitate prompt diagnosis and treatment. The current treatment modalities and management of tumors will also be reviewed.
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43
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Hong L, Ahuja N. DNA methylation biomarkers of stool and blood for early detection of colon cancer. Genet Test Mol Biomarkers 2013; 17:401-6. [PMID: 23406208 DOI: 10.1089/gtmb.2012.0478] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Detection of colorectal cancer at an early stage may significantly decrease mortality from the disease. The current screening test of colonoscopy is of high efficacy, but its acceptance in the general public is rather low. Availability of a blood- or stool-based test of DNA methylation markers is expected to improve the screening compliance for colon cancer in the general population. The goal of this review is to describe the recent advances in DNA methylation markers of stool and blood for early detection of colon cancer, and envisage future developments toward their clinical availability. More investigations should be performed to promote both basic and clinical research of DNA methylation markers in patients with colon cancer.
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Affiliation(s)
- Liu Hong
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
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Shen H, Tang Y, Xu X, Tang H. Detection of the GD2+/CD56+/CD45- immunophenotype by flow cytometry in cerebrospinal fluids from a patient with retinoblastoma. Pediatr Hematol Oncol 2013; 30:30-2. [PMID: 23126274 DOI: 10.3109/08880018.2012.737094] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Triple-color flow cytometry with a panel of antibodies comprising GD2, CD56, and CD45 was performed to analyze cerebrospinal fluids (CSF) from a patient with retinoblastoma who was suspicious of meningeal metastasis based on clinical presentation. Our results showed that the cells in CSF demonstrated the immunophenotype positive for GD2 and CD56 but negative for CD45 antigen, which suggested the presence of CSF metastasis of retinoblastoma. At the end of eight cycles of intrathecal chemotherapy, CSF specimen was analyzed with Flow cytometry immunophenotyping (FCI) again and the result showed no detectable malignant cells with the same immunophenotype. Our conclusion is that FCI can be a quick and reliable method for the diagnosis of CSF metastasis of retinoblastoma and the immunophenotype (GD2+, CD56+, and CD45-) can be used to recognize residual retinoblastoma cells in CSF.
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Affiliation(s)
- Hongqiang Shen
- Division of Hematology-Oncology, Key Laboratory of Reproductive Genetics (Zhejiang University, Ministry of Education), Children's Hospital of Zhejiang University School of Medicine, Hangzhou, PR China
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Bartesaghi S, Salomoni P. Tumor suppressive pathways in the control of neurogenesis. Cell Mol Life Sci 2013; 70:581-97. [PMID: 22802124 PMCID: PMC11113109 DOI: 10.1007/s00018-012-1063-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Revised: 06/16/2012] [Accepted: 06/18/2012] [Indexed: 12/16/2022]
Abstract
The generation of specialized neural cells in the developing and postnatal central nervous system is a highly regulated process, whereby neural stem cells divide to generate committed neuronal progenitors, which then withdraw from the cell cycle and start to differentiate. Cell cycle checkpoints play a major role in regulating the balance between neural stem cell expansion and differentiation. Loss of tumor suppressors involved in checkpoint control can lead to dramatic alterations of neurogenesis, thus contributing to neoplastic transformation. Here we summarize and critically discuss the existing literature on the role of tumor suppressive pathways and their regulatory networks in the control of neurogenesis and transformation.
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Affiliation(s)
- Stefano Bartesaghi
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD UK
| | - Paolo Salomoni
- Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD UK
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46
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Aktipis CA, Nesse RM. Evolutionary foundations for cancer biology. Evol Appl 2013; 6:144-59. [PMID: 23396885 PMCID: PMC3567479 DOI: 10.1111/eva.12034] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 10/12/2012] [Indexed: 12/16/2022] Open
Abstract
New applications of evolutionary biology are transforming our understanding of cancer. The articles in this special issue provide many specific examples, such as microorganisms inducing cancers, the significance of within-tumor heterogeneity, and the possibility that lower dose chemotherapy may sometimes promote longer survival. Underlying these specific advances is a large-scale transformation, as cancer research incorporates evolutionary methods into its toolkit, and asks new evolutionary questions about why we are vulnerable to cancer. Evolution explains why cancer exists at all, how neoplasms grow, why cancer is remarkably rare, and why it occurs despite powerful cancer suppression mechanisms. Cancer exists because of somatic selection; mutations in somatic cells result in some dividing faster than others, in some cases generating neoplasms. Neoplasms grow, or do not, in complex cellular ecosystems. Cancer is relatively rare because of natural selection; our genomes were derived disproportionally from individuals with effective mechanisms for suppressing cancer. Cancer occurs nonetheless for the same six evolutionary reasons that explain why we remain vulnerable to other diseases. These four principles-cancers evolve by somatic selection, neoplasms grow in complex ecosystems, natural selection has shaped powerful cancer defenses, and the limitations of those defenses have evolutionary explanations-provide a foundation for understanding, preventing, and treating cancer.
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Affiliation(s)
- C Athena Aktipis
- Center for Evolution and Cancer, University of California San Francisco, CA, USA ; Department of Psychology, Arizona State University Tempe, AZ, USA
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47
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Lempiäinen H, Couttet P, Bolognani F, Müller A, Dubost V, Luisier R, Del Rio Espinola A, Vitry V, Unterberger EB, Thomson JP, Treindl F, Metzger U, Wrzodek C, Hahne F, Zollinger T, Brasa S, Kalteis M, Marcellin M, Giudicelli F, Braeuning A, Morawiec L, Zamurovic N, Längle U, Scheer N, Schübeler D, Goodman J, Chibout SD, Marlowe J, Theil D, Heard DJ, Grenet O, Zell A, Templin MF, Meehan RR, Wolf RC, Elcombe CR, Schwarz M, Moulin P, Terranova R, Moggs JG. Identification of Dlk1-Dio3 imprinted gene cluster noncoding RNAs as novel candidate biomarkers for liver tumor promotion. Toxicol Sci 2012; 131:375-86. [PMID: 23091169 DOI: 10.1093/toxsci/kfs303] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, suggesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and β-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds.
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Affiliation(s)
- Harri Lempiäinen
- Discovery and Investigative Safety, Novartis Institutes for Biomedical Research, CH-4057 Basel, Switzerland
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Donovan SL, Corbo JC. Retinal horizontal cells lacking Rb1 sustain persistent DNA damage and survive as polyploid giant cells. Mol Biol Cell 2012; 23:4362-72. [PMID: 23015754 PMCID: PMC3496610 DOI: 10.1091/mbc.e12-04-0293] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
The retinoblastoma tumor susceptibility gene, Rb1, is a key regulator of the cell cycle, and mutations in this gene have been found in many human cancers. Prior studies showed that retina-specific knockout of Rb1 in the mouse results in the formation of abnormally large horizontal cells, but the development, fate, and genomic status of these cells remain unknown. In this study, we conditionally inactivate Rb1 in early retinal progenitors and show that the loss of Rb1 leads to the rapid degeneration of most retinal cells except horizontal cells, which persist as giant cells with aberrant centrosome content, DNA damage, and polyploidy/aneuploidy. We observed inappropriate cell cycle entry of Rb1-deficient horizontal cells during the first postnatal weeks, which dropped off abruptly by P30. Despite extensive DNA damage in Rb1-deficient horizontal cells, these cells can still enter mitosis. Adult Rb1-deficient horizontal cells display elevated DNA content (5N-34N) that varied continuously, suggesting the presence of aneuploidy. We also found evidence of supernumerary and disoriented centrosomes in a rare population of mitotic cells in the mutant retinas. Overall our data demonstrate that horizontal cells are a remarkably robust cell type and can survive for months despite extensive DNA damage and elevated genome content.
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Affiliation(s)
- Stacy L Donovan
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
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Abstract
Stem cells play a critical role during embryonic development and in the maintenance of homeostasis in adult individuals. A better understanding of stem cell biology, including embryonic and adult stem cells, will allow the scientific community to better comprehend a number of pathologies and possibly design novel approaches to treat patients with a variety of diseases. The retinoblastoma tumor suppressor RB controls the proliferation, differentiation, and survival of cells, and accumulating evidence points to a central role for RB activity in the biology of stem and progenitor cells. In some contexts, loss of RB function in stem or progenitor cells is a key event in the initiation of cancer and determines the subtype of cancer arising from these pluripotent cells by altering their fate. In other cases, RB inactivation is often not sufficient to initiate cancer but may still lead to some stem cell expansion, raising the possibility that strategies aimed at transiently inactivating RB might provide a novel way to expand functional stem cell populations. Future experiments dedicated to better understanding how RB and the RB pathway control a stem cell's decisions to divide, self-renew, or give rise to differentiated progeny may eventually increase our capacity to control these decisions to enhance regeneration or help prevent cancer development.
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Affiliation(s)
- Julien Sage
- Department of Pediatrics, Department of Genetics, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Institute, Stanford, California 94305, USA.
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