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Abdulrazaq JA, Zakari MA, Ibrahim Y, Ahmad H. Expression of cyclooxygenase-2 (COX-2) in colorectal carcinoma in an indigenous African population of Kano, Nigeria. Ecancermedicalscience 2024; 18:1816. [PMID: 40171463 PMCID: PMC11959126 DOI: 10.3332/ecancer.2024.1816] [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: 06/01/2024] [Indexed: 01/05/2025] Open
Abstract
Background cyclooxygenases-2 (COX-2) over-expression has been noticed in colorectal cancers (CRCs) with adverse outcomes, serving as a potential marker for prognosis, targeted therapy and as a window in CRC prevention. Unfortunately, there are scarce data regarding COX-2 expression in CRC in Africa where CRC incidence is on the increase with younger age affectation and unfavourable outcomes. Aims This retrospective study aims to determine the proportion of CRCs that over-express COX-2 and document any relationship between COX-2 over-expression with clinicopathological features such as histologic subtype, tumour grade, age and sex. Methods All the 139 CRCs that were histologically diagnosed at Aminu Kano Teaching Hospital over a 5-year period were included, but only 124 Formalin-fixed paraffin-embedded tissue blocks were sectioned and stained with COX-2 antibody. COX-2 expression was scored for distribution (no cells = 0, 1%-10% = 1, 11%-50% = 2, 51%-80% = 3, 81%-100% = 4) and intensity (no stain = 0; weak = 1; moderate = 2, strong = 3). The immunoreactive score (IRS) is a product of intensity (I) and distribution (D) as: 9-12 strongly +, 5-8 moderately +, 1-4 weakly + and 0 negative. Over-expression of COX-2 is an IRS of 5-12. Outcomes were statistically evaluated with clinicopathological data. Results The CRCs occurred more commonly in males (M: F, 2:1), in the middle age group (mostly between 30 and 59 years), and 51.1% of cases occurred before 50 years and peaked in the 6th decade. Over-expression of COX-2 was observed in 46.8% (58/124) and was strongly associated with adenocarcinoma (ADC) not otherwise specified (NOS) (moderately and poorly differentiated tumours) but not with age or sex. Conclusion The over-expression of COX-2 was significantly associated with ADC NOS (moderately and poorly differentiated tumours), indicating that it may influence the outcome of CRCs with possible variation in tumour subtype.
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Affiliation(s)
- Jimoh Ajanaku Abdulrazaq
- Department of Pathology, Federal University of Health Sciences Azare, Azare 751101, Bauchi, Nigeria
| | | | - Yusuf Ibrahim
- Department of Pathology, Aminu Kano Teaching Hospital, Kano 700101, Nigeria
| | - Hamza Ahmad
- Department of Pathology, Aminu Kano Teaching Hospital, Kano 700101, Nigeria
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Purnama A, Lukman K, Rudiman R, Prasetyo D, Fuadah Y, Nugraha P, Candrawinata VS. The prognostic value of COX-2 in predicting metastasis of patients with colorectal cancer: A systematic review and meta analysis. Heliyon 2023; 9:e21051. [PMID: 37876424 PMCID: PMC10590949 DOI: 10.1016/j.heliyon.2023.e21051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 09/30/2023] [Accepted: 10/13/2023] [Indexed: 10/26/2023] Open
Abstract
Introduction COX-2 is overexpressed in colorectal tumour tissue relative to the healthy colonic mucosa, thus we investigated the prognostic significance of COX-2 in determining the metastasis of patients with colorectal cancer. Methods PubMed, EMBASE, and Cochrane Library were searched using the following terms colorectal cancer, colon cancer, rectal cancer, colorectal carcinoma, Cyclooxygenase-2, and prognosis to identify articles providing information on the prognostic importance of COX-2 in adult patients with metastatic colorectal cancer. Review papers, non-research letters, comments, case reports, animal studies, original research with sample sizes of fewer than 20, case reports and series, non-English language articles, and pediatric studies (those under the age of 17) were excluded. The Newcastle Ottawa Scale (NOS) was used to assess the credibility of the included studies. The full texts were evaluated and this study complied with the terms of the local protocol and the Helsinki Declaration. Results Eight relevant studies were included in this review involving 937 patients. The meta-analysis revealed that COX-2 expression is associated with lymph node invasion (RR 1.85 [1.21, 2.83], P = 0.005, I2 = 88 %) and liver metastasis (RR 4.90 [1.12, 21.57], P = 0.04, I2 = 42 %), but not with venous dissemination (RR 1.48 [0.72, 3.03], P = 0.28, I2 = 87 %). Conclusion COX-2 expression is associated with lymph node invasion in colorectal cancer but further studies are required to determine the prognostic significance of COX-2 expression in determining metastasis status for colorectal cancer patients.
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Affiliation(s)
- Andriana Purnama
- Division of Digestive Surgery, Department of Surgery, Padjadjaran University, Bandung, Indonesia
| | - Kiki Lukman
- Division of Digestive Surgery, Department of Surgery, Padjadjaran University, Bandung, Indonesia
| | - Reno Rudiman
- Division of Digestive Surgery, Department of Surgery, Padjadjaran University, Bandung, Indonesia
| | - Dwi Prasetyo
- Division of Pediatric Gastroenterology, Department of Pediatric, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
| | - Yoni Fuadah
- Department of Forensic and Medicolegal, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
| | - Prapanca Nugraha
- Division of Digestive Surgery, Department of Surgery, Padjadjaran University, Bandung, Indonesia
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Yu C, Li W, Liu J, Lu J, Feng J. Autophagy: novel applications of nonsteroidal anti-inflammatory drugs for primary cancer. Cancer Med 2018; 7:471-484. [PMID: 29282893 PMCID: PMC5806108 DOI: 10.1002/cam4.1287] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 11/15/2017] [Accepted: 11/19/2017] [Indexed: 12/17/2022] Open
Abstract
In eukaryotic cells, autophagy is a process associated with programmed cell death. During this process, cytoplasmic proteins and organelles are engulfed by double-membrane autophagosomes, which then fuse with lysosomes to form autolysosomes. These autolysosomes then degrade their contents to recycle the cellular components. Autophagy has been implicated in a wide variety of physiological and pathological processes that are closely related to tumorigenesis. In recent years, an increasing number of studies have indicated that nonsteroidal anti-inflammatory drugs, such as celecoxib, meloxicam, sulindac, aspirin, sildenafil, rofecoxib, and sodium salicylate, have diverse effects in cancer that are mediated by the autophagy pathway. These nonsteroidal anti-inflammatory drugs can modulate tumor autophagy through the PI3K/Akt/mTOR, MAPK/ERK1/2, P53/DRAM, AMPK/mTOR, Bip/GRP78, CHOP/ GADD153, and HGF/MET signaling pathways and inhibit lysosome function, leading to p53-dependent G1 cell-cycle arrest. In this review, we summarize the research progress in autophagy induced by nonsteroidal anti-inflammatory drugs and the molecular mechanisms of autophagy in cancer cells to provide a reference for the potential benefits of nonsteroidal anti-inflammatory drugs in cancer chemotherapy.
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Affiliation(s)
- Chen Yu
- Department of Integrated TCM & Western MedicineJiangsu Cancer HospitalJiangsu Institute of Cancer ResearchNanjing Medical University Affiliated Cancer HospitalNanjingJiang Su210000China
| | - Wei‐bing Li
- Department of Integrated TCM & Western MedicineJiangsu Cancer HospitalJiangsu Institute of Cancer ResearchNanjing Medical University Affiliated Cancer HospitalNanjingJiang Su210000China
| | - Jun‐bao Liu
- Department of Traditional Chinese MedicineHenan Provincial People's HospitalZhengzhouHenanChina
| | - Jian‐wei Lu
- Department of MedicineJiangsu Cancer HospitalJiangsu Institute of Cancer ResearchNanjing Medical University Affiliated Cancer HospitalNanjingJiang Su210000China
| | - Ji‐feng Feng
- Department of MedicineJiangsu Cancer HospitalJiangsu Institute of Cancer ResearchNanjing Medical University Affiliated Cancer HospitalNanjingJiang Su210000China
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Ali MM, H Borai I, Ghanem HM, H Abdel-Halim A, Mousa FM. The prophylactic and therapeutic effects of Momordica charantia methanol extract through controlling different hallmarks of the hepatocarcinogenesis. Biomed Pharmacother 2017; 98:491-498. [PMID: 29287196 DOI: 10.1016/j.biopha.2017.12.096] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/17/2017] [Accepted: 12/19/2017] [Indexed: 02/08/2023] Open
Abstract
Inspite of the wide facilities for controlling cancer growth, there are little drugs to inhibit its metastasis or prevent its angiogenesis. Discovering such natural or synthetic multi-targeted agent that might strike different targets is considered as a vital goal for tumor controlling. In a previous study, the chemoprotective effect of methanol extract of Momordicacharantia (MEMC) on albino western rats bearing hepatocarcinogenesis was evaluated. The mechanism by which MEMC exert its anticancer properties was unknown. Therefore, we aimed in this study to investigate the possible role of MEMC as anti-proliferative, anti-angiogenic and anti-metastatic agent to exert its chemoprotective effect. The study was conducted on sixty albino western rats divided into six groups, 10 rats each. Diethylnitrosamine (DENA) was injected intraperitoneally (i.p.) at a dose of 200 mg/kg body weight once, 2 weeks later rats were received carbon tetrachloride (CCl4) subcutaneously (3 ml/kg/week) continued for 10 weeks. MEMC was orally produced to rats (40 mg/kg) alone, as well as before, at the same time and after DENA injection. Cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), caspase-3,-8 (Casp-3,-8), histone deacetylase (HDAC) and matrixmetalloproteinases-2,-9 (MMP-2,-9) were evaluated. MEMC treatment significantly decreased Cox-2, VEGF, HDAC and MMP-2,-9 and increased Casp-3,-8 as compared to DENAgroup,which demonstrated that the anticancer effect of MEMC may be through the inhibition of angiogenesis, proliferation and metastasis and the activation of apoptosis. The improvement in before-treated group was more pronounced than that in after- and simultaneous-treated groups, indicating thatMEMC may act as a prophylactic agent more than being a therapeutic agent.
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Affiliation(s)
- Mamdouh M Ali
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt.
| | - Ibrahim H Borai
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hala M Ghanem
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Abeer H Abdel-Halim
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt
| | - Fatma M Mousa
- Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt
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Uçan B, Özbek M, Şahin M, Kızılgül M, Çakal E. Cyclooxygenase-2 (COX-2) gene polymorphism in patients with differentiated thyroid carcinomas in the Turkish population. Turk J Med Sci 2017; 47:1848-1853. [PMID: 29306248 DOI: 10.3906/sag-1708-49] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Background/aim: The most common thyroid malignancies are papillary and follicular thyroid carcinomas. They account for approximately 85%-90% of all thyroid cancers. Recent studies have reported the relevance of cyclooxygenase-2 (COX-2) gene polymorphism in human carcinogenesis. The aim of this study was to investigate the relationship between thyroid carcinoma and COX-2 gene polymorphism in the Turkish population.Materials and methods: We included a total of 96 differentiated thyroid cancer patients (mean age: 46.9 ± 10.3 years; 14 males, 82 females) and 83 healthy control subjects (mean age: 46.0 ± 10.6 years; 39 males, 44 females). The frequency of -765G>C, -8473T>C, and 1195A>G gene polymorphisms in the COX-2 promoter region was investigated in thyroid cancer patients and the control group using the high-resolution melting method. Results: COX-2-765G>C and COX-2-1195A>G gene polymorphisms were similar between thyroid cancer patients and the control group. There was a statistically significant difference between COX-2-8473T>C gene polymorphism in the thyroid cancer group and the control group (P = 0.012).Conclusion: The single nucleotide gene polymorphism COX-2-8473T>C might contribute to genetic susceptibility to differentiated thyroid cancer in the Turkish population.
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Li H, Guo Q, Zhou B, He S. Cyclooxygenase-2 gene polymorphisms and the risk of colorectal cancer: A population-based study. Oncol Lett 2015; 10:1863-1869. [PMID: 26622766 DOI: 10.3892/ol.2015.3477] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 05/12/2015] [Indexed: 01/10/2023] Open
Abstract
The aim of the present study was to determine the association between polymorphisms in the cyclooxygenase-2 (COX-2) gene promoter region, rs20417 G/C and rs2745557 G/A, and the susceptibility to colorectal cancer (CRC) in a Han Chinese population in Shaanxi, China. Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) were used to detect the polymorphisms of COX-2, rs20417 G/C and rs2745557 G/A, in 300 patients with CRC and 300 healthy individuals in the present case-control study. The results revealed that for the COX-2 rs20417 G/C polymorphism, the GC+CC allele frequency was 80% in CRC patients and 71% in healthy controls [odds ratio (OR)=1.63; 95% confidence interval (CI), 1.12-2.38; P=0.01]. For the COX-2 rs2745557 G/A polymorphism, the GA+AA allele frequency was 84% in CRC patients and 73% in healthy controls (OR=1.94; 95% CI, 1.30-2.90; P<0.01). In addition, among individuals with a smoking history, drinking history or family history of CRC, those who were COX-2 rs20417 (GC+CC) or COX-2 rs2745557 (GA+AA) carriers had a significantly increased risk of developing CRC compared with that of GG genotype carriers (P<0.05). Furthermore, the allelic frequencies of COX-2 rs20417 G/C and rs2745557 G/A in patients with lymph node metastasis in stage III/IV of CRC were significantly different from those of COX-2 rs20417 G/C and rs2745557 G/A in patients without lymph node metastasis in stage I/II (P<0.05). In conclusion, the results of the present study revealed that COX-2 rs20417 C allele carriers and rs2745557 A allele carriers have a significantly increased risk of CRC compared with GG genotype carriers; in addition, the frequencies of these alleles were demonstrated to be associated with lymph node metastasis and CRC progression.
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Affiliation(s)
- Hongxia Li
- Department of Gastroenterology, The First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Qinyue Guo
- Department of Gastroenterology, The First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Bo Zhou
- Department of Respiration, The First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shuixiang He
- Department of Gastroenterology, The First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Lin Y, Peng N, Zhuang H, Zhang D, Wang Y, Hua ZC. Heat shock proteins HSP70 and MRJ cooperatively regulate cell adhesion and migration through urokinase receptor. BMC Cancer 2014; 14:639. [PMID: 25175595 PMCID: PMC4159539 DOI: 10.1186/1471-2407-14-639] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 08/21/2014] [Indexed: 11/30/2022] Open
Abstract
Background The urokinase-type plasminogen activator receptor (uPAR) is an important regulator of ECM proteolysis, cell-ECM interactions and cell signaling. uPAR and heat shock proteins HSP70 and MRJ (DNAJB6) have been implicated in tumor growth and metastasis. We have reported recently that MRJ (DNAJB6, a heat shock protein) can interact with uPAR and enhance cell adhesion. Here, we identified another heat shock protein HSP70 as a novel uPAR-interacting protein. Methods We performed co-immunoprecipitation in human embryonic kidney (HEK) 293 and colon cancer HCT116 cells as well as immunofluorence assays in HEK293 cells stably transfected with uPAR to investigate the association of suPAR with HSP70/MRJ. To understand the biological functions of the triple complex of suPAR/HSP70/MRJ, we determined whether HSP70 and/or MRJ regulated uPAR-mediated cell invasion, migration, adhesion to vitronectin and MAPK pathway in two pair of human tumor cells (uPAR negative HEK293 cells vs HEK293 cells stably transfected with uPAR and HCT116 cells stably transfected with antisense-uPAR vs HCT116 mock cells transfected with vector only) using transwell assay, wound healing assay, quantitative RT-PCR analyzing mmp2 and mmp9 transcription levels, cell adhesion assay and Western blotting assay. Results HSP70 and MRJ formed a triple complex with uPAR and over-expression of MRJ enhanced the interaction between HSP70 and uPAR, while knockdown of MRJ decreased soluble uPAR in HCT116 cells (P < 0.05) and reduced the formation of the triple complex, suggesting that MRJ may act as an uPAR-specific adaptor protein to link uPAR to HSP70. Further experiments showed that knockdown of HSP70 and/or MRJ by siRNA inhibited uPAR-mediated cell adhesion to vitronectin as well as suppressed cell invasion and migration. Knockdown of HSP70 and/or MRJ inhibited expression of invasion related genes mmp2 and mmp9. Finally, HSP70 and/or MRJ up-regulated phosphorylation levels of ERK1/2 and FAK suggesting MAPK pathway was involved. All the biological function experiments in cell level showed an additive effect when HSP70 and MRJ were regulated simultaneously indicating their collaborated regulation effects on uPAR. Conclusions These findings may offer a novel insight into the interactions between uPAR and HSP70/MRJ and their functions in cell adhesion and migration may provide more understanding of the roles in regulating cancer metastasis. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-639) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | | | | | | | - Yao Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, Jiangsu, P,R, China.
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Eiró N, Vizoso FJ. Inflammation and cancer. World J Gastrointest Surg 2012; 4:62-72. [PMID: 22530080 PMCID: PMC3332223 DOI: 10.4240/wjgs.v4.i3.62] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Revised: 11/17/2011] [Accepted: 11/25/2011] [Indexed: 02/06/2023] Open
Abstract
There is evidence supporting the hypothesis that inflammation participates in providing conditions that lead to cancer. An unresolved inflammation due to any failure in the precise control of the immune response can continue to perturb the cellular microenvironment, thereby leading to alterations in cancer-related genes and posttranslational modification in crucial cellular proteins involved in the cell cycle, DNA repair and apoptosis. In addition, there are data indicating that inflammatory cells and immunomodulatory mediators present in the tumor microenvironment influence tumor progression and metastasis. Historically, tumor-infiltrating leukocytes have been considered to be manifestations of an intrinsic defence mechanism against developing tumors. However, increasing evidence indicates that leukocyte infiltration can promote tumor phenotypes, such as angiogenesis, growth and invasion. This may be due to inflammatory cells that probably can influence cancer promotion by secreting cytokines, growth factors, chemokines and proteases, which stimulate proliferation and invasiveness of cancer cells. Consequently, events and molecules implicated in this cross talk between the tumor microenvironment and inflammatory process may emerge as attractive targets in anticancer therapeutic interventions with significant clinical impact.
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Affiliation(s)
- Noemí Eiró
- Noemí Eiró, Francisco J Vizoso, Research Unit, Fundación Hospital de Jove, 33290 Gijón, Asturias, Spain
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Prognostic Significance and Clinicopathological Associations of COX-2 SNP in Patients with Nonsmall Cell Lung Cancer. JOURNAL OF ONCOLOGY 2009; 2009:139590. [PMID: 20016751 PMCID: PMC2793422 DOI: 10.1155/2009/139590] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2009] [Accepted: 09/04/2009] [Indexed: 11/18/2022]
Abstract
Background. To further improve the screening, diagnosis, and therapy of patients with nonsmall cell lung cancer (NSCLC) additional diagnostic tools are urgently needed. Gene expression of Cyclooxygenase-2 (COX-2) has been linked to prognosis in patients with NSCLC. The role of the COX-2 926G>C Single Nucleotide Polymorphism (SNP) in patients with NSCLC remains unclear. The aim of this study was to investigate the potential of the COX-2 926G>C SNP as a molecular marker in this disease.
Methods. COX-2 926G>C SNP was analyzed in surgically resected tumor tissue of 85 patients with NSCLC using a PCR-based RFLP technique. Results. The COX-2 926G>C SNP genotypes were detected with the following frequencies: GG n = 62 (73%), GC n = 20 (23%), CC n = 3 (4%). There were no associations between COX-2 SNP genotype and histology, grading or gender detectable. COX-2 SNP was significantly associated with tumor stage (P = .032) and lymph node status (P = .016, Chi-square test). With a median followup of 85.9 months, the median survival was 59.7 months. There were no associations seen between the COX-2 SNP genotype and patients prognosis.
Conclusions. The COX-2 926G>C SNP is detectable at a high frequency in patients with NSCLC. The COX-2 926G>C SNP genotype is not a prognostic molecular marker in this disease. However, patients with the GC or CC genotype seem more susceptible to lymph node metastases and higher tumor stage than patients with the GG genotype. The results suggest COX-2 926G>C SNP as a molecular marker for lymph node involvement in this disease.
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Minoo P, Baker K, Baumhoer D, Terracciano L, Lugli A, Zlobec I. Urokinase-type plasminogen activator is a marker of aggressive phenotype and an independent prognostic factor in mismatch repair-proficient colorectal cancer. Hum Pathol 2009; 41:70-8. [PMID: 19740518 DOI: 10.1016/j.humpath.2009.05.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2009] [Revised: 04/17/2009] [Accepted: 05/07/2009] [Indexed: 01/08/2023]
Abstract
The aim of this study was to determine the prognostic significance of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in colorectal cancer stratified by mismatch repair status and to determine their contribution to the aggressive phenotype predicted by loss of E-cadherin and apoptosis protease activating factor-1 (APAF-1). Immunohistochemistry for uPA and uPAR was performed on a tissue microarray comprising 811 mismatch repair-proficient and 164 mismatch repair-deficient colorectal cancers. Immunoreactivity was scored semiquantitatively and the interobserver agreement between multiple pathologists was determined. Optimal cutoff scores for uPA and uPAR positivity were obtained by receiver operating characteristic curve analysis. Agreement between pathologists was excellent for uPA and uPAR. Cutoff scores of 60% for uPA and 75% for uPAR were validated by resampling of the data. In mismatch repair-proficient colorectal cancer, overexpression of uPA and uPAR was associated with advanced pT stage (P = .009, both), an infiltrating margin (P = .009 and P = .033, respectively), and poor prognosis (P = .002 and P < .001, respectively). uPA, but not uPAR, maintained its significant prognostic effect in multivariable analysis (P = .037). In addition to loss of APAF-1 (P = .002) and E-cadherin (P < .001), uPA independently predicted an infiltrating margin (P = .016). Our findings suggest that uPA, but not uPAR, is an independent prognostic factor and that this negative effect on survival is relevant specifically for mismatch repair-proficient colorectal cancers. Moreover, the combination of uPA with E-cadherin and APAF-1 is linked to an aggressive tumor phenotype and highly predictive of an infiltrating growth pattern.
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Affiliation(s)
- Parham Minoo
- Department of Pathology, University of California San Diego, San Diego, CA 92093, USA
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McArthur DR, Leung E, Morris A, Williams N. COX-2 expression is unexpectedly high in viable colorectal mucosal cells: is there life for chemoprophylaxis after VICTOR? Colorectal Dis 2009; 11:775-82. [PMID: 18691269 DOI: 10.1111/j.1463-1318.2008.01662.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Trials investigating colorectal cancer (CRC) chemoprophylaxis with cyclooxygenase-2 (COX-2) inhibitors have been discontinued because of adverse cardiovascular effects. Nevertheless, identification of patients where beneficial, chemo-prophylactic effects of COX-2 inhibitors outweigh side-effects may be possible; this study aimed to investigate whether such patient groups might exist. METHOD The COX-2 status of viable epithelial and inflammatory cells in freshly disaggregated CRC and paired normal colonic samples was assessed by three-colour flow cytometry. RESULTS 21/31 (67.7%) CRCs expressed COX-2, with inflammatory cells positive in 19/31 (61.3%), epithelial cells in 12/31 (38.7%), and both positive in 10/31 (32.3%). 25/30 (83.33%) normal samples expressed COX-2, with epithelial cells positive in 18/30 (60%), inflammatory cells in 15/30 (50%) and both positive in 10/30 (33.3%). Strength of expression by CRC and normal was similar. More advanced cancers had higher expression rates (COX-2 in 12/13 (92.3%) with nodal disease vs 9/17 (52.9%) node-negative; P = 0.04). CONCLUSION Investigation of ex-vivo CRC cells by flow cytometry demonstrated COX-2 expression rates comparable to that previously reported. However, expression by paired live normal colon was significantly greater, suggesting that COX-2 may be expressed at higher rates in normal colonic cells in patients with CRC. Patients identified at resection as expressing COX-2 in normal colon may benefit from Coxib chemo-prophylaxis, thus potentially offering a refined approach to that adopted in the VICTOR trial.
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Affiliation(s)
- D R McArthur
- Department of Surgery, University Hospitals Coventry and Warwickshire, Coventry, UK.
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Aggarwal BB, Gehlot P. Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol 2009; 9:351-69. [PMID: 19665429 PMCID: PMC2730981 DOI: 10.1016/j.coph.2009.06.020] [Citation(s) in RCA: 277] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2009] [Revised: 06/22/2009] [Accepted: 06/23/2009] [Indexed: 02/03/2023]
Abstract
Evidence has emerged in the last two decades that at the molecular level most chronic diseases, including cancer, are caused by a dysregulated inflammatory response. The identification of transcription factors such as NF-kappaB, AP-1 and STAT3 and their gene products such as tumor necrosis factor, interleukin-1, interleukin-6, chemokines, cyclooxygenase-2, 5 lipooxygenase, matrix metalloproteases, and vascular endothelial growth factor, adhesion molecules and others have provided the molecular basis for the role of inflammation in cancer. These inflammatory pathways are activated by tobacco, stress, dietary agents, obesity, alcohol, infectious agents, irradiation, and environmental stimuli, which together account for as much as 95% of all cancers. These pathways have been implicated in transformation, survival, proliferation, invasion, angiogenesis, metastasis, chemoresistance, and radioresistance of cancer, so much so that survival and proliferation of most types of cancer stem cells themselves appear to be dependent on the activation of these inflammatory pathways. Most of this evidence, however, is from preclinical studies. Whether these pathways have any role in prevention, progression, diagnosis, prognosis, recurrence or treatment of cancer in patients, is the topic of discussion of this review. We present evidence that inhibitors of inflammatory biomarkers may have a role in both prevention and treatment of cancer.
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Affiliation(s)
- Bharat B Aggarwal
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States.
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Mariani F, Sena P, Marzona L, Riccio M, Fano R, Manni P, Gregorio CD, Pezzi A, Leon MPD, Monni S, Pol AD, Roncucci L. Cyclooxygenase-2 and Hypoxia-Inducible Factor-1alpha protein expression is related to inflammation, and up-regulated since the early steps of colorectal carcinogenesis. Cancer Lett 2009; 279:221-229. [PMID: 19268443 DOI: 10.1016/j.canlet.2009.02.001] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2008] [Revised: 01/29/2009] [Accepted: 02/02/2009] [Indexed: 12/13/2022]
Abstract
Chronic mucosal inflammation is considered a risk factor for colorectal cancer. Neutrophils are a major source of oxidants, whereas cyclooxygenase 2 (COX-2) and Hypoxia Inducible Factor-1alpha (HIF-1alpha) protein expression levels are increased in inflammatory and malignant lesions. The main purpose of the present study was to evaluate myeloperoxidase (MPO) positive cell infiltration, COX-2 and HIF-1alpha protein expression in colorectal carcinogenesis, especially in its early phases, using immunohistochemistry and immunofluorescence confocal microscopy techniques. MPO, COX-2 and HIF-1alpha proteins were expressed at higher rates in the normal colorectal mucosa of patients with inflammatory bowel diseases and colorectal tumours than in patients with normal colonoscopy. A gradual increase in COX-2 and HIF-1alpha protein expression was observed in dysplastic aberrant crypt foci, adenomas and carcinomas, showing a strong relation to dysplasia. In conclusion, the present study supports the hypothesis of a key role of inflammation in malignant transformation of colorectal mucosa. The evaluation of some early markers related to inflammation in the mucosa of the large bowel may serve as potential tool for prognosis and therapeutic strategies.
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Affiliation(s)
- Francesco Mariani
- Department of Internal Medicine, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41100 Modena, Italy
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14
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Paydas S, Ergin M, Erdogan S, Seydaoglu G. Cyclooxygenase-2 expression in non-Hodgkin's lymphomas. Leuk Lymphoma 2009; 48:389-95. [PMID: 17325901 DOI: 10.1080/10428190601059787] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Cyclooxygenase 2 (Cox-2) is a key enzyme in prostaglandin synthesis and it has an important role in the pathogenesis of various malignancies. Cox-2 has been studied in solid tumors; however, studies about the role of Cox-2 in non-Hodgkin's lymphomas (NHL) are limited. The aim of this study is to determine the importance of Cox-2 expression in lymphomas. To this end, Cox-2 expression was determined in 177 cases with NHL. In histological terms, 60 cases (33%) had low grade and 117 (67%) had aggressive lymphoma. Ninety-nine cases were found to be positive for Cox-2 (56%); Cox-2 score was between 50 and 100, 101 and 200 and over 200 in 38, 46 and 15 cases, respectively. There was an important association between aggressive histology and Cox-2 expression: Cox-2 was negative in about half of the cases with indolent morphology, while two thirds of the Cox-2 positive cases had aggressive histology (p = 0.036). There was no significant association between Cox-2 expression and clinical-laboratory parameters. Although the overall survival times were longer in cases with lower or no Cox-2 expression as compared with higher Cox-2 expression, the difference was not significant. In conclusion Cox-2 expression is seen about 60% of the cases with NHL and is associated with aggressive morphology.
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Affiliation(s)
- Semra Paydas
- Department of Oncology, Faculty of Medicine, Cukurova University, Adana, Turkey.
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15
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Debucquoy A, Goethals L, Libbrecht L, Perneel C, Geboes K, Ectors N, McBride WH, Haustermans K. Molecular and clinico-pathological markers in rectal cancer: a tissue micro-array study. Int J Colorectal Dis 2009; 24:129-38. [PMID: 19050903 PMCID: PMC2745734 DOI: 10.1007/s00384-008-0608-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/12/2008] [Indexed: 02/04/2023]
Abstract
AIMS The aims of the study were to study the effect of pre-operative treatment on the expression of tumour-related proteins and to correlate the expression of these proteins with response and survival of patients with advanced rectal cancer. MATERIALS AND METHODS Tissue micro-arrays from pre- and post-treatment biopsies of 99 patients with rectal cancer treated with pre-operative (chemo)radiotherapy were stained for epidermal growth factor receptor (EGFR), carbonic anhydrase IX, Ki67, vascular endothelial growth factor, cyclo-oxygenase 2 (COX-2) and cleaved cytokeratin 18 (c-CK18). Also, fibro-inflammatory alterations after treatment were evaluated. RESULTS Pre-operative (chemo)radiotherapy caused fibro-inflammatory changes, a downregulation of proliferation (Ki67) and EGFR and an upregulation of apoptosis (cleaved CK18). Patients with a good regression during pre-operative treatment showed less proliferating and apoptotic cells in the resection specimen. Multivariate analysis showed that T downstaging, fibro-inflammatory changes in the resection specimen and COX-2 expression in the biopsy correlated with overall survival. CONCLUSIONS Pre-operative treatment has an effect on proliferation, apoptosis, inflammation and EGFR expression. The classical clinical parameters as well as fibro-inflammatory changes and COX-2 expression seem most valuable as predictors for survival.
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Affiliation(s)
- Annelies Debucquoy
- Department of Radiation Oncology, University Hospital Gasthuisberg, Herestraat 49, 3000, Leuven, Belgium.
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16
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ZAFIRELLIS KYRIAKOS, AGROGIANNIS GEORGE, ZACHAKI AGLAIA. Prognostic value of COX-2 immunohistochemical expression evaluated by quantitative image analysis in colorectal cancer. APMIS 2008; 116:912-22. [DOI: 10.1111/j.1600-0463.2008.01104.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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17
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Urade M. Cyclooxygenase (COX)-2 as a potent molecular target for prevention and therapy of oral cancer. JAPANESE DENTAL SCIENCE REVIEW 2008. [DOI: 10.1016/j.jdsr.2007.10.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
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18
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Expression of cyclooxygenase-2 and DNA topoisomerase II α in precancerous and cancerous lesions of the oral mucosa. Oral Oncol 2008; 44:664-71. [DOI: 10.1016/j.oraloncology.2007.08.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2007] [Revised: 08/29/2007] [Accepted: 08/29/2007] [Indexed: 11/19/2022]
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19
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Iwamoto J, Mizokami Y, Takahashi K, Matsuoka T, Matsuzaki Y. The effects of cyclooxygenase2-prostaglandinE2 pathway on Helicobacter pylori-induced urokinase-type plasminogen activator system in the gastric cancer cells. Helicobacter 2008; 13:174-82. [PMID: 18466392 DOI: 10.1111/j.1523-5378.2008.00597.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in the destruction of the extracellular matrix and basement membrane. The induction of uPA and uPAR in the gastric cancer cells with H. pylori has been demonstrated previously. The involvement of COX-2-PGE2 pathway in the uPA system (uPA and uPAR) expression is unclear. METHODS Gastric cancer cells (MKN45) were co-cultured with H. pylori standard strain (NCTC11637). The specific inductions of uPA and uPAR mRNA were examined by reverse transcription-polymerase chain reaction amplification. The secreted uPA antigen was measured by ELISA. To evaluate the involvement of COX-2 and PGE2 pathway in H. pylori-induced uPA and uPAR expressions, we examined the effects of COX-2 inhibitor and PGE2 receptor antagonist on H. pylori-induced uPA and uPAR expression in the gastric cancer cells. RESULTS The expressions of both uPA and uPAR mRNAs in the gastric cancer cells increased obviously (12-fold and 3-fold, respectively) with H. pylori stimulation. The amount of uPA antigen into the culture medium increased dramatically with H. pylori stimulation. The COX-2 expression level in the gastric cancer cells increased remarkably with H. pylori stimulation. H. pylori-induced uPA and uPAR expression levels were suppressed with COX2 inhibitor treatment. The amount of PGE2 antigen into the culture medium increased dramatically 24 hours after H. pylori stimulation. The gastric cancer cells expressed EP2 and EP4 subtypes. EP2 receptor antagonist suppressed the H. pylori-induced uPA and uPAR expressions in the gastric cancer cells. CONCLUSIONS Our results indicated that COX2-PGE2 pathway may be involved in H. pylori-associated uPA and uPAR induction, and that COX-2 inhibitor or EP2 receptor antagonist may inhibit angiogenesis and tumor invasion via suppression of the uPA system.
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Affiliation(s)
- Junichi Iwamoto
- Department of Gastroenterology, Kasumigaura Hospital, Tokyo Medical University, Tokyo, Japan.
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20
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Bouzourene H, Yan P, Sandmeier D, Zouhair A, Matter M, Vuilleumier H, Coucke P. The role of COX-2 in rectal cancer treated with preoperative radiotherapy. Virchows Arch 2008; 452:499-505. [DOI: 10.1007/s00428-008-0606-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2008] [Accepted: 03/09/2008] [Indexed: 11/28/2022]
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21
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Sakurai K, Urade M, Noguchi K, Hashitani S, Takaoka K, Segawa E, Kishimoto H. Prognostic significance of cyclooxygenase-2 and DNA topoisomerase IIalpha expression in oral carcinoma. Head Neck 2008; 29:1002-9. [PMID: 17427971 DOI: 10.1002/hed.20627] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Despite recent advances in the diagnosis and treatment of oral carcinoma, outcomes remain disappointing. The identification of new prognostic factors is necessary to improve survival. To determine the prognostic significance of cyclooxygenase (COX)-2 and DNA topoisomerase (DNA-Topo) IIalpha expression in patients with oral carcinoma, we immunohistochemically examined these enzymes and studied their relation to overall 5-year survival. METHODS Surgical specimens were obtained from 160 patients with oral carcinoma, 80 with and 80 without regional lymph node metastasis. The specimens were immunostained for COX-2 and DNA-Topo IIalpha as an index of cell proliferative activity. COX-2 immunoreactivity and clinicopathological data were analyzed, and 5-year survival was calculated by the Kaplan-Meier method. RESULTS COX-2 expression in primary lesions was higher in cases with lymph node metastasis than in those without lymph node metastasis. An increase in tumor size was associated with increased COX-2 expression. In most cases with lymph node metastasis, COX-2 expression was higher in metastatic lesions than in primary lesions. As COX-2 expression increased, the DNA-Topo IIalpha labeling index significantly increased and the overall 5-year survival rate decreased. CONCLUSION Expression of COX-2 and DNA-Topo IIalpha were related to lymph node metastasis, cell proliferative activity, and overall 5-year survival rate in oral carcinoma. These enzymes may therefore be valuable diagnostic and prognostic indices in oral carcinoma.
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Affiliation(s)
- Kazunari Sakurai
- Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
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22
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Lim SC, Lee TB, Choi CH, Ryu SY, Min YD, Kim KJ. Prognostic significance of cyclooxygenase-2 expression and nuclear p53 accumulation in patients with colorectal cancer. J Surg Oncol 2008; 97:51-56. [PMID: 17929263 DOI: 10.1002/jso.20907] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Cyclooxygenase (COX)-2 is believed to be an important enzyme related to the pathogenesis of colorectal cancer (CRC). p53 has been reported to be a negative regulator of COX-2 expression in in vitro studies. The aim of this study was to investigate COX-2 expression and its relationship with nuclear p53 accumulation and their prognostic significance in CRC. METHODS COX-2 expression and nuclear p53 accumulation were examined by immunohistochemistry in 231 sporadic CRCs. Their prognostic significance and interrelationship were statistically evaluated. RESULTS We found 42.4% of the 231 cases of CRCs with positive COX-2 expression. Nuclear p53 accumulation was observed in 46.8% of cases. There was no significant correlation between COX-2 expression and nuclear p53 accumulation. COX-2 expression had no correlation with patient survival, whereas nuclear p53 accumulation was significantly correlated with poor patient survival on univariate and multivariate analysis. CONCLUSIONS These results suggest that COX-2 expression does not play a role in the prognosis of CRC and COX-2 expression is not affected by the status of nuclear p53 accumulation in CRC. In addition, our findings support that nuclear p53 accumulation may be a useful prognostic marker for patients with CRC.
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Affiliation(s)
- Sung-Chul Lim
- Research Center for Resistant Cells, Chosun University College of Medicine, Gwangju, Korea
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23
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Lim SC, Lee TB, Choi CH, Ryu SY, Kim KJ, Min YD. Expression of cyclooxygenase-2 and its relationship to p53 accumulation in colorectal cancers. Yonsei Med J 2007; 48:495-501. [PMID: 17594159 PMCID: PMC2628091 DOI: 10.3349/ymj.2007.48.3.495] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2006] [Accepted: 12/30/2006] [Indexed: 02/07/2023] Open
Abstract
PURPOSE Cyclooxygenase (COX)-2 is an inducible isoform responsive to cytokines, mitogens, and growth factors, and is believed to be an important enzyme related to colorectal cancer (CRC). Existing evidence suggests that COX-2 expression is normally suppressed by wild-type p53 but not mutant p53, suggesting that loss of p53 function may result in the induction of COX-2 expression. The aim of this study was to determine the relationship between COX-2 expression and p53 levels in CRC. MATERIALS AND METHODS Patients with sporadic colorectal adenocarcinoma (n=161) who underwent curative surgery in Chosun University Hospital were enrolled in this study. Expression of COX-2 and p53 proteins was examined by immunohistochemistry in paraffin-embedded cancer tissue blocks, and the relationship between COX-2 and/or p53 expression with clinicopathologic parameters was analyzed. RESULTS Expression of COX- 2 was positive in 47.8% of colorectal cancers, and significantly associated with the depth of tumor invasion (p= 0.042). In contrast, p53 was positive in 50.3% of the cases, and was associated with both age (p=0.025) and the depth of tumor invasion (p=0.014). There was no correlation between COX-2 expression and p53 expression (p=0.118). CONCLUSION These results suggest that COX-2 expression might play an important role in the progression of colorectal cancer. However, COX-2 expression was not associated with mutational p53. Further studies are needed to clarify the regulatory mechanisms governing COX-2 overexpression in colorectal cancers.
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Affiliation(s)
- Sung-Chul Lim
- Research Center for Resistant Cells, Chosun University College of Medicine, Gwangju, Korea
| | - Tae-Beum Lee
- Research Center for Resistant Cells, Chosun University College of Medicine, Gwangju, Korea
| | - Cheol-Hee Choi
- Research Center for Resistant Cells, Chosun University College of Medicine, Gwangju, Korea
| | - So-Yeon Ryu
- Department of Preventive Medicine, Chosun University College of Medicine, Gwangju, Korea
| | - Kyung-Jong Kim
- Department of Surgery, Chosun University College of Medicine, Gwangju, Korea
| | - Young-Don Min
- Department of Surgery, Chosun University College of Medicine, Gwangju, Korea
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24
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Fakhrai H, Mantil JC, Liu L, Nicholson GL, Murphy-Satter CS, Ruppert J, Shawler DL. Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Ther 2006; 13:1052-60. [PMID: 16826191 DOI: 10.1038/sj.cgt.7700975] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
We performed a phase I clinical trial in grade IV astrocytoma to assess the safety of a whole-cell vaccine comprising autologous tumor cells genetically modified by a transforming growth factor-beta2 (TGF-beta2) antisense vector. Blocking secretion of the immunosuppressive molecule TGF-beta in this manner should inhibit one of the major mechanisms by which tumor cells evade immune surveillance and should lead to clinically effective antitumor immunity. Six patients with progressive WHO grade IV astrocytoma were enrolled in the trial. Patients received 2-7 subcutaneous injections of 5 x 10(6)-2 x 10(7) autologous tumor cells per injection. TGF-beta2 secretion by the tumor cells used to vaccinate patients was inhibited by 53-98%. Treatment was well tolerated with only low-grade, transient treatment-related toxicities reported. Two patients had partial regressions and two had stable disease following therapy. The overall median survival was 68 weeks. Median survival of the responding patients was 78 weeks, compared to a historic value of 47 weeks for glioma patients treated conventionally. There were indications of humoral and cellular immunity induced by the vaccine. These findings support further clinical evaluation of vaccines comprised of TGF-beta antisense-modified tumor cells.
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Affiliation(s)
- H Fakhrai
- Advanced Biotherapies, Inc., San Diego, CA, USA
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25
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Zhang L, Zhao ZS, Ru GQ, Ma J. Correlative studies on uPA mRNA and uPAR mRNA expression with vascular endothelial growth factor, microvessel density, progression and survival time of patients with gastric cancer. World J Gastroenterol 2006; 12:3970-6. [PMID: 16810742 PMCID: PMC4087704 DOI: 10.3748/wjg.v12.i25.3970] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the correlations between the expression of urokinase-type plasminogen activator (uPA) mRNA, uPA receptor (uPAR) mRNA and vascular endothelial growth factor (VEGF) protein and clinicopathologic features, microvessel density (MVD) and survival time.
METHODS: In situ hybridization and immuno-histochemistry techniques were used to study the expressions of uPA mRNA, uPAR mRNA, VEGF and CD34 protein in 105 gastric carcinoma specimens.
RESULTS: Expressions of uPA mRNA, uPAR mRNA and VEGF protein were observed in 61 (58.1%) cases, 70 (66.7%) cases and 67 (63.8%) cases, respectively. The uPA mRNA and uPAR mRNA positive expression rates in infiltrating-type cases (73.7%, 75.4%), stage III-IV (72.1%, 75.4%), vessel invasion (63.2%, 69.9%), lymphatic metastasis (67.1%, 74.4%) and distant metastasis (88.1%, 85.7%) were significantly higher than those of the expanding-type (χ2 = 15.57, P = 0.001; χ2 = 6.91, P = 0.046), stage I-II (χ2 = 19.22, P = 0.001; χ2 = 16.75, P = 0.001), non-vessel invasion (χ2 = 11.92, P = 0.006; χ2 = 14.15, P = 0.002), non-lymphatic metastasis (χ2 = 28.41, P = 0.001; χ2 = 22.5, P = 0.005) and non-distant metastasis (χ2 = 12.32, P = 0.004; χ2 = 17.42, P = 0.002; χ2 = 11.25, P = 0.012; χ2 = 18.12, P = 0.002).The VEGF positive expression rates in infiltrating-type cases (75.4%), stage III-IV (88.5%), vessel invasion (82.9%), lymphatic metastasis (84.3%) and distant metastasis (95.2%) were significantly higher than those of the expanding-type (χ2 = 9.61, P = 0.021), stage I-II (χ2 = 16.66, P = 0.001), non-vessel invasion (χ2 = 29.38, P = 0.001), non-lymphatic metastasis (χ2 = 18.68, P = 0.005), and non-distant metastasis (χ2 = 22.72, P = 0.007; χ2 = 21.62, P = 0.004). The mean MVD in the specimens positive for the uPA mRNA, uPAR mRNA and VEGF protein was markedly higher than those with negative expression groups. Moreover, a positive relation between MVD and uPA mRNA (rs = 0.199, P = 0.042), uPAR mRNA (rs = 0.278, P = 0.035), and VEGF (rs = 0.398, P = 0.048) expressions was observed. The mean survival time in cases with positive uPA mRNA, uPAR mRNA and VEGF protein expression or MVD value ≥ 54.9 was significantly shorter than those in cases with negative expression or MVD value < 54.9.
CONCLUSION: uPA and uPAR expressions are correlated with enhanced VEGF-induced tumor angiogenesis and may play a role in invasion and nodal metastasis of gastric carcinoma, thereby serving as prognostic markers of gastric cancer.
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Affiliation(s)
- Li Zhang
- Department of Pathology, Wenzhou Medical College, Zhejiang Province, China
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26
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Abstract
Inflammation and cancer have been viewed as closely linked for many years. This link is not merely a loose association but causative. In colorectal cancer (CRC), chronic inflammation as observed in inflammatory bowel (IBD) disease is a key predisposing factor and IBD-associated CRC comprises five percent of all CRCs. Although the molecular mechanisms linking IBD with CRC are not well understood, recent results obtained in preclinical models point to the transcription factor NF-kappaB as a central player. On the one hand, NF-kappaB regulates the expression of various cytokines and modulates the inflammatory processes in IBD. On the other, NF-kappaB stimulates the proliferation of tumor cells and enhances their survival through the regulation of anti-apoptotic genes. Furthermore, it has been clearly established that most carcinogens and tumor promoters activate NF-kappaB, while chemopreventive agents generally suppress this transcription factor. Actually, several lines of evidence suggest that activation of NF-kappaB may cause cancer. These include the finding that NF-kappaB genes can be oncogenes, and that this transcription factor controls apoptosis, cell-cycle progression and proliferation, and possibly also cell differentiation.
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27
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Chi-Man Tang T, Tung-Ping Poon R, Fan ST. The significance of cyclooxygenase-2 expression in human hepatocellular carcinoma. Biomed Pharmacother 2006; 59 Suppl 2:S311-6. [PMID: 16507400 DOI: 10.1016/s0753-3322(05)80053-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the five most common malignancies in the world and is the second leading cause of death in Hong Kong. Previous studies have shown increased levels of cyclooxygenase-2 (COX-2) in a variety of human malignancies including HCC, suggesting that abnormal COX-2 expression plays an important role in carcinogenesis. In addition, some evidence suggests that selective COX-2 inhibitors suppress the formation of tumors in experimental models. However, there are no data in the literature on using COX-2 as an inhibitor target in HCC. The main objective of this article was to give a brief summary of the recent findings of the role of COX-2 in HCC. We briefly reviewed the significance of COX-2 in varies cancers, and then focused on the recent findings of the significance of COX-2 in HCC. Finally, we further evaluated the possibility of using COX-2 as a therapeutic target in HCC.
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Affiliation(s)
- T Chi-Man Tang
- Center for the Study of Liver Disease, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, China
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28
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Jiménez-Anula J, Luque RJ, Gaforio JJ, Delgado M. [Cyclooxygenase-2 expression as a prognostic factor in sporadic colorectal cancer]. Cir Esp 2006; 78:39-44. [PMID: 16420789 DOI: 10.1016/s0009-739x(05)70882-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
INTRODUCTION The aims of the present study were to investigate cyclooxygenase-2 expression in neoplastic cells from colorectal carcinoma and to study the role of cyclooxygenase-2 expression as a prognostic factor related to distant metastases and survival. PATIENTS AND METHOD A retrospective study of 105 patients with sporadic colorectal cancer was performed. The patients underwent surgery at the General Surgery Department of the University Hospital of Jaén between 1991 and 1997. Several clinicopathological features were recorded: gender, tumor location, TNM stage, histological type and grade and the presence of venous or lymphatic invasion. The mean time of follow-up was 54 months. Immunohistochemistry: cyclooxygenase-2 expression was tested using avidin-biotin-peroxidase immunostaining. Both the intensity and extension of the stain were assessed. RESULTS Cyclooxygenase-2 expression in neoplastic cells was considered to be positive in 38 cases (36.2%). No statistically significant relationship was found between cyclooxygenase-2 expression and the clinicopathological features recorded (P >.05). Tumor recurrence: Distant metastases were diagnosed in 14 patients (13.3%). Cyclooxygenase-2 did not show a significant relationship with metastases in the multivariate analysis (HR: 0.36; 95% confidence interval [CI]: 0.07-1.69). Survival: Mean survival time was 55 months. Multivariate analysis did not show cyclooxygenase-2 as an independent risk factor of death (HR: 0.51; 95% CI: 0.22-1.21). CONCLUSIONS Cyclooxygenase-2 expression was not significantly related to clinical and histopathological features of the tumors nor was it an independent risk factor of tumour recurrence or survival.
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Affiliation(s)
- Juan Jiménez-Anula
- Servicio de Cirugía General, Hospital Universitario Médico-Quirúrgico, Jaén, Spain.
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Schottelius AJ, Dinter H. Cytokines, NF-kappaB, microenvironment, intestinal inflammation and cancer. Cancer Treat Res 2006; 130:67-87. [PMID: 16610703 DOI: 10.1007/0-387-26283-0_3] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Inflammation and cancer have been viewed as closely linked for many years. This link is not merely a loose association but causative. In colorectal cancer (CRC), chronic inflammation as observed in inflammatory bowel (IBD) disease is a key predisposing factor and IBD-associated CRC comprises five percent of all CRCs. Although the molecular mechanisms linking IBD with CRC are not well understood, recent results obtained in preclinical models point to the transcription factor NF-kappaB as a central player. On the one hand, NF-kappaB regulates the expression of various cytokines and modulates the inflammatory processes in IBD. On the other, NF-kappaB stimulates the proliferation of tumor cells and enhances their survival through the regulation of anti-apoptotic genes. Furthermore, it has been clearly established that most carcinogens and tumor promoters activate NF-kappaB, while chemopreventive agents generally suppress this transcription factor. Actually, several lines of evidence suggest that activation of NF-kappaB may cause cancer. These include the finding that NF-kappaB genes can be oncogenes, and that this transcription factor controls apoptosis, cell-cycle progression and proliferation, and possibly also cell differentiation.
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Affiliation(s)
- Arndt J Schottelius
- Development Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
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30
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Scicolone G, Sanchez V, Vauthay L, Fuentes F, Scicolone A, Scicolone L, Rapacioli M, Flores V. Tissue-type plasminogen activator activity in morphologically normal tissues adjacent to gastrointestinal carcinomas is associated with the degree of tumor progression. J Cancer Res Clin Oncol 2005; 132:309-19. [PMID: 16369808 DOI: 10.1007/s00432-005-0066-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2005] [Accepted: 11/29/2005] [Indexed: 10/25/2022]
Abstract
PURPOSE To investigate whether the level of plasminogen activator (PA) activity assayed in gastrointestinal carcinomas and the "morphologically normal tissues" adjacent to them is associated with the degree of tumor progression. METHODS Tumor and "normal tissues" were obtained from gastrointestinal surgical samples to assess urokinase-type (u-PA) and tissue-type plasminogen activator (t-PA) activities by radial caseinolytic assay and the expression of PA inhibitor-1 (PAI-1) by ELISA. We compared the PA system between the tumor and "normal tissues" and we investigated the existence of correlations between: (a) PA production in the tumor and "normal tissues", (b) different components of the PA system, and (c) PA system and the degree of tumor progression. RESULTS (1) Total PA activity, u-PA activity and PAI-1 expression are significantly higher in tumor than in "normal tissues", whereas t-PA activity does not differ between them. (2) Total PA activity mainly correlates with u-PA activity in tumor tissues and similarly with u-PA and t-PA activities in "normal tissues". (3) There is a significant association between t-PA activity in tumor and "normal tissues" and the degree of tumor progression. CONCLUSIONS "Morphologically normal tissues" adjacent to carcinomas present abnormal t-PA activity that is associated with the degree of tumor progression. Assaying of this activity could be useful as a predictive parameter.
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Affiliation(s)
- Gabriel Scicolone
- School of Medicine, Institute of Cell Biology and Neurosciences, Prof E De Robertis, University of Buenos Aires, Paraguay 2155, 1121, Buenos Aires, Argentina.
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Fux R, Schwab M, Thon KP, Gleiter CH, Fritz P. Cyclooxygenase-2 expression in human colorectal cancer is unrelated to overall patient survival. Clin Cancer Res 2005; 11:4754-60. [PMID: 16000571 DOI: 10.1158/1078-0432.ccr-04-2586] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE Cyclooxygenase-2 (COX-2) expression in human colorectal cancer and adenoma tissue seems to be higher than in normal mucosa. However, data about the relation between COX-2 expression and patient survival are inconclusive as yet. Therefore, we studied COX-2 expression in surgery tissue and survival time in a cohort of 747 colorectal cancer patients. EXPERIMENTAL DESIGN Surgical specimens of primary colorectal cancer from 747 individuals were immunostained for COX-2 and evaluated under a transmission light microscope. COX-2 expression was scored according to intensity and extent of staining, resulting in the COX-2 immunoreactivity score (IRS-COX2). All possible cutoff points for IRS-COX2 were analyzed for a relation between COX-2 expression and patient survival. RESULTS Both univariable and multivariable analysis have shown that the COX-2 expression in human tumor epithelial cells was unrelated to overall patient survival and to disease-free survival, irrespectively of the cutoff point for IRS-COX2. The survival rates for 1, 3, 5, and 10 years were 81.0%, 66.8%, 60.2%, and 49.8% (median: 117.3 months; 95% confidence interval, 102.3-132.0), respectively. In the multivariable analysis, only node and metastasis were significantly related to overall patient survival. Similar results were obtained when stage IV and rectal cancer patients were excluded from the analysis. CONCLUSIONS COX-2 expression in tumor epithelial cells does not seem to be related to survival of colorectal cancer patients. Besides COX-2, there are several targets, such as the peroxisome proliferator-activated receptors, that are involved in carcinogenesis and may be modulated by nonsteroidal anti-inflammatory drugs. Further studies are needed to determine their prognostic relevance.
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Affiliation(s)
- Richard Fux
- Abteilung Klinische Pharmakologie, Institut für Pharmakologie und Toxikologie, Universitätsklinikum Tübingen, Tübingen, Germany
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Yuan A, Yu CJ, Shun CT, Luh KT, Kuo SH, Lee YC, Yang PC. Total cyclooxygenase-2 mRNA levels correlate with vascular endothelial growth factor mRNA levels, tumor angiogenesis and prognosis in non-small cell lung cancer patients. Int J Cancer 2005; 115:545-55. [PMID: 15704107 DOI: 10.1002/ijc.20898] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Interaction between cancer cells and adjacent stromal cells is important to promote tumor development. Our aim was to study total COX-2 mRNA expression in both cancer cells and surrounding stromal cells and its association with angiogenic factor VEGF mRNA expression, tumor angiogenesis and prognosis in patients with NSCLC. COX-2 mRNA expression in both cancer cells and stromal tissue was analyzed using real-time quantitative (RTQ) RT-PCR in 60 NSCLC surgical specimens. Immunohistochemistry (IHC) was used to localize COX-2 protein in tumor specimens. Correlations between tumoral total COX-2 mRNA expression and VEGF mRNA expression (measured by RTQ RT-PCR), intratumoral microvessel counts (evaluated by IHC), other clinicopathologic variables, survival and relapse were tested. COX-2 protein expression was found in cancer as well as the surrounding stromal cells (including infiltrating inflammatory cells and endothelial cells of tumor-associated microvessels). VEGF protein expression was mainly located in cancer cells. There was a significant association between high tumoral total COX-2 mRNA expression and high VEGF mRNA expression (p = 0.01) or high intratumoral MVC (p < 0.001) but not other clinicopathologic variables, including tumor status and lymph node metastasis. Patients with higher tumoral total COX-2 mRNA expression had a statistically shorter survival time (median 15.0 +/- 2.61 months) and relapse time (median 5.0 +/- 1.37 months) than those with lower tumoral total COX-2 mRNA expression (median 40.0 +/- 3.12 and 34.0 +/- 3.11 months; p < 0.0001 and p < 0.0001, respectively, log-rank test). A significant difference in survival and relapse time was also seen between patients with high and low tumoral VEGF mRNA expression and between those with high and low intratumoral MVC (p = 0.0046 and p = 0.0038, respectively). After stratification by disease stage or histologic subtype, the prognostic significance of high total COX-2 mRNA expression was still apparent in both stage I and stage II-IV and in both squamous cell carcinoma and adenocarcinoma (p < or = 0.01 for all). Multivariate analysis using the Cox regression model with backward elimination showed that tumoral total COX-2 mRNA expression and lymph node status were the 2 most important independent prognostic predictors for survival and disease relapse. We report that total COX-2 mRNA expression in cancer cells and surrounding stromal cells correlates strongly and positively with VEGF mRNA expression, intratumoral MVC and adverse prognosis in NSCLC patients. This implies that COX-2 expression in both cancer cells and stromal cells within the tumor microenvironment may play an important role in upregulating the expression of the angiogenic factor VEGF and tumor angiogenesis in NSCLC and explains, in part, the adverse prognostic effect of COX-2 overexpression in patients with NSCLC.
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Affiliation(s)
- Ang Yuan
- Division of Chest Medicine, Departments of Internal Medicine and Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan
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O'Donoghue JA, Zanzonico P, Pugachev A, Wen B, Smith-Jones P, Cai S, Burnazi E, Finn RD, Burgman P, Ruan S, Lewis JS, Welch MJ, Ling CC, Humm JL. Assessment of regional tumor hypoxia using 18F-fluoromisonidazole and 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) positron emission tomography: Comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models. Int J Radiat Oncol Biol Phys 2005; 61:1493-502. [PMID: 15817355 DOI: 10.1016/j.ijrobp.2004.12.057] [Citation(s) in RCA: 134] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2004] [Revised: 12/06/2004] [Accepted: 12/17/2004] [Indexed: 12/22/2022]
Abstract
PURPOSE To compare two potential positron emission tomography (PET) tracers of tumor hypoxia in an animal model. METHODS AND MATERIALS The purported hypoxia imaging agents (18)F-fluoromisonidazole (FMISO) and (64)Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) were compared by serial microPET imaging of Fisher-Copenhagen rats bearing the R3327-AT anaplastic rat prostate tumor. Probe measurements of intratumoral Po(2) were compared with the image data. At the microscopic level, the relationship between the spatial distributions of (64)Cu (assessed by digital autoradiography) and tumor hypoxia (assessed by immunofluorescent detection of pimonidazole) was examined. (18)F-FMISO and (64)Cu-ATSM microPET images were also acquired in nude rats bearing xenografts derived from the human squamous cell carcinoma cell line, FaDu. RESULTS In R3327-AT tumors, the intratumoral distribution of (18)F-FMISO remained relatively constant 1-4 h after injection. However, that of (64)Cu-ATSM displayed a significant temporal evolution for 0.5-20 h after injection in most tumors. In general, only when (64)Cu-ATSM was imaged at later times (16-20 h after injection) did it correspond to the distribution of (18)F-FMISO. Oxygen probe measurements were broadly consistent with (18)F-FMISO and late (64)Cu-ATSM images but not with early (64)Cu-ATSM images. At the microscopic level, a negative correlation was found between tumor hypoxia and (64)Cu distribution when assessed at early times and a positive correlation when assessed at later times. For the FaDu tumor model, the early and late (64)Cu-ATSM microPET images were similar and were in general concordance with the (18)F-FMISO scans. CONCLUSION The difference in behavior between the R3327-AT and FaDu tumor models suggests a tumor-specific dependence of Cu-ATSM uptake and retention under hypoxic conditions.
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Affiliation(s)
- Joseph A O'Donoghue
- Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Pierga JY, Bonneton C, Magdelénat H, Vincent-Salomon A, Nos C, Boudou E, Pouillart P, Thiery JP, de Cremoux P. Real-time quantitative PCR determination of urokinase-type plasminogen activator receptor (uPAR) expression of isolated micrometastatic cells from bone marrow of breast cancer patients. Int J Cancer 2005; 114:291-8. [PMID: 15543615 DOI: 10.1002/ijc.20698] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Disseminated tumor cells (DTC) in bone marrow are independently related to poor outcome in patients with breast cancer. Phenotypic characterization of DTC may be useful to improve evaluation of the metastasizing potential of DTC and also to more accurately target aggressive tumor cells. DTC were screened in bone marrow aspirates from breast cancer patients by immunocytochemistry with an anticytokeratin (anti-CK) antibody (A45B/B3). Because the cell permeabilization and fixation required for intracellular CK staining is deleterious for mRNA, we used microaspiration to isolate single tumor cells stained with a monoclonal antibody directed against a membrane epitope, epithelial cell adhesion molecule (EpCAM), in CK-positive cases. Urokinase-type plasminogen activator receptor (uPAR) was quantified by real-time quantitative RT-PCR. The SKBR3 human breast cancer cell line was used to calibrate RT-PCR. A linear relationship was observed between the cycle threshold (Ct) of uPAR and 18S gene expression and SKBR3 cells spiked (1, 3, 7, 10 and 20) in control patient bone marrow. EpCAM-positive cells were aspirated in 21 out of 25 bone marrow specimens from breast cancer patients with CK-positive cells and uPAR mRNA expression was determined in 16 cases. A high level of uPAR mRNA in DTC was detected in 8 out of 16 patients (50%) and was associated with a more aggressive primary tumor phenotype (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative or HER2-positive) (p = 0.01). We demonstrated that real-time quantitative RT-PCR was reliably adapted to phenotype analysis of isolated micrometastatic cells. A larger study would be useful to confirm the importance of uPAR to define higher risk subgroups of breast cancer patients with micrometastatic disease.
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Affiliation(s)
- Jean-Yves Pierga
- Medical Oncology Department, Institut Curie, 26 rue d'Ulm, 75231 Paris Cedex 05, France.
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Tang TC, Poon RT, Lau CP, Xie D, Fan ST. Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma. World J Gastroenterol 2005; 11:1896-902. [PMID: 15800977 PMCID: PMC4305708 DOI: 10.3748/wjg.v11.i13.1896] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Recent studies suggested that cyclooxygenase-2 (COX-2) enhances tumor angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Although COX-2 expression has been demonstrated in hepatocellular carcinoma (HCC), the significance of COX-2 in progression of HCC remains unclear. This study evaluated the clinico-pathological correlation of COX-2 level and its relationship with VEGF level in HCC.
METHODS: Fresh tumor tissues were obtained from 100 patients who underwent resection of HCC. COX-2 protein expression was examined by immunohistochemistry, and quantitatively by an enzyme immunometric assay (EIA) of tumor cytosolic COX-2 levels. Tumor cytosolic VEGF levels were measured by an ELISA.
RESULTS: Immunostaining showed expression of COX-2 in tumor cells. Tumor cytosolic COX-2 levels correlated with VEGF levels (r = 0.469, P<0.001). Correlation with clinicopathological features showed significantly higher tumor cytosolic COX-2 levels in the presence of multiple tumors (P = 0.027), venous invasion (P = 0.030), microsatellite lesions (P = 0.037) and advanced tumor stage (P = 0.008). Higher tumor cytosolic COX-2 levels were associated with worse patient survival.
CONCLUSION: This study shows that elevated tumor COX-2 levels correlate with elevated VEGF levels and invasiveness in HCC, suggesting that COX-2 plays a significant role in the progression of HCC.
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Affiliation(s)
- Terence-C Tang
- Center for the Study of Liver Disease, Department of Surgery, University of Hong Kong, Pokfulam, Hong Kong, China
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Nozoe T, Ezaki T, Kabashima A, Baba H, Maehara Y. Significance of immunohistochemical expression of cyclooxygenase-2 in squamous cell carcinoma of the esophagus. Am J Surg 2005; 189:110-5. [PMID: 15701502 DOI: 10.1016/j.amjsurg.2004.03.019] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2003] [Revised: 03/18/2004] [Accepted: 03/18/2004] [Indexed: 02/04/2023]
Abstract
BACKGROUND The focus of studies on cyclooxygenase-2 (COX-2) have been on its ability to mediate the biological behavior of human tumors including tumorigenesis, tumor progression, apoptosis, and differentiation. The aim of the current study was to elucidate a further finding on the clinicopathologic significance of immunohistochemical expression of COX-2 in esophageal squamous cell carcinoma (ESCC). METHODS The immunohistochemical expression of COX-2 was examined for 76 specimens of ESCC and the correlation of COX-2 expression with clinicopathologic features was examined. RESULTS Twenty-eight ESCCs (36.8%) had a strong expression of COX-2. The proportion of poorly differentiated SCCs among tumors with a strong expression of COX-2 (42.8%, 12 of 28) was significantly higher than that among tumors with a weak expression of COX-2 (16.7%, 8 of 48; P = .037). The depth of the tumors (P = .003) and the stage of the tumors (P = .015) were advanced significantly more progressively in ESCCs with a strong COX-2 expression. Univariate analysis showed that the prognosis of patients with ESCCs with a strong COX-2 expression was significantly poorer than that of patients with ESCCs with a weak COX-2 expression (P = .017). Multivariate analysis showed that only such tumor-related factors as lymphatic invasion (P = .004), venous invasion (P = .003), and stage of the tumors (P = .021) were found to be associated independently with worse prognosis of the patients with ESCC. CONCLUSIONS Strong expression of COX-2 is correlated with tumor progression and poor differentiation in ESCC.
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Affiliation(s)
- Tadahiro Nozoe
- Department of Surgery, Fukuoka Higashi Medical Center, 1-1-1 Chidori, Koga 811-3195, Japan.
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Smakman N, Kranenburg O, Vogten JM, Bloemendaal AL, van Diest P, Borel Rinkes IH. Cyclooxygenase-2 Is a Target of KRASD12, Which Facilitates the Outgrowth of Murine C26 Colorectal Liver Metastases. Clin Cancer Res 2005. [DOI: 10.1158/1078-0432.41.11.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Abstract
Purpose: Mutational activation of the KRAS oncogene and overexpression of cyclooxygenase-2 (COX-2) contribute to colorectal carcinoma (CRC) development, but the relationship between these two events is unclear. This study was designed to clarify that relationship and to assess the contribution of KRAS-dependent COX-2 to the seeding of CRC cells in the liver and to their outgrowth as liver metastases in an experimental mouse model.
Experimental Design: The effect of RNA interference–mediated KRAS knockdown on COX-2 expression and activity was tested in murine C26 CRC cells. The contribution of KRAS-dependent COX-2 to early metastatic tumor cell seeding (by intravital microscopy) and outgrowth of metastases in the liver (by bioluminescence imaging) was studied by using parecoxib, a novel and highly selective liver-activated COX-2 inhibitor. Intratumoral cell proliferation, apoptosis, and tumor-associated angiogenesis were assessed by immunohistochemistry on liver tissue sections.
Results: Stable knockdown of mutant KRASD12 in murine C26 CRC cells by RNA interference lead to a dramatic reduction of COX-2 synthesis and prostaglandin E2 production. Inhibition of host or tumor cell COX-2 activity had no effect on early metastatic cell seeding in the liver but greatly reduced intrahepatic tumor cell proliferation and the rate of liver metastasis outgrowth. COX-2 inhibition had no effect on early tumor vascularization or on tumor cell apoptosis.
Conclusions: The high levels of COX-2 enzyme and prostaglandin production in C26 CRC cells are primarily caused by the presence of endogenous mutant KRASD12. Furthermore, COX-2 inhibition affects the tumoral rather than the vascular compartment during the early stages of C26 liver metastasis outgrowth.
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Affiliation(s)
| | | | | | | | - Paul van Diest
- 2Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
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Ferrandina G, Ranelletti FO, Legge F, Gessi M, Salutari V, Distefano MG, Lauriola L, Zannoni GF, Martinelli E, Scambia G. Prognostic Role of the Ratio between Cyclooxygenase-2 in Tumor and Stroma Compartments in Cervical Cancer. Clin Cancer Res 2004; 10:3117-23. [PMID: 15131052 DOI: 10.1158/1078-0432.ccr-1090-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The aim of this study was to analyze the clinical role of cyclooxygenase (COX)-2 in a large series of 175 cervical cancer patients. EXPERIMENTAL DESIGN Immunohistochemistry was performed on paraffin-embedded sections by using rabbit antiserum against COX-2. The tumor:stroma (T/S) ratio of COX-2 expression was used to define the overall COX-2 content in the tumor. RESULTS The T/S COX-2 ratio values ranged from 0.03 to 48.2 (mean +/- SE, 3.7 +/- 0.5). A total of 95 of 175 patients (54.3%) were scored as having a high (>1) T/S COX-2 ratio. In locally advanced cervical cancer patients who underwent neoadjuvant treatment, the percentage of cases showing a high T/S COX-2 ratio was greater in patients who did not respond to treatment (26 of 29 patients, 89.7%) than in patients with a partial (32 of 50 patients, 64.0%) or complete (19 of 44 patients, 43.2%) response (P = 0.0003). When logistic regression was applied, International Federation of Gynecologists and Obstetricians (FIGO) stage (chi(2) = 11.3; P = 0.0008) and T/S COX-2 ratio (chi(2) = 5.3; P = 0.021) retained an independent role in predicting a poor chance of response. Cases with a high T/S COX-2 ratio had a shorter overall survival (OS) [2-year OS, 61%(95% confidence interval 750-83)] than cases with a low T/S COX-2 ratio (2-year OS, 90%; 95% confidence interval, 81-99; P = 0.0001). In multivariate analysis, the status of T/S COX-2 IDV ratio, together with advanced stage, retained an independent negative prognostic role for OS. CONCLUSIONS The assessment of COX-2 status in both tumor and stroma compartment could provide valuable information to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant treatment and unfavorable prognosis.
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Affiliation(s)
- Gabriella Ferrandina
- Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
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Fowles RE. Potential cardiovascular effects of COX-2 selective nonsteroidal antiinflammatory drugs. J Pain Palliat Care Pharmacother 2003; 17:27-50. [PMID: 14649387 DOI: 10.1080/j354v17n02_03] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The newly developed nonsteroidal antiinflammatory drugs (NSAIDs) that selectively inhibit cyclooxygenase-2 (COX-2), are effective against pain and inflammation and appear to have less gastrointestinal toxicity than conventional NSAIDs. Their COX-2 selectivity, however, has raised concerns regarding their cardiovascular safety, since they do not inhibit COX-1, the isoform of the enzyme that is active in thrombosis and vasoconstriction. At this point there is no conclusive evidence that COX-2 inhibitors cause ischemic vascular events, because retrospective post hoc analyses conflict one another, and no specific randomized trials have yet been done. Renal effects, edema and hypertension appear to be similar between conventional NSAIDs and COX-2-selective inhibitors. Aspirin is still required for patients with cardiovascular risk who are prescribed a COX-2-selective inhibitor.
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Affiliation(s)
- Robert E Fowles
- Cardiology Division, LDS Hospital and the Salt Lake Clinic, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT, USA.
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Buecher B, Heymann MF, Lièvre A, Nguyen JM, Wilson K, Bézieau S, Mosnier JF, Galmiche JP, Blottière HM. Cyclo-oxygenase-2 over-expression in sporadic colorectal carcinoma without lymph node involvement. Aliment Pharmacol Ther 2003; 18:731-40. [PMID: 14510747 DOI: 10.1046/j.1365-2036.2003.01758.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Cyclo-oxygenase-2 over-expression has been reported in most advanced human colorectal cancers. AIMS To assess the prevalence of cyclo-oxygenase-2 over-expression in non-advanced colorectal cancers, to investigate the correlation between cyclo-oxygenase-2 status and tumour clinicopathological features and molecular phenotype, and to determine the impact of cyclo-oxygenase-2 status on long-term clinical outcome. METHODS Sixty-one patients who had undergone surgery for colorectal cancer without lymph node involvement were evaluated retrospectively. Cyclo-oxygenase-2 expression was determined by immunohistochemistry. The tumour replication error phenotype was assessed by amplification of the two microsatellites, BAT-25 and BAT-26. RESULTS Thirty-six tumours were classified as cyclo-oxygenase-2 positive and 25 as cyclo-oxygenase-2 negative. No correlation was found between cyclo-oxygenase-2 over-expression and clinicopathological features or molecular phenotype. Cyclo-oxygenase-2 over-expression was an independent predictor of a poor prognosis. Indeed, the relative risk of tumour recurrence or death for patients with cyclo-oxygenase-2-positive tumours was 2.13 times that of patients with cyclo-oxygenase-2-negative tumours (P=0.008; 95% confidence interval, 1.22-3.73). This difference remained significant when post-operative deaths were censored in the multivariate analysis (P=0.014). CONCLUSION Cyclo-oxygenase-2 over-expression is not associated with tumour phenotype, but is indicative of a poorer clinical outcome in patients with non-advanced colorectal carcinoma.
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Affiliation(s)
- B Buecher
- Department of Gastroenterology CIC INSERM-U539, Hôtel-Dieu CHU, Nantes, France
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Friedrich MG, Toma MI, Petri S, Huland H. Cyclooxygenase-2 promotes angiogenesis in pTa/T1 urothelial bladder carcinoma but does not predict recurrence. BJU Int 2003; 92:389-92. [PMID: 12930427 DOI: 10.1046/j.1464-410x.2003.04345.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To investigate the effect of cyclooxygenase-2 (COX-2) on microvessel density (MVD) and on the clinical prognosis in patients with non-muscle invasive urothelial carcinoma of the bladder, as COX-2 expression is significantly greater in epithelial tumours and there is increasing evidence that COX-2 might contribute to tumour neovascularization. PATIENTS AND METHODS We assessed tumour samples from 110 patients undergoing transurethral resection for primary pTa/pT1 bladder carcinoma (pTa, 84; pT1, 26; grade 1, 22; grade 2, 81; grade 3, seven). Paraffin sections were assessed immunohistochemically using antibodies against COX-2, CD34 (endothelial cells) and CD105 (proliferating vessels). COX-2 expression was quantified by the number of stained cells (negative, +, ++) and the MVD calculated as vessels per field. RESULTS Of the 110 tumours, 45 (41%) had no immunostaining for COX-2, 40 had faint staining with at least isolated positive cells (+) and 25 stained ++. COX-2 positive tumours had significantly greater vascularization for proliferating vessels. In COX-2 negative tumours the MVD was 22.1, identified by CD34 immunostaining, and 3.4 for proliferating vessels (CD105), whereas COX-2 positive tumours had a MVD of 18.3 (CD34), and of 5.8, respectively (CD105). Complete follow-up data were available in 91 patients; after a mean follow-up of 25 months, 18 (20%) had tumour recurrences. There was no significant difference in the recurrence rates or disease-free survival between COX-2-positive (19%, 25.6 months) or -negative patients (21%, 25.2 months). CONCLUSION These results confirm the involvement of COX-2 in angiogenesis in bladder cancer, as COX-2 promoted blood vessel proliferation in the tumour zone, and indicate the usefulness of COX-2-inhibiting drugs in preventing and treating superficial bladder cancer.
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