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1
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Nakamura N, Sato-Dahlman M, Travis E, Jacobsen K, Yamamoto M. CDX2 Promoter-Controlled Oncolytic Adenovirus Suppresses Tumor Growth and Liver Metastasis of Colorectal Cancer. Cancer Sci 2025. [PMID: 40275626 DOI: 10.1111/cas.70063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 03/03/2025] [Accepted: 03/15/2025] [Indexed: 04/26/2025] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, and liver metastasis (CRLM) is the most common among its distant metastases. We have recently generated a CDX2 promoter-controlled oncolytic adenovirus (Ad5/3-pCDX2) that showed an anticancer effect for CDX2-positive upper gastrointestinal tumors. Here, we reported the anticancer effect of Ad5/3-pCDX2 for CDX2-positive CRC and CRLM, and its combination efficacy with 5-fluorouracil (5FU) in vitro and in vivo. We used HT29 as CDX2-positive, and LS174T and SW480 as CDX2-negative CRC cell lines. Without 5FU, Ad5/3-pCDX2 killed HT29 but not LS174T and SW480 cells. In vitro, 5FU exposure upregulated CDX2 mRNA levels in all three cell lines. The 5FU combination enhanced the cytocidal effect and virus replication of Ad5/3-pCDX2 in CDX2-negative LS174T. In mouse xenograft models, Ad5/3-pCDX2 monotherapy suppressed the HT29 subcutaneous tumor growth compared to the control group. The 5FU plus Ad5/3-pCDX2 combination therapy showed a remarkable antitumor effect over the efficacy of Ad5/3-pCDX2 monotherapy. In the LS174T subcutaneous tumor, although Ad5/3-pCDX2 monotherapy did not show an antitumor effect, the 5FU plus Ad5/3-pCDX2 combination therapy significantly suppressed the tumor growth compared to the Ad5/3-pCDX2 monotherapy. In mice with HT29 liver metastasis, intrasplenic injection of Ad5/3-pCDX2 induced virus replication in liver tumors and thus successfully attenuated tumor growth. In conclusion, Ad5/3-pCDX2 showed a significant anticancer effect that was enhanced by 5FU treatment in not only CDX2-positive but also negative CRCs. Ad5/3-pCDX2 is a promising therapeutic modality for metastatic CRC such as CRLM.
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Affiliation(s)
- Naohiko Nakamura
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Mizuho Sato-Dahlman
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Elise Travis
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kari Jacobsen
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Masato Yamamoto
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
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2
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Shou S, Maolan A, Zhang D, Jiang X, Liu F, Li Y, Zhang X, Geer E, Pu Z, Hua B, Guo Q, Zhang X, Pang B. Telomeres, telomerase, and cancer: mechanisms, biomarkers, and therapeutics. Exp Hematol Oncol 2025; 14:8. [PMID: 39871386 PMCID: PMC11771031 DOI: 10.1186/s40164-025-00597-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 01/15/2025] [Indexed: 01/29/2025] Open
Abstract
Telomeres and telomerase play crucial roles in the initiation and progression of cancer. As biomarkers, they aid in distinguishing benign from malignant tissues. Despite the promising therapeutic potential of targeting telomeres and telomerase for therapy, translating this concept from the laboratory to the clinic remains challenging. Many candidate drugs remain in the experimental stage, with only a few advancing to clinical trials. This review explores the relationship between telomeres, telomerase, and cancer, synthesizing their roles as biomarkers and reviewing the outcomes of completed trials. We propose that changes in telomere length and telomerase activity can be used to stratify cancer stages. Furthermore, we suggest that differential expression of telomere and telomerase components at the subcellular level holds promise as a biomarker. From a therapeutic standpoint, combining telomerase-targeted therapies with drugs that mitigate the adverse effects of telomerase inhibition may offer a viable strategy.
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Affiliation(s)
- Songting Shou
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ayidana Maolan
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Di Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaochen Jiang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fudong Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yi Li
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiyuan Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - En Geer
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhenqing Pu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Baojin Hua
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Qiujun Guo
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Xing Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Bo Pang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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3
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Styk J, Buglyó G, Pös O, Csók Á, Soltész B, Lukasz P, Repiská V, Nagy B, Szemes T. Extracellular Nucleic Acids in the Diagnosis and Progression of Colorectal Cancer. Cancers (Basel) 2022; 14:3712. [PMID: 35954375 PMCID: PMC9367600 DOI: 10.3390/cancers14153712] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/21/2022] [Accepted: 07/26/2022] [Indexed: 12/02/2022] Open
Abstract
Colorectal cancer (CRC) is the 3rd most common malignant neoplasm worldwide, with more than two million new cases diagnosed yearly. Despite increasing efforts in screening, many cases are still diagnosed at a late stage, when mortality is high. This paper briefly reviews known genetic causes of CRC (distinguishing between sporadic and familial forms) and discusses potential and confirmed nucleic acid biomarkers obtainable from liquid biopsies, classified by their molecular features, focusing on clinical relevance. We comment on advantageous aspects such as better patient compliance due to blood sampling being minimally invasive, the possibility to monitor mutation characteristics of sporadic and hereditary CRC in a disease showing genetic heterogeneity, and using up- or down-regulated circulating RNA markers to reveal metastasis or disease recurrence. Current difficulties and thoughts on some possible future directions are also discussed. We explore current evidence in the field pointing towards the introduction of personalized CRC management.
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Affiliation(s)
- Jakub Styk
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
- Comenius University Science Park, Comenius University, 841 04 Bratislava, Slovakia; (O.P.); (B.N.); (T.S.)
- Geneton Ltd., 841 04 Bratislava, Slovakia
| | - Gergely Buglyó
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (G.B.); (Á.C.); (B.S.)
| | - Ondrej Pös
- Comenius University Science Park, Comenius University, 841 04 Bratislava, Slovakia; (O.P.); (B.N.); (T.S.)
- Geneton Ltd., 841 04 Bratislava, Slovakia
| | - Ádám Csók
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (G.B.); (Á.C.); (B.S.)
| | - Beáta Soltész
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (G.B.); (Á.C.); (B.S.)
| | - Peter Lukasz
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, 1082 Budapest, Hungary;
| | - Vanda Repiská
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
- Medirex Group Academy, n.p.o., 949 05 Nitra, Slovakia
| | - Bálint Nagy
- Comenius University Science Park, Comenius University, 841 04 Bratislava, Slovakia; (O.P.); (B.N.); (T.S.)
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (G.B.); (Á.C.); (B.S.)
| | - Tomáš Szemes
- Comenius University Science Park, Comenius University, 841 04 Bratislava, Slovakia; (O.P.); (B.N.); (T.S.)
- Geneton Ltd., 841 04 Bratislava, Slovakia
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 842 05 Bratislava, Slovakia
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Novel Diagnostic Biomarkers in Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23020852. [PMID: 35055034 PMCID: PMC8776048 DOI: 10.3390/ijms23020852] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used for risk stratification and early detection, which might prolong overall survival. Nowadays, the widespread use of semi-invasive endoscopic methods and feacal blood tests characterised by suboptimal accuracy of diagnostic results has led to the detection of cases at later stages. New molecular noninvasive tests based on the detection of CRC alterations seem to be more sensitive and specific then the current methods. Therefore, research aiming at identifying molecular markers, such as DNA, RNA and proteins, would improve survival rates and contribute to the development of personalized medicine. The identification of “ideal” diagnostic biomarkers, having high sensitivity and specificity, being safe, cheap and easy to measure, remains a challenge. The purpose of this review is to discuss recent advances in novel diagnostic biomarkers for tumor tissue, blood and stool samples in CRC patients.
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Combination of resveratrol and BIBR1532 inhibits proliferation of colon cancer cells by repressing expression of LncRNAs. Med Oncol 2021; 39:12. [PMID: 34779924 DOI: 10.1007/s12032-021-01611-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 11/06/2021] [Indexed: 12/14/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. The development of tumor drug resistance is observed in the treatment of CRC. Combinations of anticancer agents are attracting considerable interest in order to overcome drug resistance in CRC. This study aims to investigate the effect of resveratrol and BIBR1532, either alone or in combination, on the cell viability as well as on expression of long non-coding RNAs (LncRNAs) for HT-29 colon adenocarcinoma cells. The cytotoxic effects of resveratrol and BIBR1532 on HT-29 cells were determined using WST-1 test. Flow cytometry was used to determine apoptotic cell death after treatments. Real-Time PCR was used to identify expression of LncRNAs after treatments. LncExpDB and GEPIA2 were used to evaluate expression profiles of LncRNAs, whose expression levels were decreased in HT-29 cells after treatments, in normal tissues and colon adenocarcinoma tumors. IC50 concentrations of BIBR1532 and resveratrol were found to be 50.81 μM at 48 h and 86.23 μM at 72 h, respectively. Combination index value was 1.07617. BIBR1532, resveratrol, or their combination reduced the cell viability of HT-29 cells. CCAT1, CRNDE, HOTAIR, PCAT1, PVT1, SNHG16 were down-regulated after treatments. In silico analysis revealed that LncRNAs whose expression levels were decreased after treatments were associated with CRC. Resveratrol, BIBR1532, or their combination may have anti-proliferative effect on colorectal cancer cells through repressing expression of LncRNAs that are involved in progression of CRC.
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Eslamizadeh S, Zare AA, Talebi A, Tabaeian SP, Eshkiki ZS, Heydari-Zarnagh H, Akbari A. Differential Expression of miR-20a and miR-145 in Colorectal Tumors as Potential Location-specific miRNAs. Microrna 2020; 10:66-73. [PMID: 33349227 DOI: 10.2174/2211536609666201221123604] [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: 06/17/2020] [Revised: 10/16/2020] [Accepted: 11/27/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs), as tissue specific regulators of gene transcription, may be served as biomarkers for Colorectal Cancer (CRC). OBJECTIVE This study aimed to investigate the potential role of the cancer-related hsa-miRNAs as biomarkers in Colon Cancer (CC) and Rectal Cancer (RC). METHODS A total of 148 CRC samples (74 rectum and 74 colon) and 74 adjacent normal tissues were collected to examine the differential expression of selected ten hsa-miRNAs using quantitative Reverse Transcriptase PCR (qRT-PCR). RESULTS The significantly elevated levels of miR-21, miR-133b, miR-18a, miR-20a, and miR-135b, and decreased levels of miR-34a, miR-200c, miR-145, and let-7g were detected in colorectal tumors compared to the healthy tissues (P<0.05). Hsa-miR-20a was significantly overexpressed in rectum compared to colon (p =0.028) from a cut-off value of 3.15 with a sensitivity of 66% and a specificity of 60% and an AUC value of 0.962. Also, hsa-miR-145 was significantly overexpressed in colon compared to the rectum (p =0.02) from a cut-off value of 3.9 with a sensitivity of 55% and a specificity of 61% and an AUC value of 0.91. CONCLUSION In conclusion, hsa-miR-20a and hsa-miR-145, as potential tissue-specific biomarkers for distinguishing RC and CC, improve realizing the molecular differences between these local tumors.
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Affiliation(s)
- Sara Eslamizadeh
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Zare
- Young Researchers and Elites club, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Atefeh Talebi
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Zahra Shokati Eshkiki
- Alimentary Tract Research Center, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hafez Heydari-Zarnagh
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
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7
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He H, Chen E, Lei L, Yan B, Zhao X, Zhu Z, Li Q, Zhang P, Zhang W, Xing J, Du L, Dong J, Yang J. Alteration of the tumor suppressor SARDH in sporadic colorectal cancer: A functional and transcriptome profiling-based study. Mol Carcinog 2019; 58:957-966. [PMID: 30693981 DOI: 10.1002/mc.22984] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Revised: 01/21/2019] [Accepted: 01/24/2019] [Indexed: 01/05/2023]
Abstract
Sporadic colorectal cancer (sCRC) is one of the leading causes of cancer death worldwide. As a highly heterogeneous complex disease, the currently reported classical genetic markers for sCRC, including APC, KRAS, BRAF, and TP53 gene mutations and epigenetic alterations, can explain only some sCRC patients. Here, we first reported a deleterious c.551C>T mutation in SARDH in sCRC. SARDH was identified as a novel tumor suppressor gene and was abnormally decreased in sCRC at both the transcriptional and the translational level. SARDH mRNA levels were also down-regulated in oesophageal cancer, lung cancer, liver cancer, and pancreatic cancer in the TCGA database. SARDH overexpression inhibited the proliferation, migration, and invasion of CRC cell lines, whereas its depletion improved these processes. SARDH overexpression was down-regulated in multiple pathways, especially in the chemokine pathway. The SARDH transcript level was positively correlated with the methylation states of CXCL1 and CCL20. Therefore, we concluded that SARDH depletion is involved in the development of sCRC.
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Affiliation(s)
- Hongjuan He
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Shaanxi, China
| | - Erfei Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Shaanxi, China
| | - Lei Lei
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Shaanxi, China
| | - Bianbian Yan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Shaanxi, China
| | - Xiaojuan Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Shaanxi, China
| | - Ziqing Zhu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Shaanxi, China
| | - Qiqi Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Shaanxi, China
| | - Pan Zhang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Shaanxi, China
| | - Wei Zhang
- The Helmholtz Sino-German Laboratory for Cancer Research, Department of Pathology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jinliang Xing
- State Key Laboratory of Cancer Biology and Experimental Teaching Centre of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Le Du
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Shaanxi, China
| | - Jing Dong
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Shaanxi, China
| | - Jin Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China.,Institute of Preventive Genomic Medicine, Shaanxi, China
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8
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Angiodrastic Chemokines in Colorectal Cancer: Clinicopathological Correlations. Anal Cell Pathol (Amst) 2018; 2018:1616973. [PMID: 29850390 PMCID: PMC5926520 DOI: 10.1155/2018/1616973] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 03/19/2018] [Indexed: 12/26/2022] Open
Abstract
Aim To study the expression of angiodrastic chemokines in colorectal tumors and correlate findings with clinicopathological parameters and survival. Methods The proangiogenic factor VEGF, the angiogenic chemokines CXCL8 and CXCL6, and the angiostatic chemokine CXCL4 were measured by ELISA in tumor and normal tissue of 35 stage II and III patients and correlated with the histopathology markers Ki67, p53, p21, bcl2, EGFR, and MLH1 and 5-year survival. The Wilcoxon and chi-square tests were used for statistical comparisons. Results There was a significant increase of CXCL6 (p = 0.005) and VEGF (p = 0.003) in cancerous tissue compared to normal. Patients with lower levels of CXCL8 and CXCL4 lived significantly longer. Patients with loss of EGFR expression had higher levels of CXCL8 while p21 loss was associated with higher levels of CXCL6. Chemokine levels were not correlated with TNM or Dukes classification. Strong expression of p53 was accompanied by decreased survival. Conclusions (1) The angiogenic factors CXCL6 and VEGF are increased in colorectal cancer tissue with no association with the clinical stage of the disease or survival. (2) However, increased levels of tissue CXCL8 and CXCL4 are associated with poor survival. (3) Strong expression of p53 is found in patients with poor survival.
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9
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Lim LC, Lim YM. Proteome Heterogeneity in Colorectal Cancer. Proteomics 2018; 18. [PMID: 29316255 DOI: 10.1002/pmic.201700169] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 12/17/2017] [Indexed: 01/26/2023]
Abstract
Tumor heterogeneity is an important feature of colorectal cancer (CRC) manifested by dynamic changes in gene expression, protein expression, and availability of different tumor subtypes. Recent publications in the past 10 years have revealed proteome heterogeneity between different colorectal tumors and within the same tumor site. This paper reviews recent research works on the proteome heterogeneity in CRC, which includes the heterogeneity within a single tumor (intratumor heterogeneity), between different anatomical sites at the same organ, and between primary and metastatic sites (intertumor heterogeneity). The potential use of proteome heterogeneity in precision medicine and its implications in biomarker discovery and therapeutic outcomes will be discussed. Identification of the unique proteome landscape between and within individual tumors is imperative for understanding cancer biology and the management of CRC patients.
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Affiliation(s)
- Lay Cheng Lim
- Centre for Cancer Research, Faculty of Medicine and Health Sciences, University of Tunku Abdul Rahman, Selangor, Malaysia
| | - Yang Mooi Lim
- Centre for Cancer Research, Faculty of Medicine and Health Sciences, University of Tunku Abdul Rahman, Selangor, Malaysia
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10
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Suraweera N, Mouradov D, Li S, Jorissen RN, Hampson D, Ghosh A, Sengupta N, Thaha M, Ahmed S, Kirwan M, Aleva F, Propper D, Feakins RM, Vulliamy T, Elwood NJ, Tian P, Ward RL, Hawkins NJ, Xu ZZ, Molloy PL, Jones IT, Croxford M, Gibbs P, Silver A, Sieber OM. Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer. Oncotarget 2017; 7:36474-36488. [PMID: 27167335 PMCID: PMC5095014 DOI: 10.18632/oncotarget.9015] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 04/10/2016] [Indexed: 01/02/2023] Open
Abstract
Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles.
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Affiliation(s)
- Nirosha Suraweera
- Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK
| | - Dmitri Mouradov
- Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, Victoria, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Shan Li
- Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, Victoria, Australia
| | - Robert N Jorissen
- Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, Victoria, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Debbie Hampson
- Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK
| | - Anil Ghosh
- Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK
| | - Neel Sengupta
- Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK
| | - Mohamed Thaha
- Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK.,Academic Surgical Unit, The Royal London Hospital, Whitechapel, London, UK
| | - Shafi Ahmed
- Academic Surgical Unit, The Royal London Hospital, Whitechapel, London, UK
| | - Michael Kirwan
- Centre for Paediatrics, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK
| | - Floor Aleva
- Department of Medical Oncology, St Bartholomew's Hospital, Little Britain, London, UK
| | - David Propper
- Department of Medical Oncology, St Bartholomew's Hospital, Little Britain, London, UK
| | - Roger M Feakins
- Department of Pathology, The Royal London Hospital, Whitechapel, London, UK
| | - Tom Vulliamy
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK
| | - Ngaire J Elwood
- Cord Blood Research, Murdoch Children's Research Institute, Melbourne, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Australia
| | - Pei Tian
- Cord Blood Research, Murdoch Children's Research Institute, Melbourne, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Australia
| | - Robyn L Ward
- The University of Queensland, Brisbane, Queensland, Australia
| | - Nicholas J Hawkins
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Zheng-Zhou Xu
- CSIRO Preventative Health Flagship, North Ryde, NSW, Australia
| | - Peter L Molloy
- CSIRO Preventative Health Flagship, North Ryde, NSW, Australia
| | - Ian T Jones
- Department of Colorectal Surgery, Royal Melbourne Hospital, Parkville, Victoria, Australia.,Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia
| | - Matthew Croxford
- Department of Colorectal Surgery, Western Hospital, Footscray, Victoria, Australia
| | - Peter Gibbs
- Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, Victoria, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.,Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Andrew Silver
- Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK
| | - Oliver M Sieber
- Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, Victoria, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.,Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia.,School of Biomedical Sciences, Monash University, Victoria, Australia
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Ye L, Yang Y, Ma XY, Li D, Xu ML, Tan P, Long LM, Wang HQ, Liu T, Guo YH. Construction of a novel vector expressing Survivin-shRNA and fusion suicide gene yCDglyTK and its application in inhibiting proliferation and migration of colon cancer cells. Exp Ther Med 2017; 14:4721-4728. [PMID: 29201172 PMCID: PMC5704315 DOI: 10.3892/etm.2017.5154] [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: 03/02/2016] [Accepted: 06/02/2017] [Indexed: 11/05/2022] Open
Abstract
Despite progress achieved in cancer chemotherapy in recent decades, adverse effects remain a limiting factor for a number of patients with colorectal cancer, suggesting the requirement for novel therapeutic strategies. Gene therapy appears to be a promising strategy for treating cancer. The present study aimed to investigate the anti-tumor effect of a combined gene therapy, using Survivin downregulation by RNAi and a fusion suicide gene yCDglyTK therapy system. A triple-gene vector expressing Survivin-targeted small hairpin RNA (Survivin-shRNA) and fusion suicide gene yCDglyTK was constructed, and administered to HCT116 cells. Survivin expression decreased significantly and yCDglyTK fusion gene expression was confirmed by both reverse transcription-quantitative polymerase chain reaction and western blot analysis. Introduction of Survivin-shRNA into yCDglyTK/prodrug system eradicated colon cancer cells and induced apoptosis more effectively. Furthermore, this therapeutic system is able to inhibit the migration of HCT116 cells. These results indicate that the recombinant plasmid may serve as a novel gene therapy approach to treat colorectal carcinoma.
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Affiliation(s)
- Ling Ye
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Yuan Yang
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Xin-Yu Ma
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Dan Li
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Mei-Li Xu
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Pan Tan
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Li-Min Long
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Hai-Qin Wang
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
| | - Ting Liu
- Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
| | - Yong-Hong Guo
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China
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12
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Doi H, Uemoto K, Suzuki O, Yamada K, Masai N, Tatsumi D, Shiomi H, Oh RJ. Effect of primary tumor location and tumor size on the response to radiotherapy for liver metastases from colorectal cancer. Oncol Lett 2017; 14:453-460. [PMID: 28693191 PMCID: PMC5494798 DOI: 10.3892/ol.2017.6167] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Accepted: 03/31/2017] [Indexed: 02/07/2023] Open
Abstract
Metastatic liver tumors (MLTs) from colorectal cancer (CRC) are often treated with stereotactic body radiation therapy (SBRT). The present study aimed to examine the predictive factors for response of MLTs to SBRT. A total of 39 MLTs from 24 patients with CRC were retrospectively analyzed. Radiotherapy for MLT was typically performed with a prescribed dose equivalent to a biologically effective dose (BED)10 of 100 Gy. The median follow-up period was 16 months (range, 5-64 months). The median prescribed dose and total BED10 were 56 Gy (range, 45-72 Gy) and 97.5 Gy (range, 71.7-115.5 Gy), respectively, in a median of 8 fractions (range, 4-33 fractions). The 1- and 2-year local control rates were 67.2 and 35.9%, respectively. For patients with MLT treated with ablative SBRT (BED10 ≥100 Gy in ≤5 fractions), the 1- and 2-year local control rates were 83.3 and 62.5%, respectively. Univariate analysis showed that primary tumor location (left-sided colon), maximum tumor diameter (≤30 mm) and ablative SBRT (BED10 ≥100 Gy in ≤5 fractions) were significantly associated with improved local control (P=0.0058, P=0.0059 and P=0.0268, respectively). Multivariate analysis showed that tumor diameter was significantly associated with improved local control (P=0.0314). In addition, patients who received ablative SBRT had significantly prolonged overall survival times compared with those treated with non-ablative SBRT (P=0.0261). To conclude, tumors ≤30 mm that can be treated with ablative SBRT are associated with good local control rates. The primary tumor location may affect the radiosensitivity of MLTs.
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Affiliation(s)
- Hiroshi Doi
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
| | - Kenji Uemoto
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
- Division of Health Sciences, Osaka University Graduate School of Medicine and Health Science, Suita, Osaka 565-0871, Japan
| | - Osamu Suzuki
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
- Department of Carbon Ion Radiotherapy, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Koichi Yamada
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
| | - Norihisa Masai
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
| | | | - Hiroya Shiomi
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
| | - Ryoong-Jin Oh
- Miyakojima IGRT Clinic, Miyakojima, Osaka 534-0021, Japan
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13
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Piñol-Felis C, Fernández-Marcelo T, Viñas-Salas J, Valls-Bautista C. Telomeres and telomerase in the clinical management of colorectal cancer. Clin Transl Oncol 2016; 19:399-408. [DOI: 10.1007/s12094-016-1559-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 10/03/2016] [Indexed: 01/17/2023]
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14
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Affiliation(s)
- Elias Kouroumalis
- a Department of Gastroenterology ; University of Crete Medical School ; Crete , Greece
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15
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Xie XC, Ge LY, Lai H, Qiu H, Tang F, Qin YZ. The Relationship between Telomerase Activity and Clinicopathological Parameters in Colorectal Cancer: A Meta-Analysis. Balkan Med J 2016; 33:64-71. [PMID: 26966620 DOI: 10.5152/balkanmedj.2015.151182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Accepted: 05/19/2015] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Recently, accumulated research has found that the expression of telomerase activity (TA) was associated with colorectal cancer (CRC) advancement, whereas the TA prognostic effect in CRC patients is still controversial. AIMS To investigate relationships between TA and CRC clinicopathological parameters. STUDY DESIGN Meta-analysis study. METHODS We searched published studies in databases, such as EMBASE, the Cochrane Library, PubMed, and Ovid databases (last search updated to October 2014) by meeting specified search criteria. The quality of the included studies was usually evaluated and a meta-analysis was implemented by Stata 12.0 software. We used an odds ratio (OR) with a 95% confidence interval (CI) to evaluate relationship strengths between TA and CRC clinicopathological parameters. RESULTS In total, 11 studies (715 patients) were included to assess the relation between TA and metastasis-related parameters in CRC patients. The results indicate that a senior TA expression was connected with the existence of lymph node metastasis (180 patients; OR=2.85, 95% CI=1.40-5.81, p=0.004), and tumor site (522 patients; OR=2.93, 95% CI=1.29-6.67, p=0.010). However, a senior TA expression was not connected with tumor size (137 patients; OR=1.57, 95% CI=0.71-3.47, p=0.267), histological differentiation (570 patients; OR=1.28, 95% CI=0.78-2.09, p=0.332), depth of invasion (57 patients; OR=3.76, 95% CI=0.61-23.04, p=0.152), distant metastasis (123 patients; OR=1.76, 95% CI=0.54-5.74, p=0.346), and clinical stage of the cancer (543 patients; OR=1.59, 95% CI=0.74-3.38, p=0.232). CONCLUSION This meta-analysis suggests that a positive TA was correlated with lymph node metastasis progression and tumor site of the CRC but did not correlate with other important clinicopathological parameters. TA can play a useful part in the prognosis and treatment of CRC patients, but further studies are required to confirm this.
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Affiliation(s)
- Xue-Cheng Xie
- Department of Gastrointestinal Surgery, Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Lian-Ying Ge
- Department of Endoscopy Center, Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Hao Lai
- Department of Gastrointestinal Surgery, Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Hai Qiu
- Department of Gastrointestinal Surgery, Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Fan Tang
- Department of Gastrointestinal Surgery, Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Yu-Zhou Qin
- Department of Gastrointestinal Surgery, Tumor Hospital of Guangxi Medical University, Nanning, China
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16
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Fernández-Marcelo T, Sánchez-Pernaute A, Pascua I, De Juan C, Head J, Torres-García AJ, Iniesta P. Clinical Relevance of Telomere Status and Telomerase Activity in Colorectal Cancer. PLoS One 2016; 11:e0149626. [PMID: 26913901 PMCID: PMC4767779 DOI: 10.1371/journal.pone.0149626] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 02/03/2016] [Indexed: 12/29/2022] Open
Abstract
The role of telomeres and telomerase in colorectal cancer (CRC) is well established as the major driving force in generating chromosomal instability. However, their potential as prognostic markers remains unclear. We investigated the outcome implications of telomeres and telomerase in this tumour type. We considered telomere length (TL), ratio of telomere length in cancer to non-cancer tissue (T/N ratio), telomerase activity and TERT levels; their relation with clinical variables and their role as prognostic markers. We analyzed 132 CRCs and paired non-cancer tissues. Kaplan-Meier curves for disease-free survival were calculated for TL, T/N ratio, telomerase activity and TERT levels. Overall, tumours had shorter telomeres than non-tumour tissues (P < 0.001) and more than 80% of CRCs displayed telomerase activity. Telomere lengths of non-tumour tissues and CRCs were positively correlated (P < 0.001). Considering telomere status and clinical variables, the lowest degree of telomere shortening was shown by tumours located in the rectum (P = 0.021). Regarding prognosis studies, patients with tumours showing a mean TL < 6.35 Kb experienced a significantly better clinical evolution (P < 0.001) and none of them with the highest degree of tumour telomere shortening relapsed during the follow-up period (P = 0.043). The mean TL in CRCs emerged as an independent prognostic factor in the Cox analysis (P = 0.017). Telomerase-positive activity was identified as a marker that confers a trend toward a poor prognosis. In CRC, our results support the use of telomere status as an independent prognostic factor. Telomere status may contribute to explaining the different molecular identities of this tumour type.
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Affiliation(s)
- Tamara Fernández-Marcelo
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, 28040-Madrid, Spain
- Sanitary Research Institute of San Carlos Hospital (IdISSC), 28040-Madrid, Spain
| | - Andrés Sánchez-Pernaute
- Service of General Surgery and Digestive Tract, San Carlos Hospital, 28040-Madrid, Spain
- Sanitary Research Institute of San Carlos Hospital (IdISSC), 28040-Madrid, Spain
| | - Irene Pascua
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, 28040-Madrid, Spain
- Sanitary Research Institute of San Carlos Hospital (IdISSC), 28040-Madrid, Spain
| | - Carmen De Juan
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, 28040-Madrid, Spain
- Sanitary Research Institute of San Carlos Hospital (IdISSC), 28040-Madrid, Spain
| | - Jacqueline Head
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, 28040-Madrid, Spain
- Sanitary Research Institute of San Carlos Hospital (IdISSC), 28040-Madrid, Spain
| | - Antonio-José Torres-García
- Service of General Surgery and Digestive Tract, San Carlos Hospital, 28040-Madrid, Spain
- Sanitary Research Institute of San Carlos Hospital (IdISSC), 28040-Madrid, Spain
| | - Pilar Iniesta
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University, 28040-Madrid, Spain
- Sanitary Research Institute of San Carlos Hospital (IdISSC), 28040-Madrid, Spain
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