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Tan L, Peng D, Cheng Y. Significant position of C-myc in colorectal cancer: a promising therapeutic target. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2022; 24:2295-2304. [PMID: 35972682 DOI: 10.1007/s12094-022-02910-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/23/2022] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) is a malignant tumor initiating from the mucosa of the colorectum. According to the 2020 statistics from the World Health Organization, there are 10.0% CRC cases among all 19.3 million new cancers, followed by lung and breast cancer, and 9.4% CRC cases among all 9.9 million cancer deaths, ranking second. The population of CRC patients in China is large, and its incidence and mortality continue to increase each year. Despite the continuous development of surgical methods, chemotherapy, radiotherapy, targeted therapy and immunotherapy, the overall survival of CRC patients remains low. Past research has suggested that c-myc plays a pivotal role in the development of CRC. A higher expression level of c-Myc is a negative prognostic marker in CRC. However, there are few drugs targeting c-myc directly. Therefore, we focused on discovering the mechanism of c-myc in CRC to provide a reference for a better therapy choice for patients.
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Affiliation(s)
- Li Tan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Dong Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Yong Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Baba-Ahmed F, Guedri K, Trea F, Ouali K. Protective role of a melon superoxide dismutase combined with gliadin (GliSODin) on the status of lipid peroxidation and antioxidant defense against azoxymethane-induced experimental colon carcinogenesis. J Cancer Res Ther 2021; 17:1445-1453. [PMID: 34916376 DOI: 10.4103/jcrt.jcrt_175_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Background Azoxymethane (AOM) is a potent carcinogenic agent commonly used to induce colon cancer in rats and mice, with the cytotoxicity of AOM mediated by oxidative stress. Aim of Study This study investigated the protective effect of a natural antioxidant (GliSODin) against AOM-induced oxidative stress and carcinogenesis in rat colon. Methods Twenty male Wistar rats were randomly divided into four groups (five rats/group). The control group was fed a basal diet. AOM-treated group (AOM) was fed a basal diet and received intraperitoneal injections of AOM for 2 weeks at a dose of 15 mg/kg. The GliSODin treatment group (superoxide dismutase [SOD]) received oral supplementation of GliSODin (300 mg/kg) for 3 months, and the fourth combined group received AOM and GliSODin (AOM + SOD). All animals were continuously fed ad libitum until the age of 16 weeks when all rats were sacrificed. The colon tissues were examined microscopically for pathological changes and aberrant crypt foci (ACF) development, oxidant status (lipid peroxidation-LPO), and enzyme antioxidant system (glutathione [GSH], GSH-S-transferase, catalase, and SOD). Results Our results showed that AOM induced ACF development and oxidative stress (GSH depletion and lipid peroxidation) in rat colonic cells. The concomitant treatment of AOM with GliSODin significantly ameliorated the cytotoxic effects of AOM. Conclusion The results of this study provide in vivo evidence that GliSODin reduced the AOM-induced colon cancer in rats, through their potent antioxidant activities.
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Affiliation(s)
- Fedia Baba-Ahmed
- Department of Biology University El hadj Lakhder-Batna, University El Hadj Lakhder-Batna, Batna, Algeria
| | - Kamilia Guedri
- Department of Biology, University of Tebessa, University Larbi Tebessi, Tebessa, Algeria
| | - Fouzia Trea
- Department of Animal Biology University, University of Badji Mokhtar Annaba, Laboratory of Environmental Bio Surveillance, University of Badji Mokhtar-Annaba, Annaba, Algeria
| | - Kheireddine Ouali
- Department of Animal Biology University, University of Badji Mokhtar Annaba, Laboratory of Environmental Bio Surveillance, University of Badji Mokhtar-Annaba, Annaba, Algeria
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Yang L, Lei Q, Li L, Yang J, Dong Z, Cui H. Silencing or inhibition of H3K79 methyltransferase DOT1L induces cell cycle arrest by epigenetically modulating c-Myc expression in colorectal cancer. Clin Epigenetics 2019; 11:199. [PMID: 31888761 PMCID: PMC6937672 DOI: 10.1186/s13148-019-0778-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 11/12/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Epigenetic regulations play pivotal roles in tumorigenesis and cancer development. Disruptor of telomeric silencing-1-like (DOT1L), also known as KMT4, is the only identified histone methyltransferase that catalyzes the mono-, di-, and tri-methylation of lysine 79 histone 3 (H3K79). However, little is known about the effect of H3K79 methylation on the modulation of colorectal cancer (CRC) development. METHODS DOT1L expression profiles in different subgroups of CRC tissues and its clinical significances were analyzed from some online datasheets. DOT1L in CRC cell lines was silenced by either lentivirus-mediated knockdown or inhibited by its specific inhibitor, EPZ004777. Then cell proliferation was detected by MTT assay, BrdU assay, and soft agar assay; cell cycle was detected by cytometry; and tumorigenicity was detected by using nude mice xenograft models. Clinical co-expression was analyzed between DOT1L and c-Myc. Chromatin immunoprecipitation (ChIP) assay was used to determine whether the translation of c-Myc was epigenetically regulated by H3K79me2 induced by DOT1L. c-Myc overexpression was used to rescue the cell cycle arrest and tumor growth induced by DOT1L silencing or inhibition in CRC. RESULTS We found that DOT1L was highly expressed in colorectal cancer and was negatively related to the prognosis of patients with CRC. Silencing or inhibition of DOT1L blocked cell proliferation, BrdU incorporation, self-renewal capability in vitro, and tumorigenicity in vivo. Besides, inhibition or silencing of DOT1L also induced cell cycle arrest at S phase, as well as decreased the expression of CDK2 and Cyclin A2. Furthermore, in the clinical databases of CRC, we found that the expression of DOT1L was positively correlated with that of c-Myc, a major regulator in the upstream of cell cycle-related factors. Besides, c-Myc expression was downregulated after DOT1L knockdown and c-Myc restoration rescued decrease of cell proliferation, BrdU corporation, self-renewal capability, cell cycle progression in vitro and tumorigenicity in vivo induced by DOT1L silencing. Then we found that H3K79 methylation was decreased after DOT1L knockdown. ChIP assay showed that H3K79me2 was enriched on the - 682~+ 284 region of c-Myc promoter, and the enrichment was decreased after DOT1L inhibition. CONCLUSIONS Our results show that DOT1L epigenetically promotes the transcription of c-Myc via H3K79me2. DOT1L silencing or inhibition induces cell cycle arrest at S phase. DOT1L is a potential marker for colorectal cancer and EPZ004777 may be a potential drug for the treatment of colorectal cancer.
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Affiliation(s)
- Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, No.2, Tiansheng Road, Beibei, Chongqing, 400716, China.,Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing, 400716, China
| | - Qian Lei
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, No.2, Tiansheng Road, Beibei, Chongqing, 400716, China.,Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing, 400716, China
| | - Lin Li
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, No.2, Tiansheng Road, Beibei, Chongqing, 400716, China.,Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing, 400716, China
| | - Jie Yang
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, No.2, Tiansheng Road, Beibei, Chongqing, 400716, China.,Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, 400716, China.,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing, 400716, China.,Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing, 400716, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, No.2, Tiansheng Road, Beibei, Chongqing, 400716, China. .,Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, 400716, China. .,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing, 400716, China. .,Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing, 400716, China.
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, No.2, Tiansheng Road, Beibei, Chongqing, 400716, China. .,Cancer Center, Medical Research Institute, Southwest University, Beibei, Chongqing, 400716, China. .,Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Beibei, Chongqing, 400716, China. .,Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Southwest University, Beibei, Chongqing, 400716, China.
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Smurf1 regulation of DAB2IP controls cell proliferation and migration. Oncotarget 2018; 7:26057-69. [PMID: 27036023 PMCID: PMC5041964 DOI: 10.18632/oncotarget.8424] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 03/07/2016] [Indexed: 11/25/2022] Open
Abstract
Tumor cell proliferation, survival and migration are regulated by the deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP), a tumor suppressor that serves as a scaffold protein for H-Ras and TRAF2. Importantly, the oncogenic histone methyl-transferase EZH2 epigenetically down-regulates DAB2IP in a variety of tumors. Recently, we demonstrated that DAB2IP is negatively regulated by Akt-dependent phosphorylation and SCFFbw7-mediated degradation. Here, we further identify the oncoprotein Smurf1, an E3-ubiquitin ligase, as a novel negative regulator of DAB2IP. Smurf1-mediated cellular proliferation and migration are largely dependent on the presence of DAB2IP, suggesting that DAB2IP is a key effector molecule of Smurf1 oncogenic function. Additionally, we identify that similar to DAB2IP, Smurf1 is also a target of phosphorylation by both Akt1 and Akt2 kinases, which enhances Smurf1 abundance, leading to a reduction in DAB2IP. Given the role of DAB2IP in tumorigenesis and metastasis, our data identify Smurf1 as an upstream oncogenic factor that negatively regulates DAB2IP to govern aberrant cell growth and migration.
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LIU RONG, MARTIN TRACEYA, JORDAN NICOLAJ, RUGE FIONA, YE LIN, JIANG WENG. Metastasis suppressor 1 expression in human ovarian cancer: The impact on cellular migration and metastasis. Int J Oncol 2015; 47:1429-39. [DOI: 10.3892/ijo.2015.3121] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 05/26/2015] [Indexed: 11/05/2022] Open
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Abstract
Deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP), is a tumor suppressor that serves as a scaffold protein involved in coordinately regulating cell proliferation, survival and apoptotic pathways. DAB2IP is epigenetically down-regulated in a variety of tumors through the action of the histone methyltransferase EZH2. Although DAB2IP is transcriptionally down-regulated in a variety of tumors, it remains unclear if other mechanisms contribute to functional inactivation of DAB2IP. Here we demonstrate that DAB2IP can be functionally down-regulated by two independent mechanisms. First, we identified that Akt1 can phosphorylate DAB2IP on S847, which regulates the interaction between DAB2IP and its effector molecules H-Ras and TRAF2. Second, we demonstrated that DAB2IP can be degraded in part through ubiquitin-proteasome pathway by SCFFbw7. DAB2IP harbors two Fbw7 phosho-degron motifs, which can be regulated by the kinase, CK1δ. Our data hence indicate that in addition to epigenetic down-regulation, two additional pathways can functional inactivate DAB2IP. Given that DAB2IP has previously been identified to possess direct causal role in tumorigenesis and metastasis, our data indicate that a variety of pathways may pass through DAB2IP to govern cancer development, and therefore highlight DAB2IP agonists as potential therapeutic approaches for future anti-cancer drug development.
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Affiliation(s)
- Xiangping Dai
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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Pandurangan AK, Esa NM. Dietary non-nutritive factors in targeting of regulatory molecules in colorectal cancer: an update. Asian Pac J Cancer Prev 2015; 14:5543-52. [PMID: 24289544 DOI: 10.7314/apjcp.2013.14.10.5543] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Colorectal cancer (CRC), a complex multi-step process involving progressive disruption of homeostatic mechanisms controlling intestinal epithelial proliferation/inflammation, differentiation, and programmed cell death, is the third most common malignant neoplasm worldwide. A number of promising targets such as inducible nitric acid (iNOS), cyclooxygenase (COX)-2, NF-E2-related factor 2 (Nrf2), Wnt/β-catenin, Notch and apoptotic signaling have been identified by researchers as useful targets to prevent or therapeutically inhibit colon cancer development. In this review article, we aimed to explore the current targets available to eliminate colon cancer with an update of dietary and non-nutritional compounds that could be of potential use for interaction with regulatory molecules to prevent CRC.
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Affiliation(s)
- Ashok Kumar Pandurangan
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia E-mail :
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Pandurangan AK, Saadatdoust Z, Esa NM, Hamzah H, Ismail A. Dietary cocoa protects against colitis-associated cancer by activating the Nrf2/Keap1 pathway. Biofactors 2015; 41:1-14. [PMID: 25545372 DOI: 10.1002/biof.1195] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 12/01/2014] [Indexed: 12/21/2022]
Abstract
Colorectal cancer (CRC) is the third most common malignancy in males and the second most common cancer worldwide. Chronic colonic inflammation is a known risk factor for CRC. Cocoa contains many polyphenolic compounds that have beneficial effects in humans. The objective of this study is to explore the antioxidant properties of cocoa in the mouse model of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated cancer, focusing on the activation of Nrf2 signaling. Mice were treated with AOM/DSS and randomized to receive either a control diet or a 5 and 10% cocoa diet during the study period. On day 62 of the experiment, the entire colon was processed for biochemical and histopathological examination and further evaluations. Increased levels of malondialdehyde (MDA) were observed in AOM/DSS-induced mice; however, subsequent administration of cocoa decreased the MDA. Enzymatic and nonenzymatic antioxidants, such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, were decreased in the AOM/DSS mice. Cocoa treatment increases the activities/levels of enzymatic and nonenzymatic antioxidants. Inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, were elevated during AOM/DSS-induction, and treatment with 5 and 10% cocoa effectively decreases the expression of iNOS and COX-2. The NF-E2-related factor 2 and its downstream targets, such as NQO1 and UDP-GT, were increased by cocoa treatment. The results of our study suggest that cocoa may merit further clinical investigation as a chemopreventive agent that helps prevent CAC.
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Affiliation(s)
- Ashok Kumar Pandurangan
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
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Zhong J, Shaik S, Wan L, Tron AE, Wang Z, Sun L, Inuzuka H, Wei W. SCF β-TRCP targets MTSS1 for ubiquitination-mediated destruction to regulate cancer cell proliferation and migration. Oncotarget 2014; 4:2339-53. [PMID: 24318128 PMCID: PMC3926831 DOI: 10.18632/oncotarget.1446] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Metastasis suppressor 1 (MTSS1) is an important tumor suppressor protein, and loss of MTSS1 expression has been observed in several types of human cancers. Importantly, decreased MTSS1 expression is associated with more aggressive forms of breast and prostate cancers, and with poor survival rate. Currently, it remains unclear how MTSS1 is regulated in cancer cells, and whether reduced MTSS1 expression contributes to elevated cancer cell proliferation and migration. Here we report that the SCFβ-TRCP regulates MTSS1 protein stability by targeting it for ubiquitination and subsequent destruction via the 26S proteasome. Notably, depletion of either Cullin 1 or β-TRCP1 led to increased levels of MTSS1. We further demonstrated a crucial role for Ser322 in the DSGXXS degron of MTSS1 in governing SCFβ-TRCP-mediated MTSS1 degradation. Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation. Importantly, introducing wild-type MTSS1 or a non-degradable MTSS1 (S322A) into breast or prostate cancer cells with low MTSS1 expression significantly inhibited cellular proliferation and migration. Moreover, S322A-MTSS1 exhibited stronger effects in inhibiting cell proliferation and migration when compared to ectopic expression of wild-type MTSS1. Therefore, our study provides a novel molecular mechanism for the negative regulation of MTSS1 by β-TRCP in cancer cells. It further suggests that preventing MTSS1 degradation could be a possible novel strategy for clinical treatment of more aggressive breast and prostate cancers.
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Affiliation(s)
- Jiateng Zhong
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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Zong L, Chen P, Wang DX. Death decoy receptor overexpression and increased malignancy risk in colorectal cancer. World J Gastroenterol 2014; 20:4440-4445. [PMID: 24764685 PMCID: PMC3989983 DOI: 10.3748/wjg.v20.i15.4440] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 12/06/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate human epidermal growth factor receptor 2 (HER2) and death decoy receptor (DcR3) as colorectal cancer prognostic indicators. METHODS Colorectal carcinoma specimens from 300 patients were analyzed by immunohistochemistry to detect the staining patterns of HER2 and DcR3. Classification of HER2 staining was carried out using the United States Food and Drug Administration semi-quantitative scoring system, with scores of 0 or 1+ indicating a tumor-negative (normal expression) status and scores of 2+ and 3+ indicating a tumor-positive (overexpression) status. Classification of DcR3 was carried out by quantitating the percentage of positive cells within the stained section, with < 10% indicating a tumor-negative status and ≥ 10% indicating a tumor-positive status. Correlation of the HER2 and DcR3 staining status with clinicopathological parameters [age, sex, tumor size, differentiation, and the tumor, node, metastasis (pTNM) classification] and survival was statistically assessed. RESULTS Tumor-positive status for HER2 and DcR3 was found in 18.33% and 58.33% of the 300 colorectal carcinoma specimens, respectively. HER2 tumor-positive status showed a significant correlation with tumor size (P = 0.003) but not with other clinicopathological parameters. DcR3 tumor-positive status showed a significant correlation with tumor differentiation (P < 0.001), pTNM stage (P < 0.001), and lymph node metastasis (P < 0.001). However, correlation coefficient analysis did not indicate that a statistically significant correlation exists between tumor-positive status for the HER2 and DcR3 overexpression (P = 0.236). Patients with specimens classified as DcR3-overexpressing had a significantly worse overall survival (OS) rate than those without DcR3 overexpression (median OS: 42.11 vs 61.21 mo; HR = 50.27, 95%CI: 44.90-55.64, P < 0.001). HER2 overexpression had no significant impact on median OS (35.10 mo vs 45.25 mo; HR = 44.40, 95%CI: 39.32-49.48, P = 0.344). However, patients with specimens classified as both HER2- and DcR3-overexpressing had a significantly poorer median OS than those with only HER2 overexpression (31.80 mo vs 52.20 mo; HR = 35.10, 95%CI: 22.04-48.16, P = 0.006). CONCLUSION HER2 overexpression is not an independent prognostic marker of colorectal cancer, but DcR3 overexpression is highly correlated with lymph node metastasis and poor OS.
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Li Q, Wang D, Li J, Chen P. Clinicopathological and prognostic significance of HER-2/neu and VEGF expression in colon carcinomas. BMC Cancer 2011; 11:277. [PMID: 21708009 PMCID: PMC3144457 DOI: 10.1186/1471-2407-11-277] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2010] [Accepted: 06/27/2011] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND HER-2/neu and VEGF expression is correlated with disease behaviors in various cancers. However, evidence for their expression in colon cancer is rather contradictory both for the protein expression status and prognostic value. HER-2/neu is found to participate in VEGF regulation, and has known correlation with VEGF expression in some tumors. In this study, we investigated HER-2/neu and VEGF expression in Chinese colon patients and explored whether there was any correlation between their expression patterns. METHODS HER-2/neu and VEGF were investigated immunohistochemically using tumor samples obtained from 317 colon cancer patients with all tumor stages. Correlation of the degree of staining with clinicopathological parameters and survival was investigated. RESULTS Positive expression rates of HER-2/neu and VEGF in colon cancer were 15.5% and 55.5% respectively. HER-2/neu expression was significantly correlated with tumor size and distant metastases (P < 0.05), but was not an independent prognostic marker of survival (P > 0.05). Expression of VEGF was significantly correlated with tumor size, tumor stage, lymph node metastases, and distant metastases (P < 0.05). The 5-year survival rate in patients with negative and positive VEGF expression was 70.2% and 61.9% respectively; the difference was not statistically significant (P = 0.146). No correlation between HER-2/neu and VEGF expression was detected (P = 0.151). CONCLUSIONS HER-2/neu and VEGF are not important prognostic markers of colon cancer. The present results do not support any association between HER2/neu and VEGF expression in this setting.
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Affiliation(s)
- Qingguo Li
- Department of General Surgery, First Clinic Medical School of Yangzhou University, Yangzhou, China
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Govindarajan A, Paty PB. Predictive markers of colorectal cancer liver metastases. Future Oncol 2011; 7:299-307. [DOI: 10.2217/fon.10.184] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Liver metastases are the most common site of distant failure after curative resection of colorectal cancer and a source of significant cancer-related morbidity and mortality. Currently, imaging and conventional histopathologic features, such as T-stage and N-stage, are used by clinicians to inform prognosis and guide adjuvant treatment to reduce the risk of developing distant metastases. However, these tools only have a moderate ability to predict the development of liver metastases. Novel methods, including the detection of circulating tumor cells and carcinoembryonic antigens in serum, have been developed, and their prognostic and predictive characteristics have been assessed. In addition, several molecular and genetic markers in the primary tumor have been studied. Unfortunately, these studies are often small and their results have been mixed, yielding no consistent sets of externally validated predictors of colorectal liver metastases. For widespread clinical relevance, future tests need to be independently carried out on large independent patient samples.
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Affiliation(s)
- Anand Govindarajan
- Department of Surgery, Memorial Sloan–Kettering Cancer Center, 444 E 68th St, Box 453, New York, NY 10065, USA
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Chen J, Li Q, Wang C, Wu J, Zhao G. Prognostic significance of c-erbB-2 and vascular endothelial growth factor in colorectal liver metastases. Ann Surg Oncol 2010; 17:1555-63. [PMID: 20069460 DOI: 10.1245/s10434-009-0897-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2009] [Indexed: 12/22/2022]
Abstract
BACKGROUND The prognostic value of c-erbB-2 and vascular endothelial growth factor (VEGF) expression in colorectal liver metastases (CLM) is unclear. The purpose of this study was to clarify the relationship of c-erbB-2 and VEGF with the clinicopathological parameters and the survival results in CLM. METHODS For 44 patients who had undergone liver resection for CLM at Fudan University Cancer Hospital from 2000 to 2007, the expression of c-erbB-2 and VEGF in CLM and the corresponding primary cancer specimens were evaluated immunohistochemically. The correlations among c-erbB-2 and VEGF, clinicopathologic factors, and survival were then statistically analyzed. RESULTS Positive expression rates of c-erbB-2 and VEGF in CLM lesions were 38.64% and 52.72%, respectively. The expression of c-erbB-2 and VEGF in CLM were similar to that of corresponding primary tumor. c-erbB-2 expression correlated with number of metastatic lesions and the distribution of liver metastases. The expression of VEGF correlated with the size of liver metastatic lesion and distribution of liver metastases. A statistically significant association between the expression of c-erbB-2 and VEGF in both CLM and primary tumor was noted. Univariate analysis showed that VEGF was a prognostic factor. However, on multivariate analysis, expression of VEGF was not an independent prognostic marker. Patients with both negative expression of c-erbB-2 and VEGF expression had a better outcome than others. CONCLUSIONS VEGF might be a statistically significant prognostic factor. The combined analysis of c-erbB-2 and VEGF is of added prognostic value. An association exists between c-erbB-2 and VEGF. However, further studies are required to confirm this issue.
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Affiliation(s)
- Jinggui Chen
- Department of Abdominal Surgery, Cancer Hospital, Fudan University, Shanghai, People's Republic of China
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Protective role of luteolin on the status of lipid peroxidation and antioxidant defense against azoxymethane-induced experimental colon carcinogenesis. Biomed Pharmacother 2008; 62:590-7. [PMID: 18692983 DOI: 10.1016/j.biopha.2008.06.031] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2008] [Accepted: 06/12/2008] [Indexed: 02/07/2023] Open
Abstract
The modifying effect of dietary exposure to a flavonoid, luteolin (LUT) during the azoxymethane (AOM)-induced colon carcinogenesis was investigated in this study. Aberrant crypt foci (ACF), lipid peroxidation (LPO), enzymic and non-enzymic antioxidants and histopathological analysis were performed. Colon carcinogenesis was induced by injecting 15 mg/body kg weight of AOM, intraperitoneally (i.p.), once in a week for 3 weeks in male Balb/c mice. AOM-induced mice were treated with LUT (1.2mg of LUT/kg body weight/day orally). After the experimental period, frequency of ACF, levels of thiobarbutaric acid reactive substances (TBARS) and hydroxy radical (OH ) were found to be increased, whereas glutathione (GSH), Vitamins C, E and A were decreased in the plasma and colon of AOM-induced mice. However, LUT treatment to AOM-induced mice significantly decreased the incidence of ACF, levels of TBARS and OH with a concordant increase in non-enzymic antioxidants in plasma and colon tissue. The activities of the antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were found to be decreased due to the induction of colon cancer in mouse. LUT treatment ameliorated the activities of these antioxidant enzymes. The histological study revealed a significant increase in the enlarged nuclei and hyperchromatism of cells in AOM-induced mice whereas LUT significantly reduced the signs in the colon. The immunohistochemical expression of MDA-DNA adduct was studied. In AOM-induced group, the expression was increased and treatment with LUT decreased significantly. The present study depicts that LUT can act as an effective chemopreventive agent against colon cancer.
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Rubio CA. Further studies on the arrest of cell proliferation in tumor cells at the invading front of colonic adenocarcinoma. J Gastroenterol Hepatol 2007; 22:1877-81. [PMID: 17914963 DOI: 10.1111/j.1440-1746.2007.04839.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM The author has previously reported that neoplastic glands at the leading invading edge of colorectal carcinomas often display flat tumor cells and cellular gaps called glandular pores. The aim of this study was to audit cell proliferation and p53 mutation in flat tumor cells and in tumor cells at the tip of glandular pores at the leading invading front of colonic carcinomas. METHODS Sections from 40 colonic adenocarcinomas were immunostained with the proliferation marker Ki67 and with p53 protein. Expression was assessed at the leading invading front in consecutive neoplastic glands having flat tumor cells and epithelial pores and in neoplastic glands showing neither flat tumor cells nor glandular pores. RESULTS Flat tumor cells in neoplastic glands usually showed no Ki67 expression but overexpressed p53 mutation. In neoplastic glands with pores 40% of the tumor cells at the tip of the pores showed no Ki67, but they overexpressed p53 mutation. CONCLUSIONS The results showed, for the first time, that p53-positive flat neoplastic colonic cells arrest their proliferation at the invading front. It is possible that these p53-positive/Ki67-negative neoplastic cells were temporarily removed from the cell cycle (G0). This paradoxical biological behavior of tumor cells might be connected with the formation of glandular pores and appears to indicate that arrest of cell proliferation at the advancing tumor front in colonic carcinomas occurs independently of p53 mutation. The possible existence of two independent molecular systems at the advancing tumor edge of colonic carcinomas, one supervising cell proliferation and the other zealously transferring the p53 mutation to daughter cells, is suggested.
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Affiliation(s)
- Carlos A Rubio
- Gastrointestinal and Liver Pathology Research Laboratory, Department of Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden.
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16
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Chiu KP, Ariyaratne P, Xu H, Tan A, Ng P, Liu ETB, Ruan Y, Wei CL, Sung WKK. Pathway aberrations of murine melanoma cells observed in Paired-End diTag transcriptomes. BMC Cancer 2007; 7:109. [PMID: 17594473 PMCID: PMC1929113 DOI: 10.1186/1471-2407-7-109] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2007] [Accepted: 06/26/2007] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Melanoma is the major cause of skin cancer deaths and melanoma incidence doubles every 10 to 20 years. However, little is known about melanoma pathway aberrations. Here we applied the robust Gene Identification Signature Paired End diTag (GIS-PET) approach to investigate the melanoma transcriptome and characterize the global pathway aberrations. METHODS GIS-PET technology directly links 5' mRNA signatures with their corresponding 3' signatures to generate, and then concatenate, PETs for efficient sequencing. We annotated PETs to pathways of KEGG database and compared the murine B16F1 melanoma transcriptome with three non-melanoma murine transcriptomes (Melan-a2 melanocytes, E14 embryonic stem cells, and E17.5 embryo). Gene expression levels as represented by PET counts were compared across melanoma and melanocyte libraries to identify the most significantly altered pathways and investigate the expression levels of crucial cancer genes. RESULTS Melanin biosynthesis genes were solely expressed in the cells of melanocytic origin, indicating the feasibility of using the PET approach for transcriptome comparison. The most significantly altered pathways were metabolic pathways, including upregulated pathways: purine metabolism, aminophosphonate metabolism, tyrosine metabolism, selenoamino acid metabolism, galactose utilization, nitrobenzene degradation, and bisphenol A degradation; and downregulated pathways: oxidative phosphorylation, ATPase synthesis, TCA cycle, pyruvate metabolism, and glutathione metabolism. The downregulated pathways concurrently indicated a slowdown of mitochondrial activities. Mitochondrial permeability was also significantly altered, as indicated by transcriptional activation of ATP/ADP, citrate/malate, Mg++, fatty acid and amino acid transporters, and transcriptional repression of zinc and metal ion transporters. Upregulation of cell cycle progression, MAPK, and PI3K/Akt pathways were more limited to certain region(s) of the pathway. Expression levels of c-Myc and Trp53 were also higher in melanoma. Moreover, transcriptional variants resulted from alternative transcription start sites or alternative polyadenylation sites were found in Ras and genes encoding adhesion or cytoskeleton proteins such as integrin, beta-catenin, alpha-catenin, and actin. CONCLUSION The highly correlated results unmistakably point to a systematic downregulation of mitochondrial activities, which we hypothesize aims to downgrade the mitochondria-mediated apoptosis and the dependency of cancer cells on angiogenesis. Our results also demonstrate the advantage of using the PET approach in conjunction with KEGG database for systematic pathway analysis.
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Affiliation(s)
- Kuo Ping Chiu
- Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, 138672, Singapore
| | - Pramila Ariyaratne
- Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, 138672, Singapore
| | - Han Xu
- Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, 138672, Singapore
| | - Adrian Tan
- Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, 138672, Singapore
| | - Patrick Ng
- Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, 138672, Singapore
| | - Edison Tak-Bun Liu
- Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, 138672, Singapore
| | - Yijun Ruan
- Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, 138672, Singapore
| | - Chia-Lin Wei
- Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, 138672, Singapore
| | - Wing-Kin Ken Sung
- Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, 138672, Singapore
- Department of Computer Science, National University of Singapore, 3 Science Drive 2, 117543, Singapore
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Park DI, Kang MS, Oh SJ, Kim HJ, Cho YK, Sohn CI, Jeon WK, Kim BI, Han WK, Kim H, Ryu SH, Sepulveda AR. HER-2/neu overexpression is an independent prognostic factor in colorectal cancer. Int J Colorectal Dis 2007; 22:491-7. [PMID: 16947041 DOI: 10.1007/s00384-006-0192-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/11/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The HER-2/neu protein is intimately involved with normal cell proliferation and tissue growth, as it is extensively homologous and is related to the epidermal growth factor receptor. This phenomenon has been most intensively studied in the context of breast carcinoma, in which its amplification and overexpression correlate with the overall course of disease and poor prognoses, and also constitute a predictive factor of poor response to chemotherapy and endocrine therapy. In this study, we investigated the relationships between the expression of HER-2/neu and the clinicopathological characteristics of colorectal cancer, including survival. This study was performed with a view toward the future introduction of Herceptin therapy for colorectal cancer patients. PATIENTS AND METHODS HER-2/neu overexpression and gene amplification were examined via semiquantitative standardized immunohistochemical staining and fluorescence in situ hybridization (FISH) in 137 colorectal cancer patients who underwent curative surgery at the Kangbuk Samsung Hospital. RESULTS Sixty-five (47.4%) out of 137 patients were determined by immunohistochemistry to have overexpressed HER-2/neu protein. HER-2/neu gene amplification was detected in two patients by FISH. Tumors with HER-2/neu overexpression showed higher postoperative recurrence rate (39.3% vs 14.6%, p=0.013). Tumors with HER-2/neu overexpression were associated with poor 3-year (70.8% vs 83.7%) and 5-year survival rates (55.1% vs 78.3%, p<0.05). Advanced TNM stage, postoperative recurrence, and overexpression of HER-2/neu were found to be independently related to survival by multivariate analysis. CONCLUSION HER-2/neu overexpression may constitute an independent prognostic factor in colorectal cancer patients, and patients exhibiting HER-2/neu overexpression might constitute potential candidates for a new adjuvant therapy which involves the use of humanized monoclonal antibodies.
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Affiliation(s)
- Dong Il Park
- Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Abstract
Metastatic growth is a selective, non-random process, which in the case of colorectal cancer, frequently occurs in the liver and is the major cause of cancer related death in these patients. This review summarises attempts to find biological and molecular markers of metastasis and their role in establishment of secondary tumours. Recent evidence suggests that liver metastases are phenotypically different to the primary from which they were derived and thus represent a separate disease entity.
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Affiliation(s)
- Nigel C Bird
- Liver Research Group, Clinical Sciences (South), Royal Hallamshire Hospital, Sheffield, United Kingdom.
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19
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Grabowski P, Sturm I, Schelwies K, Maaser K, Buhr HJ, Dörken B, Zeitz M, Daniel PT, Scherübl H. Analysis of neuroendocrine differentiation and the p53/BAX pathway in UICC stage III colorectal carcinoma identifies patients with good prognosis. Int J Colorectal Dis 2006; 21:221-30. [PMID: 16485142 DOI: 10.1007/s00384-005-0779-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2005] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Neuroendocrine differentiation is an independent prognostic factor in colorectal cancer. Moreover, an altered p53/BAX pathway is associated with a poor clinical outcome in Union Internationale Contre le Cancer (UICC) stage III disease. Because these markers are involved in different genetic events disrupted in colorectal cancer, we investigated the prognostic power of a multimarker analysis. PATIENTS AND METHODS Specimens were analyzed from 59 patients with UICC stage III disease who underwent surgery for colorectal adenocarcinoma at our institution and were followed up for 5 years or until death. Tumors were studied for both p53 mutation and BAX protein expression as well as for the expression of neuroendocrine markers. Statistical analysis of each marker alone or in combination was performed. RESULTS p53 status/BAX expression and neuroendocrine differentiation are not correlated in stage III colorectal cancers. However, the combination of both independent events identified a subgroup of patients with an excellent prognosis: Patients whose tumors were neuroendocrine marker-negative and who exhibited an intact p53/BAX pathway lived longer (mean survival, 93 months; range, 82-104 months) than patients whose tumors were either neuroendocrine marker-positive or whose tumors had a completely disrupted apoptotic pathway (41 months; range, 26-57 months; p<0.00001). In multivariate regression analysis, neuroendocrine marker-positive, p53 mutated, low-BAX-expressing tumors revealed an almost fivefold higher risk for earlier death (p<0.0001). CONCLUSION Disruption of the p53/BAX pathway is not pathognomonic for colorectal cancers with neuroendocrine differentiation. Both represent independent prognostic markers in UICC stage III disease. Therefore, the combined analysis of p53 status, BAX expression and neuroendocrine differentiation allows one to identify subgroups of patients with either very good or very poor prognosis.
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Affiliation(s)
- Patricia Grabowski
- Medizinische Klinik I, Gastroenterologie/Infektiologie/Rheumatologie, Charité-Campus Benjamin Franklin, Berlin, Germany
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20
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Tozawa K, Okamoto T, Kawai N, Hashimoto Y, Hayashi Y, Kohri K. Positive correlation between sialyl Lewis X expression and pathologic findings in renal cell carcinoma. Kidney Int 2005; 67:1391-6. [PMID: 15780091 DOI: 10.1111/j.1523-1755.2005.00216.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Interaction between tumor cells and endothelium plays a major role in cancer invasion and metastasis. Among various cell adhesion molecules, the cognate interaction between sialyl Lewis antigen expressed in the tumor cell surface and E-selectin expressed on endothelial cells is considered to be crucial for the tumor cell adhesion to the endothelium. METHODS The sialyl Lewis X (sL(X)) expression in 45 specimens from renal cell carcinoma patients was examined using immunohistochemistry. RESULTS In this study, we demonstrate that the immunoreactivity for sL(X) in renal cell carcinoma specimens not only correlates with conventional histopathologic parameters but also serves as a useful indicator for the prognosis of renal cell carcinoma. CONCLUSION Since beneficial effect of cimetidine has been reported and ascribed to its inhibitory action on the expression of E-selectin, a ligand molecule of sialyl Lewis antigen, cimetidine may also show inhibitory effect on the tumor recurrence and metastasis of renal cell carcinoma with high level of sL(X) expression.
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Affiliation(s)
- Keiichi Tozawa
- Department of Nephro-urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan
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21
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Aghmesheh M, Edwards L, Clarke CL, Byth K, Katzenellenbogen BS, Russell PJ, Friedlander M, Tucker KM, de Fazio A. Expression of steroid hormone receptors in BRCA1-associated ovarian carcinomas. Gynecol Oncol 2005; 97:16-25. [PMID: 15790432 DOI: 10.1016/j.ygyno.2004.12.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2004] [Indexed: 10/25/2022]
Abstract
OBJECTIVE BRCA1 mutations predispose to cancer in hormone responsive tissues. A predominance of estrogen receptor (ER)-negative breast cancers in BRCA1 mutation carriers and potential interactions between ERalpha and BRCA1 suggest a link between hormones and BRCA1. However, the expression pattern of ERalpha and other hormone receptors in BRCA1-associated ovarian cancer was unknown. METHODS Twenty-two BRCA1-associated ovarian cancer cases were matched with sporadic cases (no family history of ovarian or breast cancer) for FIGO stage, grade, histologic subtype, and patient age and hormone receptor expression was measured immunohistochemically. RESULTS ERalpha expression was similar in BRCA1-associated ovarian cancer compared with matched sporadic counterparts, in contrast with previous findings in BRCA1-linked breast cancer. There was also no significant difference in expression of progesterone receptors and androgen receptor between the matched cases in the two groups. However, differences were noted in the relative expression of receptor isotypes, in particular, levels of ERalpha and ERbeta were positively correlated in sporadic tumors but inversely related in BRCA1-associated tumors. CONCLUSION Similar hormone receptor expression in BRCA1-associated ovarian cancer and matched sporadic counterparts may be further evidence that at least a proportion of sporadic ovarian tumors and BRCA1-associated tumors develop through similar pathways.
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Affiliation(s)
- Morteza Aghmesheh
- Oncology Research Centre, Prince of Wales Hospital, Randwick, NSW 2031, Australia.
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22
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Ramanathan RK, Hwang JJ, Zamboni WC, Sinicrope FA, Safran H, Wong MK, Earle M, Brufsky A, Evans T, Troetschel M, Walko C, Day R, Chen HX, Finkelstein S. Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A phase II trial. Cancer Invest 2005; 22:858-65. [PMID: 15641483 DOI: 10.1081/cnv-200039645] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND To determine the response rate of trastuzumab and irinotecan in HER-2/neu overexpressing advanced colorectal cancer (CRC), determine the frequency of HER-2/neu expression in CRC, and evaluate the pharmacokinetics of trastuzumab in a phase II study. PATIENTS AND METHODS Patients were screened for HER-2/neu by immunohistochemistry (DAKO HercepTest). Prior chemotherapy was limited to one regimen. Trastuzumab was administered weekly (loading dose of 4 mg/kg i.v. and 2 mg/kg thereafter). Irinotecan 125 mg/m2, i.v. was administered weekly for 4 weeks with a 2-week rest period. RESULTS HER-2/neu overexpression was detected in 11 of 138 (8.0%) of screened tumors (2+ in 5 and 3+ in 6 patients). Nine patients were entered in the study; 6 had received prior chemotherapy. Partial responses were seen in 5 of 7 evaluable patients. Grade 3-4 toxicities in 31 cycles of therapy included diarrhea (19%), nausea (10%), and vomiting (6%). Leukopenia occurred in 6%, and congestive heart failure and acute renal failure (secondary to diarrhea and dehydration) were seen in 3% of cycles. The study was prematurely closed due to low accrual. CONCLUSIONS The low overexpression rate of HER-2/neu (8.0%) in advanced CRC limits the potential for further investigation of regimens involving trastuzumab, despite evidence suggestive of activity. Irinotecan did not alter the pharmacokinetic disposition of trastuzumab.
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Affiliation(s)
- Ramesh K Ramanathan
- University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15232, USA.
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Aghmesheh M, Nesland JM, Kaern J, Dorum A, Edwards L, Byth K, Friedlander M, Jackson P, Tucker KM, Russell PJ. No differences in p53 mutation frequencies between BRCA1-associated and sporadic ovarian cancers. Gynecol Oncol 2004; 95:430-6. [PMID: 15581943 DOI: 10.1016/j.ygyno.2004.08.035] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2004] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Mutation of the BRCA1 gene, which has incomplete penetrance, is involved in ovarian cancer development. Cell cycle check point inactivation via acquired somatic mutations in the check point regulatory genes, particularly p53, may be required for BRCA1-linked ovarian tumorigenesis. In the few studies directly comparing p53 mutations in BRCA1-linked and sporadic ovarian cancers, data have been contradictory. This study aimed to clarify the role of p53 mutation in BRCA1-associated and sporadic ovarian cancer by comparing two, large, matched cohorts from two different populations who developed BRCA1-linked or sporadic ovarian cancers. METHODS Forty-eight BRCA1-associated ovarian tumor samples (22 from Australia and 26 from Norway) were collected and matched with 48 sporadic ovarian cancers for tumor stage, grade, histological subtype, and patient age. Expression of p53 protein was measured by immunohistochemistry (IHC). RESULTS Consistent with the presence of a mutated p53 protein, the majority of BRCA1-associated (79%) and sporadic (73%) ovarian carcinomas from Australia and Norway overexpressed p53 protein. There was no significant difference between BRCA1-linked ovarian cancers and their sporadic counterparts with regard to p53 protein expression (P = 0.5). CONCLUSION Our results suggest that p53 inactivation is associated with both BRCA1-associated and sporadic ovarian tumorigenesis, and that BRCA1-linked and sporadic ovarian cancers may develop through a similar carcinogenic pathway.
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Affiliation(s)
- Morteza Aghmesheh
- Oncology Research Centre, Prince of Wales Hospital, Randwick, NSW 2031, Australia
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24
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Menon AG, Tollenaar RAEM, van de Velde CJH, Putter H, Janssen-van Rhijn CM, Keijzer R, Fleuren GJ, Kuppen PJK. p53 and HLA class-I expression are not down-regulated in colorectal cancer liver metastases. Clin Exp Metastasis 2004; 21:79-85. [PMID: 15065606 DOI: 10.1023/b:clin.0000017206.08931.42] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
p53 overexpression occurs in more than 50% of colorectal carcinomas, which makes it an interesting target for immunotherapy. HLA class I expression on tumor cells is required for the presentation of p53 peptides and an effective T-cell mediated-immune response to ensue. To analyze to which extent p53 and HLA-I expression in a primary tumor reflects expression in liver metastases, we investigated p53, HLA-A and HLA-B/C expression in 82 colorectal carcinomas and 143 associated liver metastases of 82 patients. We used the monoclonal antibodies DO-7 (p53), HCA2 (HLA-A) and HC-10 (HLA-B/C) on formalin-fixed, paraffin embedded tissue. The percentage of expressing cells was estimated. P53 was overexpressed in 73% of the colorectal carcinomas and 66% of liver metastases. HLA-A was expressed in 98% and 96% and HLA-B/C in 100% and 94% of colorectal cancers and liver metastases respectively. There were no significant differences between the primary tumors and the liver metastases for each marker. The concordance was also very high in those cases in which more than one metastasis was available. Discordant cases consisted of tumors in which expression of p53 or HLA-A was lost in the liver metastases, whereas it was present in only a few tumor cells in the primary tumor. The combined analysis of p53 and HLA-I expression in liver metastases demonstrated that both molecules were expressed in 63% of the cases. P53 and HLA-I were expressed in the majority of primary tumors and their associated liver metastases. This allows to select patients for p53-immunotherapy on the basis of p53 and HLA-I expression in the primary tumor.
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Affiliation(s)
- Anand G Menon
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
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Seidler HBK, Utsuyama M, Nagaoka S, Takemura T, Kitagawa M, Hirokawa K. Expression level of Wnt signaling components possibly influences the biological behavior of colorectal cancer in different age groups. Exp Mol Pathol 2004; 76:224-33. [PMID: 15126105 DOI: 10.1016/j.yexmp.2003.12.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2003] [Indexed: 11/29/2022]
Abstract
Advancing of age apparently influences the behavior of colorectal cancer (CRC). The pattern of activation and expression of Wnt target genes may influence the behavior of the cancer. In the present study, the level of activation of some elements of Wnt signaling was evaluated and correlated with the patient's age and clinicopathological characteristics of the tumor. Beta-catenin and c-Myc mRNA expressions were evaluated by semiquantitative real-time PCR, and subcellular localization of the beta-catenin protein was evaluated by immunohistochemistry. Patients aged 70-84 tended to have locally advanced disease more frequently than younger patients. The same group of patients also more frequently had high nuclear expression of beta-catenin protein and higher expression of c-Myc mRNA. Beta-catenin mRNA had a rather constant expression with advancing of age. High nuclear expression of beta-catenin and high expression of c-Myc were apparently also correlated with locally advanced disease. We concluded that the level of Wnt signaling activation might influence the behavior of the disease in different age groups.
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Affiliation(s)
- Heinrich B K Seidler
- Department of Pathology and Immunology, Aging and Developmental Sciences, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8519, Japan
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Sengupta A, Ghosh S, Das S. Modulatory influence of garlic and tomato on cyclooxygenase-2 activity, cell proliferation and apoptosis during azoxymethane induced colon carcinogenesis in rat. Cancer Lett 2004; 208:127-36. [PMID: 15142670 DOI: 10.1016/j.canlet.2003.11.024] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2003] [Revised: 11/18/2003] [Accepted: 11/19/2003] [Indexed: 01/20/2023]
Abstract
Preventive intervention of colorectal cancer has become essential as a major portion of the population may develop the disease at some points during their lives. Diet and nutrition play an important role during this multistep colon carcinogenic process. Inhibitory activity of aqueous suspensions of garlic and tomato, individually and in combination, were tested on azoxymethane induced colon carcinogenesis in Sprague-Dawley rats. The effect was observed on aberrant crypt foci (ACF), the preneoplastic lesion. To investigate the mechanism of action of the agents used, cell proliferation and the level of apoptosis were determined and the expression of cyclooxygenase-2 (COX-2) protein was analyzed in the colon. Following treatment, significant inhibition of the level of cell proliferation (P<0.01 in garlic; P<0.001 in tomato and P<0.001 in combination treatment group with respect to the carcinogen control group), significant induction of apoptosis (P<0.01 in garlic treated; P<0.01 in tomato treated and P<0.001 in combination treatment group with respect to the carcinogen control group) and suppression of COX-2 expression among the treated groups resulted in significant reduction in the incidences of ACF (by 45.27% in garlic, 68.24% in tomato and 71.62% in combination treatment group). The preventive effect was better when the combination of garlic and tomato was administered in comparison to the individual treatment groups, suggesting the synergistic action of garlic and tomato.
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Affiliation(s)
- Archana Sengupta
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700026, India.
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Nathanson DR, Culliford AT, Shia J, Chen B, D'Alessio M, Zeng ZS, Nash GM, Gerald W, Barany F, Paty PB. HER 2/neu expression and gene amplification in colon cancer. Int J Cancer 2003; 105:796-802. [PMID: 12767065 DOI: 10.1002/ijc.11137] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
HER 2/neu is an important oncogene in breast cancer, but the prevalence and significance of HER 2/neu gene amplification in colon cancer have been poorly documented. We have evaluated HER 2/neu gene amplification and protein overexpression in a series of colon cancers to assess the frequency, concordance and clinical significance of these events. HER 2/neu gene copy number was measured in 154 primary colon tumors, 15 liver metastases and matched normal tissues using a quantitative PCR/ligase detection reaction (LDR) technique developed and validated in our laboratory. HER 2/neu copy number was confirmed by fluorescent in situ hybridization (FISH) in all tumors found to have gene amplification. In an independent and blinded fashion, HER 2/neu expression was assessed in paraffin sections from 139 of the tumor specimens using the HercepTest kit. HER 2/neu gene amplification was observed in 4 (2.4%) of the 169 tumor specimens and in none of the normal tissues. There was no apparent association with stage of disease, tumor grade or patient survival. Among 139 cases evaluated by immunohistochemistry (IHC), HER 2/neu overexpression was seen in 5 cases (3.6%). There was extremely high concordance (kappa = 0.852) between gene amplification and protein overexpression. The low prevalence of HER 2/neu gene amplification and protein overexpression suggests that this oncogene plays an infrequent role in the development and progression of colon cancer. These data indicate that the primary mechanism of dysregulated HER 2/neu expression in colon cancer, as in breast cancer, is gene amplification.
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Affiliation(s)
- Daniel R Nathanson
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
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28
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Seetoo DQ, Crowe PJ, Russell PJ, Yang JL. Quantitative expression of protein markers of plasminogen activation system in prognosis of colorectal cancer. J Surg Oncol 2003; 82:184-93. [PMID: 12619063 DOI: 10.1002/jso.10210] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVES Certain pathophysiological markers may be helpful in selecting further therapies for patients with resected colorectal cancer (CRC). The aim of this study was to determine whether expression of proteins of the plasminogen activation system (PAS), which are important in tumor spread and growth, can predict outcome of human CRC. METHODS Protein expression of the PAS, including urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen (Plg), and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2), was determined in the colonic tissue samples of 56 patients with resected primary CRC by quantitative immunohistochemistry and correlated with clinicopathological parameters and patient outcome. RESULTS Overexpression of uPA (t-test, P < 0.001), uPAR (P < 0.001) and PAI-1 (P = 0.031) was significantly associated with liver metastatic CRC tumors. Higher uPA or uPAR expression level was significantly correlated with overall survival (OS; log-rank, P = 0.001 and P < 0.0001) and cancer-specific survival (CSS; P = 0.001 and P < 0.0001) after the first CRC resection. The predictive value of both uPA and uPAR in liver metastasis, OS and CSS was independent from other parameters (multivariate Cox regression: all P < 0.001). CONCLUSIONS uPA and uPAR may be independent predictors of liver metastasis, patient overall survival and cancer-specific survival after resection of colorectal tumors.
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Affiliation(s)
- Da-Qiang Seetoo
- Department of Surgery, Prince of Wales Hospital, Sydney, New South Wales, Australia
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Backus HHJ, Van Groeningen CJ, Vos W, Dukers DF, Bloemena E, Wouters D, Pinedo HM, Peters GJ. Differential expression of cell cycle and apoptosis related proteins in colorectal mucosa, primary colon tumours, and liver metastases. J Clin Pathol 2002; 55:206-211. [PMID: 11896073 PMCID: PMC1769617 DOI: 10.1136/jcp.55.3.206] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2001] [Indexed: 11/04/2022]
Abstract
AIMS Tumour cell growth results from a disturbance in the balance between the rate of proliferation and cell death. In this study, proteins involved in the regulation of cell cycle arrest and apoptosis were studied as possible factors responsible for uncontrolled cell growth in colorectal cancer. METHODS The expression of proteins involved in these processes was investigated in 48 metastases from patients with colorectal cancer and compared with eight normal colon mucosa samples and 14 primary tumours. Both primary tumours and metastases were obtained from eight patients. The expression of thymidylate synthase (TS), p53, retinoblastoma protein (Rb), Fas receptor, Fas ligand, bcl-2, mcl-1, bax, and bcl-x was measured using immunohistochemistry. Proliferation was determined by Ki67 staining, whereas apoptosis was assessed by M30 immunostaining, which recognises cleaved cytokeratin 18. RESULTS In the limited number of cases in which paired comparisons were possible, the expression of TS and Ki67 was significantly higher in metastases than in the matched primary tumour samples (p = 0.014 and 0.016, respectively), whereas Rb expression was lower in metastases than in primary tumours (p = 0.024). Fas receptor expression was high in normal mucosa but absent in primary tumours and metastases, whereas the opposite was seen for p53. The expression of bax, mcl-1, and bcl-x in normal mucosa was more apical than that seen in malignant cells, where a more diffuse expression pattern was seen (p < 0.04). Apoptosis was more abundant in primary tumours than in metastases. CONCLUSIONS These results demonstrate that proliferation and apoptosis are disturbed during colorectal cancer progression, and this is accompanied by loss of Rb and Fas expression, the accumulation of p53 and TS, and changes in the expression patterns of bax, mcl-1, and bcl-xl.
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Affiliation(s)
- H H J Backus
- Department of Medical Oncology, VU University Medical Center, PO Box 7057, De Boelelaan 1117, 1007 MB Amsterdam, The Netherlands
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Bhatavdekar JM, Patel DD, Chikhlikar PR, Shah NG, Vora HH, Ghosh N, Trivedi TI. Molecular markers are predictors of recurrence and survival in patients with Dukes B and Dukes C colorectal adenocarcinoma. Dis Colon Rectum 2001; 44:523-33. [PMID: 11330579 DOI: 10.1007/bf02234324] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE The goal was to investigate the prognostic value of various molecular markers like CEA, Cyclin D1, Bcl-2, c-Myc, p53, p21ras, Ki-67, CD44, Factor VIII-related antigen, cytokeratin-19, adenoma antigen, and prolactin in patients with Dukes B and Dukes C colorectal adenocarcinoma. METHODS These molecular markers were localized immunohistochemically in nonmalignant (n = 36) and malignant (n = 98) diseases of the colorectum. Data were analyzed statistically using the SPSS software program. The patients with colorectal cancer were followed for a period of five years or their death within that period. RESULTS The expression of carcinoembryonic antigen, Cyclin D1, Bcl-2, CD44, cytokeratin-19 and prolactin was significantly higher in malignant diseases (P < 0.05), whereas, p21ras was found to be significantly higher in nonmalignant diseases (P = 0.002) as compared with their respective counterparts. Besides Dukes stage, multivariate analysis indicated a significantly reduced relapse-free survival in patients expressing CD44 and cytokeratin-19 (P < 0.005). Similarly, besides Dukes stage, multivariate analysis indicated a significantly poor overall survival in patients expressing CD44, cytokeratin-19 and prolactin (P < 0.01). In patients with Dukes B disease, only cytokeratin-19 and CD44 expression attained statistical significance (P < 0.05), whereas in patients with Dukes C disease, CD44, p21ras- and c-Myc expression attained statistical significance (P < 0.018). Also, a multivariate analysis in relation to treatment given was performed using CD44 and cytokeratin-19. CONCLUSION Besides Dukes stage, multivariate analysis of all the studied molecular markers showed that patients expressing CD44 and cytokeratin-19 had a significantly reduced relapse-free and poor overall survival. Moreover, patients expressing both these markers (CD44 and cytokeratin-19) had the lowest significant relative risk for developing recurrence than patients with both markers negative when treated with surgery followed by adjuvant chemotherapy as compared with patients treated with surgery alone. Thus, in patients with colorectal cancer, immunohistochemical localization of CD44 and cytokeratin-19 may be included as a part of routine pathologic evaluation along with conventional prognostic factors.
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Affiliation(s)
- J M Bhatavdekar
- Department of Cancer Biology, Cancer Society Ahmedabad, India
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Yang JL, Seetoo DQ, Wang Y, Ranson M, Berney CR, Ham JM, Russell PJ, Crowe PJ. Urokinase-type plasminogen activator and its receptor in colorectal cancer: independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets. Int J Cancer 2000; 89:431-9. [PMID: 11008205 DOI: 10.1002/1097-0215(20000920)89:5<431::aid-ijc6>3.0.co;2-v] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen (Plg), and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) have been observed in many cancers and may contribute to progression and metastasis. In our study, we examined the expression of the 5 proteins by immunohistochemistry in 59 consecutive primary colorectal cancers (CRC) and correlated the protein expression with patient outcome. In addition, we determined the effect of down-regulation of uPAR on the invasive/metastatic capability of CRC cells, by measuring antisense-uPAR transfected HCT116 and control cell lines, in terms of uPAR expression, uPA-binding activity, invasiveness through Matrigel in vitro and metastasis after cecal orthotopic implantation in nude mice in vivo. We found that higher expression of uPA or uPAR in primary tumor tissues was positively correlated with distant metastasis of CRC (Mann-Whitney, p < 0.02) and negatively correlated with both patient overall survival (OS) and cancer-specific survival (CSS; Cox model, p < 0.04). The prognostic value of uPA and uPAR for both OS and CSS was independent of other variables (multivariate Cox model, p < 0. 007). Antisense-uPAR transfected HCT116 cells, which expressed significantly lower levels of total cellular and cell surface uPAR proteins and uPA-binding activity compared with either wild-type or cells transfected with vector alone (Bonferroni, p < 0.05/3), consistently showed decreased invasiveness through Matrigel (Bonferroni, p < 0.05/3) and decreased metastasis formation in nude mice (Fisher, p < 0.05). Our data suggest that uPAR and uPA are independent prognostic factors in CRC; anti-uPAR treatment, which affects both uPAR and uPA levels, may have potential for new treatment of the disease.
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Affiliation(s)
- J L Yang
- Department of Surgery, Faculty of Medicine of University of New South Wales, Prince of Wales Hospital, Randwick, Australia.
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Rask K, Thörn M, Pontén F, Kraaz W, Sundfeldt K, Hedin L, Enerbäck S. Increased expression of the transcription factors CCAAT-enhancer binding protein-beta (C/EBBeta) and C/EBzeta (CHOP) correlate with invasiveness of human colorectal cancer. Int J Cancer 2000; 86:337-43. [PMID: 10760820 DOI: 10.1002/(sici)1097-0215(20000501)86:3<337::aid-ijc6>3.0.co;2-3] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Regulation of cell differentiation is most often impaired in malignant tumors and may represent a key mechanism for the progression of the disease. CCAAT-enhancer binding protein (C/EBP) is a family of transcription factors involved in the regulation of embryonic gut development in rodents, which has also been detected in various malignancies, e.g., liposarcomas and breast and ovarian epithelial tumors. We studied the relationship between C/EBP and tumor histology (Duke's invasive stage and pathological grade) in colorectal cancer. Immunoblotting techniques were used on microdissected fresh frozen tumor specimens, and expression of C/EBPalpha, C/EBPbeta and C/EBPzeta (CHOP) was analyzed in addition to that of the cell-cycle regulator p53 and the proliferation marker PCNA. Expression of C/EBPbeta (LAP isoforms) was markedly increased in all tumors compared with normal colon mucosa. Although the inter-patient variability was large, we found that LIP, the isoform of C/EBPbeta known to inhibit transcription, was expressed at higher levels in Duke's stage B tumors compared with Duke's stage A, whereas Duke's C tumors had the lowest LIP expression. A similar relationship was seen for CHOP. The cell-cycle regulator gene p53 was the only factor that clearly correlated with pathological grade: a decrease in p53 expression was demonstrated. Our data suggest that genetic and cellular events involving C/EBPbeta and CHOP are important for tumor invasion and that these events do not appear to be related to the pathological grade of the tumor.
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Affiliation(s)
- K Rask
- Department of Physiology, Göteborg University, Göteborg, Sweden
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Berney CR, Fisher RJ, Yang J, Russell PJ, Crowe PJ. Genomic alterations (LOH, MI) on chromosome 17q21-23 and prognosis of sporadic colorectal cancer. Int J Cancer 2000; 89:1-7. [PMID: 10719723 DOI: 10.1002/(sici)1097-0215(20000120)89:1<1::aid-ijc1>3.0.co;2-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Genomic alterations at the long arm of chromosome 17, and in particular at the nm23 locus, are still controversial in colorectal cancer (CRC). Our aim was to investigate the possible relationship of loss of heterozygosity (LOH) and microsatellite instability (MI), at 4 microsatellite loci spanning the 17q21-23 region, to the risk of liver metastasis and nm23 protein expression. Genomic DNA extracted from 58 primary and 54 liver secondary formalin-fixed and paraffin-embedded CRCs was obtained from 82 patients. A fluorescent PCR coupled with an automated DNA sequencer was applied. Increasing fraction of loci showing LOH was positively associated with risk of liver metastases (logrank test for trend, p = 0.005); this remained independent after adjusting to T-stage (Cox regression, p = 0.022), N-stage (p = 0.007), or Dukes' stage (p = 0.012). Conversely, increasing frequency of MI was associated with a reduced risk of liver metastases in Dukes' B tumours (logrank test for trend, p = 0.032). When comparing 30 primary and matched liver secondary lesions, we found concordant genomic alteration in 72% (NME1) to 43% (D17S579). Finally, we observed a trend in association between the proportion of loci with LOH and nm23 positivity (chi2 test for trend, p = 0.024). Our findings suggest that genomic alterations in the 17q21-23 region may affect prognosis of CRC as well as regulation of the nm23 protein expression via an unknown underlying mechanism.
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Affiliation(s)
- C R Berney
- Department of Surgery, Prince of Wales Hospital, University of New South Wales, Randwick, Australia
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Berney CR, Fisher RJ, Yang J, Russell PJ, Crowe PJ. Protein markers in colorectal cancer: predictors of liver metastasis. Ann Surg 1999; 230:179-84. [PMID: 10450731 PMCID: PMC1420859 DOI: 10.1097/00000658-199908000-00007] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To assess the significance of the expression of five protein markers (nm23, p53, c-erbB-2, u-PA, and VEGF) to the development of metastasis in colorectal cancer. SUMMARY BACKGROUND DATA The metastatic cascade is a complex multistep process involving several genetic alterations, angiogenesis activation, and tissue proteolysis. Although the prognosis of colorectal cancer depends on the stage of the tumor, the development of metastasis is difficult to predict. METHODS Paraffin-embedded specimens of 58 patients who underwent surgery for colorectal cancer were retrospectively analyzed by immunohistochemistry, and the coexpression of these protein markers was related to patient outcome. RESULTS The risk of developing liver secondaries was correlated with the expression of nm23 protein (p < 0.0001); this was also the case in those patients with Dukes' stage B showing positive nm23 immunostaining (p = 0.006). The determination of the number of positive markers or the cumulative intensity score did not improve the predictive value over and above that of nm23 protein alone. CONCLUSION Expression of nm23 protein is correlated with the risk of developing liver metastasis. Its evaluation alone may help to determine which patients who have undergone apparently curative resection of a colorectal cancer have an increased risk of liver recurrence, especially those with Dukes' stage B tumors who might be considered for adjuvant chemotherapy.
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Affiliation(s)
- C R Berney
- Department of Surgery, Prince of Wales Hospital, University of New South Wales, Randwick, Australia
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Abstract
c-myc, N-myc and L-myc are the three members of the myc oncoprotein family whose role in the pathogenesis of many human neoplastic diseases has received wide empirical support. In this review, we first summarize data, derived mainly from non-clinical studies, indicating that these oncoproteins actually serve quite different roles in vivo. This concept necessarily lies at the heart of the basis for the observation that the deregulated expression of each MYC gene is reproducibly associated with only certain naturally occurring malignancies in humans and that these genes are not interchangeable with respect to their aberrant functional consequences. We also review evidence implicating each of the above MYC genes in specific neoplastic diseases and have attempted to identify unresolved questions which deserve further basic or clinical investigation. We have made every attempt to review those diseases for which significant and confirmatory evidence, based on studies with primary tumor material, exists to implicate MYC members in their causation and/or progression.
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Affiliation(s)
- C E Nesbit
- Department of Pediatrics, Children's Hospital of Pittsburgh, Pennsylvania 15213, USA
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