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      COX-2 Promotes Migration and Invasion by the Side Population of Cancer Stem Cell-Like Hepatocellular Carcinoma Cells

      research-article
      Author(s): , MD, PhD, , MD, , MD, , MD, , MD, , MD, , MD, , MD, , MD, PhD, , MD, PhD, , MD, PhD
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      Publication date (Electronic):
      Journal: Medicine
      Publisher: Wolters Kluwer Health

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          Abstract

          Cancer stem cells (CSCs) are thought to be responsible for tumor relapse and metastasis due to their abilities to self-renew, differentiate, and give rise to new tumors. Cyclooxygenase-2 (COX-2) is highly expressed in several kinds of CSCs, and it helps promote stem cell renewal, proliferation, and radioresistance. Whether and how COX-2 contributes to CSC migration and invasion is unclear. In this study, COX-2 was overexpressed in the CSC-like side population (SP) of the human hepatocellular carcinoma (HCC) cell line HCCLM3. COX-2 overexpression significantly enhanced migration and invasion of SP cells, while reducing expression of metastasis-related proteins PDCD4 and PTEN. Treating SP cells with the selective COX-2 inhibitor celecoxib down-regulated COX-2 and caused a dose-dependent reduction in cell migration and invasion, which was associated with up-regulation of PDCD4 and PTEN. These results suggest that COX-2 exerts pro-metastatic effects on SP cells, and that these effects are mediated at least partly through regulation of PDCD4 and PTEN expression. These results further suggest that celecoxib may be a promising anti-metastatic agent to reduce migration and invasion by hepatic CSCs.

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          PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells.

          Anne-Marie Bleau, Dolores Hambardzumyan, Tatsuya Ozawa … (2009)
          In normal brain, the side population (SP) phenotype is generated by ABC transporter activity and identifies stem cell and endothelial cell subpopulations by dye exclusion. By drug efflux, the ABCG2 transporter provides chemoresistance in stem cells and contributes to the blood brain barrier (BBB) when active in endothelial cells. We investigated the SP phenotype of mouse and human gliomas. In glioma endothelial cells, ABC transporter function is impaired, corresponding to disruption of the BBB in these tumors. By contrast, the SP phenotype is increased in nonendothelial cells that form neurospheres and are highly tumorigenic. In this cell population, Akt, but not its downstream target mTOR, regulates ABCG2 activity, and loss of PTEN increases the SP. This Akt-induced ABCG2 activation results from its transport to the plasma membrane. Temozolomide, the standard treatment of gliomas, although not an ABCG2 substrate, increases the SP in glioma cells, especially in cells missing PTEN.
          Article 0 comments Cited 246 times – based on 0 reviews     Review now
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            Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma.

            Ronnie Tung-Ping Poon, Sheung-Tat Fan, John Y.F. Wong (2000)
            To evaluate the current knowledge on the risk factors for recurrence, efficacy of adjuvant therapy in preventing recurrence, and the optimal management of recurrence after resection of hepatocellular carcinoma (HCC). The long-term prognosis after resection of HCC remains unsatisfactory as a result of a high incidence of recurrence. Prevention and effective management of recurrence are the most important strategies to improve the long-term survival results. A review of relevant English articles was undertaken based on a Medline search from January 1980 to July 1999. Pathologic factors indicative of tumor invasiveness such as venous invasion, presence of satellite nodules, large tumor size, and advanced pTNM stage, are the best-established risk factors for recurrence. Active hepatitis activity in the nontumorous liver and perioperative transfusion also appear to enhance recurrence. Recent molecular research has identified tumor biologic factors such as the proliferative and angiogenic activities of the tumor as new risk factors for recurrence. There is a lack of convincing evidence for the efficacy of neoadjuvant or adjuvant therapy in preventing recurrence. Retrospective studies suggested that postoperative hepatic arterial chemotherapy might improve disease-free survival, but results were conflicting. For the management of postoperative recurrence, studies have consistently indicated that surgical resection should be the treatment of choice for localized recurrence, be it in the liver remnant or extrahepatic organs. Transarterial chemoembolization and percutaneous ethanol injection are widely used to prolong survival in patients with unresectable intrahepatic recurrence, and combined therapy with these two modalities may offer additional benefit. Knowledge of the risk factors for postoperative recurrence provides a basis for logical approaches to prevention. Minimal surgical manipulation of tumors to prevent tumor cell dissemination, avoidance of perioperative blood transfusion, and suppression of chronic hepatitis activity in the liver remnant are strategies that may be useful in preventing recurrence. The efficacy of postoperative adjuvant regional chemotherapy deserves further evaluation. New concepts on the influence of tumor biologic factors such as angiogenic activity on recurrence of HCC suggest a potential role of novel approaches such as antiangiogenesis for adjuvant therapy in the future. Currently, the most realistic approach in prolonging survival after resection of HCC is early detection and aggressive management of recurrence. Randomized trials are needed to define the roles of various treatment modalities for recurrence and the benefit of multimodality therapy.
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              Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties.

              Tetsuhiro Chiba, Kaoru Kita, Yun-Wen Zheng … (2006)
              Recent advances in stem cell biology enable us to identify cancer stem cells in solid tumors as well as putative stem cells in normal solid organs. In this study, we applied side population (SP) cell analysis and sorting to established hepatocellular carcinoma (HCC) cell lines to detect subpopulations that function as cancer stem cells and to elucidate their roles in tumorigenesis. Among four cell lines analyzed, SP cells were detected in Huh7 (0.25%) and PLC/PRF/5 cells (0.80%), but not in HepG2 and Huh6 cells. SP cells demonstrated high proliferative potential and anti-apoptotic properties compared with those of non-SP cells. Immunocytochemistry examination showed that SP fractions contain a large number of cells presenting characteristics of both hepatocyte and cholangiocyte lineages. Non-obese diabetic/severe combined immunodeficiency (NOD/SCID) xenograft transplant experiments showed that only 1 x 10(3) SP cells were sufficient for tumor formation, whereas an injection of 1 x 10(6) non-SP cells did not initiate tumors. Re-analysis of SP cell-derived tumors showed that SP cells generated both SP and non-SP cells and tumor-initiating potential was maintained only in SP cells in serial transplantation. Microarray analysis discriminated a differential gene expression profile between SP and non-SP cells, and several so-called "stemness genes" were upregulated in SP cells in HCC cells. In conclusion, we propose that a minority population, detected as SP cells in HCC cells, possess extreme tumorigenic potential and provide heterogeneity to the cancer stem cell system characterized by distinct hierarchy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Medicine (Baltimore)
                Journal ID (iso-abbrev): Medicine (Baltimore)
                Journal ID (publisher-id): MEDI
                Title: Medicine
                Publisher: Wolters Kluwer Health
                ISSN (Print): 0025-7974
                ISSN (Electronic): 1536-5964
                Publication date Collection: November 2015
                Publication date (Electronic): 06 November 2015
                Volume: 94
                Issue: 44
                Electronic Location Identifier: e1806
                Affiliations
                From the Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, P.R. China (ZG, H-JY, F-QY, Y-PQ, L-QL, B-DX); Department of Thyroid and Breast Surgery, The Central Hospital of Wuhan, Wuhan, P.R. China (ZG); Department of General Surgery, The Second People's Hospital of The Second People's Hospital of Jingmen, Jingmen, P.R. China (J-HJ); Department of Ultrasound, Wuhan No. 1 Hospital, Wuhan, P.R. China (JZ); Medical Science Experimental Center, Guangxi Medical University, Nanning, P.R. China (Y-PZ, JS); Department of Immunology, School of Preclinical Medicine, Biological Targeting Diagnosis and Therapy Research Center, Guangxi Medical University, Nanning, P.R. China (R-RY).
                Author notes
                Correspondence: Le-Qun Li and Bang-De Xiang, Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning 530021 Guangxi, China (e-mail: xiaopushu-213163.com [L-QL] and zheguophd@ 123456163.com [B-DX] ).
                Article
                Accession ID: 01806
                DOI: 10.1097/MD.0000000000001806
                PMC ID: 4915881
                PubMed ID: 26554780
                SO-VID: bc7fbabc-464e-430d-9d25-a048adf4d971
                Copyright © Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
                License:

                This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                Date received : 29 July 2015
                Date revision received : 11 September 2015
                Date accepted : 13 September 2015
                Categories
                Subject: 5700
                Subject: Research Article
                Subject: Observational Study
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