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Fadlallah H, El Masri J, Fakhereddine H, Youssef J, Chemaly C, Doughan S, Abou-Kheir W. Colorectal cancer: Recent advances in management and treatment. World J Clin Oncol 2024; 15:1136-1156. [PMID: 39351451 PMCID: PMC11438855 DOI: 10.5306/wjco.v15.i9.1136] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 06/11/2024] [Accepted: 07/29/2024] [Indexed: 08/29/2024] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, and the second most common cause of cancer-related death. In 2020, the estimated number of deaths due to CRC was approximately 930000, accounting for 10% of all cancer deaths worldwide. Accordingly, there is a vast amount of ongoing research aiming to find new and improved treatment modalities for CRC that can potentially increase survival and decrease overall morbidity and mortality. Current management strategies for CRC include surgical procedures for resectable cases, and radiotherapy, chemotherapy, and immunotherapy, in addition to their combination, for non-resectable tumors. Despite these options, CRC remains incurable in 50% of cases. Nonetheless, significant improvements in research techniques have allowed for treatment approaches for CRC to be frequently updated, leading to the availability of new drugs and therapeutic strategies. This review summarizes the most recent therapeutic approaches for CRC, with special emphasis on new strategies that are currently being studied and have great potential to improve the prognosis and lifespan of patients with CRC.
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Affiliation(s)
- Hiba Fadlallah
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Jad El Masri
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Hiam Fakhereddine
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Joe Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Chrystelle Chemaly
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Samer Doughan
- Department of Surgery, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
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2
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Woischke C, Michl M, Neumann J. [Molecular pathology of colorectal cancer]. PATHOLOGIE (HEIDELBERG, GERMANY) 2023; 44:279-286. [PMID: 37277480 DOI: 10.1007/s00292-023-01201-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/20/2023] [Indexed: 06/07/2023]
Abstract
In recent years, the treatment of colorectal carcinoma has experienced increasing individualization. In addition to RAS and BRAF mutational status that is firmly established in routine diagnostics, new therapeutic options evolved based on MSI and HER2 status as well as primary tumour localization. Offering the best targeted options in therapy requires new evidence-based decision-making algorithms regarding timing and scope of molecular pathological diagnostics in order for patients to receive an optimized therapy according to current treatment guidelines. New targeted therapies, some of which are about to be approved and for which pathology has to provide new molecular pathological biomarkers, will also play an increasingly important role in the future.
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Affiliation(s)
- Christine Woischke
- Pathologisches Institut, Medizinische Fakultät, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, 80337, München, Deutschland
| | - Marlies Michl
- Medizinische Klinik und Poliklinik III, Klinikum der Universität München, Ludwig-Maximilians-Universität München, München, Deutschland
- Facharztpraxis für Innere Medizin, Hämatologie und Onkologie mit Tagesklinik, Praxis Dr. Michl, München, Deutschland
| | - Jens Neumann
- Pathologisches Institut, Medizinische Fakultät, Ludwig-Maximilians-Universität München, Thalkirchner Str. 36, 80337, München, Deutschland.
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3
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PELI1 and EGFR cooperate to promote breast cancer metastasis. Oncogenesis 2023; 12:9. [PMID: 36841821 PMCID: PMC9968314 DOI: 10.1038/s41389-023-00457-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/14/2023] [Accepted: 02/15/2023] [Indexed: 02/27/2023] Open
Abstract
Pellino-1 (PELI1) is an E3 ubiquitin ligase acting as a key regulator for the inflammation and autoimmunity via the ubiquitination of the substrate proteins. There is increasing evidence to support that PELI1 functions as an oncoprotein in tumorigenesis and metastasis. However, the molecular mechanism underlying the high expression and oncogenic roles of PELI1 in cancers remains limited. Herein, we revealed a novel regulation mechanism by which PELI1 and EGFR cooperate to promote breast cancer metastasis. EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase. Simultaneously, PELI1 physically interacted with and enhanced the stability of EGFR via the K63-linked polyubiquitination in reverse. The co-inhibition of the PELI1-EGFR showed synergetic effect to repress breast cancer metastasis. Furthermore, we identified a compound S62 as a small molecule disruptor of PELI1/EGFR that effectively repressed breast cancer metastasis. Our study not only uncovered the emerging roles of PELI1/EGFR interaction in the progression of breast cancer, but also provided an effective strategy for the inhibition of metastasis in breast cancer.
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Wang C, Aikemu B, Shao Y, Zhang S, Yang G, Hong H, Huang L, Jia H, Yang X, Zheng M, Sun J, Li J. Genomic signature of MTOR could be an immunogenicity marker in human colorectal cancer. BMC Cancer 2022; 22:818. [PMID: 35883111 PMCID: PMC9327395 DOI: 10.1186/s12885-022-09901-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 07/13/2022] [Indexed: 12/24/2022] Open
Abstract
Background The mTOR signaling pathway plays an important role in cancer. As a master regulator, the status of MTOR affects pathway activity and the efficacy of mTOR inhibitor therapy. However, little research has been performed to explore MTOR in colorectal cancer (CRC). Methods In this study, gene expression and clinical data were analyzed using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Signaling pathways related to MTOR in CRC were identified by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). Somatic mutation data were downloaded from TCGA and analyzed using the maftools R package. Tumor Immune Estimation Resource (TIMER) and CIBERSORT were used to analyze correlations between MTOR and tumor-infiltrating immune cells (TIICs). Finally, we detected MTOR mutations in a CRC cohort from our database using whole-exome sequencing. Results We found that MTOR was overexpressed in Asian CRC patients and associated with a poor prognosis. Enrichment analysis showed that MTOR was involved in metabolism, cell adhesion, and translation pathways in CRC. High MTOR expression was correlated with high tumor mutation burden (TMB) and several TIICs. Finally, we found that the mTOR signaling pathway was activated in CRC lines characterized by microsatellite instability (MSI), and the frequency of MTOR mutations was higher in MSI-high (MSI-H) patients than in microsatellite stable (MSS) patients. Conclusions MTOR may represent a comprehensive indicator of prognosis and immunological status in CRC. The genomic signatures of MTOR may provide guidance for exploring the role of mTOR inhibitors in CRC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09901-w.
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Affiliation(s)
- Chenxing Wang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Batuer Aikemu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yanfei Shao
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Sen Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Guang Yang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Hiju Hong
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ling Huang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Hongtao Jia
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xiao Yang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Minhua Zheng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jing Sun
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. .,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Jianwen Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. .,Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Pashirzad M, Khorasanian R, Fard MM, Arjmand MH, Langari H, Khazaei M, Soleimanpour S, Rezayi M, Ferns GA, Hassanian SM, Avan A. The Therapeutic Potential of MAPK/ERK Inhibitors in the Treatment of Colorectal Cancer. Curr Cancer Drug Targets 2021; 21:932-943. [PMID: 34732116 DOI: 10.2174/1568009621666211103113339] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 05/16/2021] [Accepted: 08/24/2021] [Indexed: 11/22/2022]
Abstract
The MAPK/ERK signaling pathway regulates cancer cell proliferation, apoptosis, inflammation, angiogenesis, metastasis and drug resistance. Mutations and up-regulation of components of the MAPK/ERK signaling pathway, as well as over-activation of this critical signaling pathway, are frequently observed in colorectal carcinomas. Targeting the MAPK/ERK signaling pathway, using specific pharmacological inhibitors, elicits potent anti-tumor effects, supporting the therapeutic potential of these inhibitors in the treatment of CRC. Several drugs have recently been developed for the inhibition of the MEK/ERK pathway in preclinical and clinical settings, such as MEK162 and MK-2206. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity for the treatment of this malignancy. This review summarizes the current knowledge on the role of the MAPK/ERK signaling pathway in the pathogenesis of CRC and the potential clinical value of synthetic inhibitors of this pathway in preventing CRC progression for a better understanding, and hence, better management of colorectal cancer.
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Affiliation(s)
- Mehran Pashirzad
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Reihaneh Khorasanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Maryam Mahmoudi Fard
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Mohammad-Hassan Arjmand
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord. Iran
| | - Hadis Langari
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord. Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Saman Soleimanpour
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Majid Rezayi
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord. Iran
| | - Gordon A Ferns
- Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, MO. United States
| | - Seyed Mahdi Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad. Iran
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6
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El agy F, el Bardai S, El Otmani I, Benbrahim Z, Karim IMH, Mazaz K, Benjelloun EB, Ousadden A, El Abkari M, Ibrahimi SA, Chbani L. Mutation status and prognostic value of KRAS and NRAS mutations in Moroccan colon cancer patients: A first report. PLoS One 2021; 16:e0248522. [PMID: 33784337 PMCID: PMC8009361 DOI: 10.1371/journal.pone.0248522] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 02/27/2021] [Indexed: 12/12/2022] Open
Abstract
This study aimed to estimate the incidence of KRAS, NRAS, and BRAF mutations in the Moroccan population, and investigate the associations of KRAS and NRAS gene mutations with clinicopathological characteristics and their prognosis value. To achieve these objectives, we reviewed medical and pathology reports for 210 patients. RAS testing was investigated by Sanger sequencing and Pyrosequencing technology. BRAF (exon 15) status was analyzed by the Sanger method. The expression of MMR proteins was evaluated by Immunohistochemistry. KRAS and NRAS mutations were found in 36.7% and 2.9% of 210 patients, respectively. KRAS exon 2 mutations were identified in 76.5% of the cases. RAS-mutated colon cancers were significantly associated with female gender, presence of vascular invasion, classical adenocarcinoma, moderately differentiated tumors, advanced TNM stage III-IV, left colon site, higher incidence of distant metastases at the time of diagnostic, microsatellite stable phenotype, lower number of total lymph nodes, and higher means of positive lymph nodes and lymph node ratio. KRAS exon 2-mutated colon cancers, compared with KRAS wild-type colon cancers were associated with the same clinicopathological features of RAS-mutated colon cancers. NRAS-mutated patients were associated with lower total lymph node rate and the presence of positive lymph node. Rare RAS-mutated tumors, compared with wild-type tumors were more frequently moderately differentiated and associated with lower lymph node rate. We found that KRAS codon 13-mutated, tumors compared to codon 12-mutated tumors were significantly correlated with a higher death cases number, a lower rate of positive lymph, lower follow-up time, and poor overall survival. Our findings show that KRAS and NRAS mutations have distinct clinicopathological features. KRAS codon 13-mutated status was the worst predictor of prognosis at all stages in our population.
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Affiliation(s)
- Fatima El agy
- Faculty of Medicine and Pharmacy, Laboratory of Biomedical and Translational Research, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- * E-mail:
| | - Sanae el Bardai
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Ihsane El Otmani
- Faculty of Medicine and Pharmacy, Laboratory of Biomedical and Translational Research, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- Unit of Medical Genetics and Oncogenetics, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Zineb Benbrahim
- Department of Oncology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Ibn Majdoub Hassani Karim
- Department of General Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Khalid Mazaz
- Department of General Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - El Bachir Benjelloun
- Department of General Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Abdelmalek Ousadden
- Department of General Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Mohammed El Abkari
- Department of Gastroenterology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Sidi Adil Ibrahimi
- Department of General Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Laila Chbani
- Faculty of Medicine and Pharmacy, Laboratory of Biomedical and Translational Research, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
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Tabibzadeh A, Tameshkel FS, Moradi Y, Soltani S, Moradi-Lakeh M, Ashrafi GH, Motamed N, Zamani F, Motevalian SA, Panahi M, Esghaei M, Ajdarkosh H, Mousavi-Jarrahi A, Niya MHK. Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis. Sci Rep 2020; 10:18713. [PMID: 33127962 PMCID: PMC7599243 DOI: 10.1038/s41598-020-73770-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023] Open
Abstract
The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study. The study was performed based on the PRISMA criteria. Random models by confidence interval (CI: 95%) were used to calculate the pooled estimate of prevalence via Metaprop command. The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3-8%), 12% (95% CI: 8-18%), 17% (95% CI: 14-20%), and 20% (95% CI: 5-41%), respectively. Also, the mutation rates for Wnt pathway and MAPK pathway were calculated to be 23% (95% CI, 14-33%) and 20% (95% CI, 17-24%), respectively. Moreover, the most popular genes were APC (in Wnt pathway), KRAS (in MAPK pathway) and PIK3CA (in PI3K pathway) in the colorectal cancer, pancreatic cancer, and gastric cancer while they were beta-catenin and CTNNB1 in liver cancer. The most altered pathway was Wnt pathway followed by the MAPK pathway. In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis. Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations.
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Affiliation(s)
- Alireza Tabibzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Safarnezhad Tameshkel
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Yousef Moradi
- Social Determinants of Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Saber Soltani
- Department of Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Maziar Moradi-Lakeh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
- Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - G Hossein Ashrafi
- Cancer Theme SEC Faculty, Kingston University, Penrhyn Road, London, KT1 2EE, UK
| | - Nima Motamed
- Department of Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Abbas Motevalian
- Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mahshid Panahi
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Esghaei
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
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Stahler A, Stintzing S, Modest DP, Ricard I, Giessen-Jung C, Kapaun C, Ivanova B, Kaiser F, Fischer von Weikersthal L, Moosmann N, Schalhorn A, Stauch M, Kiani A, Held S, Decker T, Moehler M, Neumann J, Kirchner T, Jung A, Heinemann V. Amphiregulin Expression Is a Predictive Biomarker for EGFR Inhibition in Metastatic Colorectal Cancer: Combined Analysis of Three Randomized Trials. Clin Cancer Res 2020; 26:6559-6567. [PMID: 32943459 DOI: 10.1158/1078-0432.ccr-20-2748] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/18/2020] [Accepted: 09/10/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Amphiregulin (AREG) and epiregulin (EREG) are ligands of EGFR. Predictive information for anti-EGFR treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited. EXPERIMENTAL DESIGN Ligand mRNA expression; RAS, BRAF, PIK3CA mutations; and EGFR expression were assessed by qRT-PCR, pyrosequencing, and IHC, respectively, in mCRC tumor tissue of patients participating in the randomized controlled trials FIRE-1, CIOX, and FIRE-3. Normalized mRNA expression was dichotomized using median and third quartile. Overall (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method including univariate and multivariate Cox regression analyses. Penalized spline regression analysis tested interaction of mRNA expression and outcome. RESULTS Of 688 patients with available material, high AREG expression was detected in 343 (>median) and 172 (>3rd quartile) patients. High AREG expression was associated with significantly higher OS [26.2 vs. 21.5 months, HR = 0.80; 95% confidence interval (CI), 0.68-0.94; P = 0.007], PFS (10.0 vs. 8.1 months, HR = 0.74; 95% CI, 0.63-0.86; P = 0.001), and objective response rate (63.1% vs. 51.6%, P = 0.004) compared to low expression at both threshold values. This effect remained significant in multivariate Cox regression analysis (OS: P = 0.01, PFS: P = 0.002). High AREG mRNA expression interacted significantly with the efficacy of cetuximab compared with bevacizumab (OS: P = 0.02, PFS: P = 0.04) in RAS WT mCRC. CONCLUSIONS High AREG mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti-EGFR treatment.
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Affiliation(s)
- Arndt Stahler
- Department of Internal Medicine III and Comprehensive Cancer Centre Munich, University Hospital Grosshadern, Ludwig-Maximilian-Universitaet Muenchen, Munich, Germany.
| | - Sebastian Stintzing
- Medical Department, Division of Hematology, Oncology and Tumor Immunology (CCM), Charité Universitaetsmedizin Berlin, Berlin, Germany.,DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Dominik P Modest
- DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Medical Department, Division of Hematology, Oncology and Tumor Immunology (CVK), Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Ingrid Ricard
- Department of Internal Medicine III and Comprehensive Cancer Centre Munich, University Hospital Grosshadern, Ludwig-Maximilian-Universitaet Muenchen, Munich, Germany
| | - Clemens Giessen-Jung
- Department of Internal Medicine III and Comprehensive Cancer Centre Munich, University Hospital Grosshadern, Ludwig-Maximilian-Universitaet Muenchen, Munich, Germany
| | - Christine Kapaun
- Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Boryana Ivanova
- Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | | | | | - Nicolas Moosmann
- Department for Hematology and Oncology, Klinikum Barmherzige Brüder, Regensburg, Germany
| | - Andreas Schalhorn
- Department of Internal Medicine III and Comprehensive Cancer Centre Munich, University Hospital Grosshadern, Ludwig-Maximilian-Universitaet Muenchen, Munich, Germany
| | | | - Alexander Kiani
- Department of Medicine IV, Klinikum Bayreuth GmbH, Bayreuth, Germany
| | | | | | - Markus Moehler
- I. Department of Internal Medicine, University Medical Center Mainz, Mainz, Germany
| | - Jens Neumann
- DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Thomas Kirchner
- DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Andreas Jung
- DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Volker Heinemann
- Department of Internal Medicine III and Comprehensive Cancer Centre Munich, University Hospital Grosshadern, Ludwig-Maximilian-Universitaet Muenchen, Munich, Germany.,DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
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9
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Jin J, Shi Y, Zhang S, Yang S. PIK3CA mutation and clinicopathological features of colorectal cancer: a systematic review and Meta-Analysis. Acta Oncol 2020; 59:66-74. [PMID: 31545109 DOI: 10.1080/0284186x.2019.1664764] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background: There is conflicting evidence regarding the association between PIK3CA mutations and clinicopathological features of colorectal cancer (CRC). We performed a comprehensive meta-analysis investigating the association between PIK3CA mutations and clinicopathological features in CRC, including subgroup analysis of mutations in exons 9 and 20, to elucidate the role of PIK3CA mutations in CRC.Materials and Methods: A detailed literature search was performed within the PubMed, Web of Science, and Embase databases, examining the associations between PIK3CA mutations and demographic characteristics, clinicopathologic parameters, and molecular features in patients with CRC. The odds ratios with 95% confidence intervals were used to estimate the effect of PIK3CA mutations on outcome parameters.Results: Forty-four studies enrolling 17621 patients were eligible for inclusion. PIK3CA mutations were associated with proximal tumor location, mucinous differentiation, KRAS mutations, and microsatellite instability (MSI). Subgroup analysis demonstrated that PIK3CA exon 9 mutations were positively associated with proximal tumor location and KRAS mutations, and negatively associated with BRAF mutations and MSI; exon 20 mutations were associated with proximal tumor location, KRAS mutations, BRAF mutations and MSI.Conclusions: Our findings suggest that overall or exon-specific PIK3CA mutations showed null associations with key clinicopathological parameters, including disease stage and tumor differentiation, indicating that PIK3CA mutations do not predict aggressive clinicopathological characteristics in CRC. As PIK3CA mutations were found to be closely associated with KRAS mutations, their relationship warrants further investigation. Since PIK3CA exon 9 and 20 mutations showed different tendencies with regard to BRAF mutation and MSI status, they may have distinct molecular impacts on CRC.
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Affiliation(s)
- Juan Jin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yaqin Shi
- Department of Medical Oncology, the First Hospital Affiliated to Soochow University, Suzhou, China
| | - Shu Zhang
- Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shuofei Yang
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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Huang D, Sun W, Zhou Y, Li P, Chen F, Chen H, Xia D, Xu E, Lai M, Wu Y, Zhang H. Mutations of key driver genes in colorectal cancer progression and metastasis. Cancer Metastasis Rev 2019; 37:173-187. [PMID: 29322354 DOI: 10.1007/s10555-017-9726-5] [Citation(s) in RCA: 205] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The association between mutations of key driver genes and colorectal cancer (CRC) metastasis has been investigated by many studies. However, the results of these studies have been contradictory. Here, we perform a comprehensive analysis to screen key driver genes from the TCGA database and validate the roles of these mutations in CRC metastasis. Using bioinformatics analysis, we identified six key driver genes, namely APC, KRAS, BRAF, PIK3CA, SMAD4 and p53. Through a systematic search, 120 articles published by November 30, 2017, were included, which all showed roles for these gene mutations in CRC metastasis. A meta-analysis showed that KRAS mutations (combined OR 1.18, 95% CI 1.05-1.33) and p53 mutations (combined OR 1.49, 95% CI 1.23-1.80) were associated with CRC metastasis, including lymphatic and distant metastases. Moreover, CRC patients with a KRAS mutation (combined OR 1.29, 95% CI 1.13-1.47), p53 mutation (combined OR 1.35, 95% CI 1.06-1.72) or SMAD4 mutation (combined OR 2.04, 95% CI 1.41-2.95) were at a higher risk of distant metastasis. Subgroup analysis stratified by ethnic populations indicated that the BRAF mutation was related to CRC metastasis (combined OR 1.42, 95% CI 1.18-1.71) and distant metastasis (combined OR 1.51, 95% CI 1.20-1.91) in an Asian population. No significant association was found between mutations of APC or PIK3CA and CRC metastasis. In conclusion, mutations of KRAS, p53, SMAD4 and BRAF play significant roles in CRC metastasis and may be both potential biomarkers of CRC metastasis as well as therapeutic targets.
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Affiliation(s)
- Dongdong Huang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Wenjie Sun
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Yuwei Zhou
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Peiwei Li
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China
- Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Fang Chen
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Hanwen Chen
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China
| | - Dajing Xia
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China
| | - Enping Xu
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Maode Lai
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Yihua Wu
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China.
| | - Honghe Zhang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
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11
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Ben Brahim E, Ayari I, Jouini R, Atafi S, Koubaa W, Elloumi H, Chadli A. Expression of epidermal growth factor receptor (EGFR) in colorectal cancer: An immunohistochemical study. Arab J Gastroenterol 2018; 19:121-124. [PMID: 30243897 DOI: 10.1016/j.ajg.2018.08.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 04/14/2018] [Accepted: 08/06/2018] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND STUDY AIM The epidermal growth factor receptor (EGFR) plays an important role in tumourigenesis and tumour progression of colorectal cancer (CRC) and leads to the activation of intracellular signaling pathways. The use of anti-EGFR-targeted therapy has increased for patients with metastatic CRC. Today, the clinical utility of immunohistochemistry has remained somewhat inconclusive. It is based on EGFR screening methods using paraffin-embedded tumour specimen to select patients eligible for treatment. There is still lack of agreement on reproducible scoring criteria for EGFR immunohistochemistry has in various clinical trials. PATIENTS AND METHODS We retrospectively reviewed 36 CRC patients who underwent surgeries during 2011 in Habib Thameur hospital in Tunis. We analyzed the immunohistochemical overexpression of EGFR using a score based on immunostaining intensity. In addition, we analyzed the correlation between this overexpression and patients' clinicopathologic parameters. RESULTS The positive expression rate of EGFR was 78% (28/36). Using the immunoreactivity score, 21 cases were considered low grade expression and 15 tumours were high grade. Immunohistochemical expression of EGFR showed a significant difference with tumour's location (p = 0.034) and vascular invasion (p = 0.03). This expression was not significantly associated with age, gender, tumour size, histological type, grade, TNM staging and perineural invasion. CONCLUSIONS EGFR expression by immunohistochemistry in CRC is variably correlated with clinicopathological parameters. Its assessment by this method has still not proved its predictive value.
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Affiliation(s)
- Ehsen Ben Brahim
- Pathology Department in Habib Thameur Hospital and Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia.
| | - Imen Ayari
- Pathology Department in Habib Thameur Hospital and Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
| | - Raja Jouini
- Pathology Department in Habib Thameur Hospital and Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
| | - Salsabil Atafi
- Pathology Department in Habib Thameur Hospital and Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
| | - Wafa Koubaa
- Pathology Department in Habib Thameur Hospital and Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
| | - Hela Elloumi
- Gastroenterology Department in Habib Thameur Hospital and Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
| | - Aschraf Chadli
- Pathology Department in Habib Thameur Hospital and Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
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12
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Sun X, Xiao Z, Chen G, Han Z, Liu Y, Zhang C, Sun Y, Song Y, Wang K, Fang F, Wang X, Lin Y, Xu L, Shao L, Li J, Cheng Z, Gambhir SS, Shen B. A PET imaging approach for determining EGFR mutation status for improved lung cancer patient management. Sci Transl Med 2018; 10:eaan8840. [PMID: 29515002 DOI: 10.1126/scitranslmed.aan8840] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 01/29/2018] [Indexed: 12/11/2022]
Abstract
Tumor heterogeneity and changes in epidermal growth factor receptor (EGFR) mutation status over time challenge the design of effective EGFR tyrosine kinase inhibitor (TKI) treatment strategies for non-small cell lung cancer (NSCLC). Therefore, there is an urgent need to develop techniques for comprehensive tumor EGFR profiling in real time, particularly in lung cancer precision medicine trials. We report a positron emission tomography (PET) tracer, N-(3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2-18F-fluoroethoxy) ethoxy) ethoxy) ethoxy)-6-methoxyquinazolin-4-amine (18F-MPG), with high specificity to activating EGFR mutant kinase. We evaluate the feasibility of using 18F-MPG PET for noninvasive imaging and quantification of EGFR-activating mutation status in preclinical models of NSCLC and in patients with primary and metastatic NSCLC tumors. 18F-MPG PET in NSCLC animal models showed a significant correlation (R2 = 0.9050) between 18F-MPG uptake and activating EGFR mutation status. In clinical studies with NSCLC patients (n = 75), the concordance between the detection of EGFR activation by 18F-MPG PET/computed tomography (CT) and tissue biopsy reached 84.29%. There was a greater response to EGFR-TKIs (81.58% versus 6.06%) and longer median progression-free survival (348 days versus 183 days) in NSCLC patients when 18F-MPG PET/CT SUVmax (maximum standard uptake value) was ≥2.23 versus <2.23. Our study demonstrates that 18F-MPG PET/CT is a powerful method for precise quantification of EGFR-activating mutation status in NSCLC patients, and it is a promising strategy for noninvasively identifying patients sensitive to EGFR-TKIs and for monitoring the efficacy of EGFR-TKI therapy.
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Affiliation(s)
- Xilin Sun
- Molecular Imaging Research Center, Harbin Medical University (MIRC), Harbin, Heilongjiang 150028, China
- TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Zunyu Xiao
- Molecular Imaging Research Center, Harbin Medical University (MIRC), Harbin, Heilongjiang 150028, China
| | - Gongyan Chen
- Department of Respiratory Medical Oncology, The Tumor Hospital Affiliated Harbin Medical University, Harbin, Heilongjiang 150049, China
| | - Zhaoguo Han
- Molecular Imaging Research Center, Harbin Medical University (MIRC), Harbin, Heilongjiang 150028, China
| | - Yang Liu
- Molecular Imaging Research Center, Harbin Medical University (MIRC), Harbin, Heilongjiang 150028, China
| | - Chongqing Zhang
- Molecular Imaging Research Center, Harbin Medical University (MIRC), Harbin, Heilongjiang 150028, China
| | - Yingying Sun
- TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China
| | - Yan Song
- Molecular Imaging Research Center, Harbin Medical University (MIRC), Harbin, Heilongjiang 150028, China
| | - Kai Wang
- Molecular Imaging Research Center, Harbin Medical University (MIRC), Harbin, Heilongjiang 150028, China
- TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China
| | - Fang Fang
- TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China
| | - Xiance Wang
- Molecular Imaging Research Center, Harbin Medical University (MIRC), Harbin, Heilongjiang 150028, China
| | - Yanhong Lin
- Molecular Imaging Research Center, Harbin Medical University (MIRC), Harbin, Heilongjiang 150028, China
| | - Lili Xu
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Liming Shao
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Jin Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Zhen Cheng
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Sanjiv Sam Gambhir
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Baozhong Shen
- Molecular Imaging Research Center, Harbin Medical University (MIRC), Harbin, Heilongjiang 150028, China.
- TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150028, China
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13
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Huang CW, Chen YT, Tsai HL, Yeh YS, Su WC, Ma CJ, Tsai TN, Wang JY. EGFR expression in patients with stage III colorectal cancer after adjuvant chemotherapy and on cancer cell function. Oncotarget 2017; 8:114663-114676. [PMID: 29383110 PMCID: PMC5777722 DOI: 10.18632/oncotarget.23072] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 11/14/2017] [Indexed: 12/31/2022] Open
Abstract
The epidermal growth factor receptor (EGFR)/RAS/RAF/MEK/MAPK pathway plays a crucial role in the carcinogenesis, invasion and metastasis of colorectal cancer (CRC). However, its role in the prognosis and prediction of relapse in patients with stage III CRC after adjuvant chemotherapy remains controversial. In the present study, the clinicopathological features of 173 patients with stage III CRC who underwent radical resection and adjuvant chemotherapy with the fluoropyrimidine/folinic acid, and oxaliplatin (FOLFOX) regimen, and their prognostic values of EGFR expression were retrospectively analyzed. By conducting an in vitro CRC cell line study through the knockdown of EGFR expression, we analyzed cell proliferation, colony formation and migration. Positive EGFR expression and an abnormal postoperative serum carcinoembryonic antigen (CEA) level were found to be significant independent negative predictive factors for postoperative relapse. Furthermore, positive EGFR expression was a significant independent negative prognostic factor for disease-free survival (DFS) and overall survival (OS). Additionally, an in vitro cell line study showed that the knockdown of EGFR expression significantly reduced CRC cell proliferation, colony formation and migration. The results of in vitro and in vivo experiments demonstrated that EGFR expression had a prognostic value for OS and DFS, as well as predictive roles for postoperative relapse, in patients with stage III CRC. By analyzing both EGFR expression and the postoperative CEA, the patients with stage III CRC who were at a high risk of postoperative relapse, or mortality following adjuvant chemotherapy could be identified. In short, CRC cells with EGFR expression would exhibit a highly malignant behavior.
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Affiliation(s)
- Ching-Wen Huang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Ting Chen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsiang-Lin Tsai
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yung-Sung Yeh
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Trauma and Surgical Critical Care, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wei-Chih Su
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Jen Ma
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tsen-Ni Tsai
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jaw-Yuan Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Biomarkers and Biotech Drugs, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Research Center for Environmental Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan
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14
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Schubert-Fritschle G, Combs SE, Kirchner T, Nüssler V, Engel J. Use of Multicenter Data in a Large Cancer Registry for Evaluation of Outcome and Implementation of Novel Concepts. Front Oncol 2017; 7:234. [PMID: 29046867 PMCID: PMC5632760 DOI: 10.3389/fonc.2017.00234] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 09/11/2017] [Indexed: 01/22/2023] Open
Abstract
Large clinical cancer registries (CCRs) in Germany shall be strengthened by the German Social Code Book V (SGB V) and implemented until the end of 2017. There are currently several large cancer registries that support clinical data for outcome analysis and knowledge acquisition. The various examples of the Munich Cancer Registry outlined in this paper present many-sided possibilities using and analyzing registry data. The main objective of population-based cancer registration within a defined area and the performance of outcomes research is to provide feedback regarding the results to the broad public, the reporting doctors, and the scientific community. These tasks determine principles of operation and data usage by CCRs. Each clinical department delivers its own findings and applied therapy. The compilation of these data in CCRs provides information on patient progress through the regional network of medical care and delivers meaningful information on the course of oncological diseases. Successful implementation of CCRs allows for presenting the statistical outcomes of health-care delivery, improving the quality of care within the region, accelerating the process of implementing innovative therapies, and generating new hypotheses as a stimulus for research activities.
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Affiliation(s)
- Gabriele Schubert-Fritschle
- Munich Cancer Registry (MCR) of the Munich Tumour Centre (TZM), Institute for Medical Information Processing, Biometry and Epidemiology (IBE), University Hospital of Munich, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Stephanie E. Combs
- Munich Tumour Centre (TZM), Medical Faculties, Ludwig-Maximilians-University (LMU) and the Technical University of Munich (TUM), Munich, Germany
- Department of Radiation Oncology, Technische Universität Munich (TUM), Klinikum rechts der Isar, Munich, Germany
- Department of Radiation Sciences (DRS), Institute for Innovative Radiotherapy (iRT), Helmholtz Zentrum Munich, Oberschleißheim, Germany
- Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, Munich, Germany
| | - Thomas Kirchner
- Munich Tumour Centre (TZM), Medical Faculties, Ludwig-Maximilians-University (LMU) and the Technical University of Munich (TUM), Munich, Germany
- Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, Munich, Germany
- Institute for Pathology, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Volkmar Nüssler
- Munich Tumour Centre (TZM), Medical Faculties, Ludwig-Maximilians-University (LMU) and the Technical University of Munich (TUM), Munich, Germany
| | - Jutta Engel
- Munich Cancer Registry (MCR) of the Munich Tumour Centre (TZM), Institute for Medical Information Processing, Biometry and Epidemiology (IBE), University Hospital of Munich, Ludwig-Maximilians-University (LMU), Munich, Germany
- Munich Tumour Centre (TZM), Medical Faculties, Ludwig-Maximilians-University (LMU) and the Technical University of Munich (TUM), Munich, Germany
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15
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Goblirsch M, Richtig G, Slaby O, Berindan-Neagoe I, Gerger A, Pichler M. MicroRNAs as a tool to aid stratification of colorectal cancer patients and to guide therapy. Pharmacogenomics 2017. [PMID: 28639472 DOI: 10.2217/pgs-2017-0004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer is a common type of malignant disease with high rates of morbidity and mortality. Although treatment options have been expanded over the last years, the mainstay of curative treatment remains surgical removal of the tumor-bearing organ. Systemic treatment options include classic cytotoxic drugs as well as some biological agents. Noncoding RNAs are an evolving field in cancer diagnosis, prognosis and possible treatment. Noncoding miRNAs are small molecules with huge impact on gene expression. They have been a substantial part of cancer research for more than a decade. In this review article, the current knowledge of miRNAs and colorectal cancer diagnosis, prognosis and novel or evolving therapeutic concepts are discussed. Examples of how miRNAs might change the management of the disease will be described.
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Affiliation(s)
- Matthew Goblirsch
- College of Science, Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Georg Richtig
- Institute of Experimental & Clinical Pharmacology, Medical University of Graz, 8010 Graz, Austria
| | - Ondrej Slaby
- Molecular Oncology II - Solid Cancers, Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Ioana Berindan-Neagoe
- Department of Functional Genomics, The Oncology Institute, Cluj-Napoca, Romania Department of Immunology & Research Center for Functional Genomics, Biomedicine & Translational Medicine University of Medicine & Pharmacy 'I. Hatieganu' 400337 Cluj-Napoca România
| | - Armin Gerger
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
| | - Martin Pichler
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
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16
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Mahasneh A, Al-Shaheri F, Jamal E. Molecular biomarkers for an early diagnosis, effective treatment and prognosis of colorectal cancer: Current updates. Exp Mol Pathol 2017; 102:475-483. [PMID: 28506769 DOI: 10.1016/j.yexmp.2017.05.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 05/11/2017] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer in the world. Globally, it has been estimated that about 1.4 million new cases of colorectal cancer are diagnosed every year. CRC is a multifactorial disease that arises due to genetics as well as epigenetic alterations in a number of oncogenes, tumor suppressor genes, mismatch repair genes, as well as cell cycle regulating genes in colon mucosal cells. These molecular alterations have been considered as potential CRC biomarkers because they can provide the physicians with diagnostic, prognostic and treatment response information. The goal is to identify relevant, cheap and applicable biomarkers that contribute to patient management decisions, resulting in direct benefits to patients. In this review, we will outline the most currently available and developing tumor tools, and blood molecular biomarkers. Also, we will illustrate their diagnostic, therapeutic and prognostic applications.
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Affiliation(s)
- Amjad Mahasneh
- Faculty of Arts and Science, Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid, Jordan.
| | - Fawaz Al-Shaheri
- Faculty of Applied Medical Sciences, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan
| | - Eshraq Jamal
- Faculty of Applied Medical Sciences, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan
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17
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Abstract
With the development of sophisticated individualized therapeutic approaches, the role of pathology in classification of tumors is enormously increasing. The solely morphological characterization of neoplastic process is no more sufficient for qualified decision on optimal therapeutic approach. Thus, morphologic diagnosis must be supplemented by molecular analysis of the lesion with emphasis on the detection of status of certain markers used as predictive factors for targeted therapy. Both intrinsic and acquired types of intratumor heterogeneity have an impact at various moments of cancer diagnostics and therapy. The primary heterogeneity of neoplastic tissue represents a significant problem in patients, where only limited biopsy samples from the primary tumor are available for diagnosis, such as core needle biopsy specimens in breast cancer, transthoracic or endobronchial biopsies in lung cancer, or endoscopic biopsies in gastric cancer. Detection of predictive markers may be influenced by this heterogeneity, and the marker detection may be falsely negative or (less probably) falsely positive. In addition, as these markers are often detected in the tissue samples from primary tumor, the differences between molecular features of the primary lesion and its metastases may be responsible for failure of systemic therapy in patients with discordant phenotype between primary and metastatic disease. The fact of tumor heterogeneity must be taken into consideration already in establishing pathological diagnosis. One has to be aware that limited biopsy specimen must not always be fully representative of the entire tumor volume. To overcome these limitations, there does not exist one single simple solution. Examination of more tissue (preference of surgical resection specimens over biopsies, whenever possible), use of ultra-sensitive methods able to identify the minute subclones as a source of possible resistance to treatment, and detection of secondary molecular events from the circulating tumor cells or circulating cell-free DNA are potential solutions how to handle this issue.
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Affiliation(s)
- Aleš Ryška
- The Fingerland Department of Pathology, Charles University Medical Faculty Hospital, 500 05, Hradec Králové, Czech Republic.
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18
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Al-Shamsi HO, Jones J, Fahmawi Y, Dahbour I, Tabash A, Abdel-Wahab R, Abousamra AOS, Shaw KR, Xiao L, Hassan MM, Kipp BR, Kopetz S, Soliman AS, McWilliams RR, Wolff RA. Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern. J Gastrointest Oncol 2016; 7:882-902. [PMID: 28078112 DOI: 10.21037/jgo.2016.11.02] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The frequency rates of mutations such as KRAS, NRAS, BRAF, and PIK3CA in colorectal cancer (CRC) differ among populations. The aim of this study was to assess mutation frequencies in the Arab population and determine their correlations with certain clinicopathological features. METHODS Arab patients from the Arab Gulf region and a population of age- and sex-matched Western patients with CRC whose tumors were evaluated with next-generation sequencing (NGS) were identified and retrospectively reviewed. The mutation rates of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC were recorded, along with clinicopathological features. Other somatic mutation and their rates were also identified. Fisher's exact test was used to determine the association between mutation status and clinical features. RESULTS A total of 198 cases were identified; 99 Arab patients and 99 Western patients. Fifty-two point seven percent of Arab patients had stage IV disease at initial presentation, 74.2% had left-sided tumors. Eighty-nine point two percent had tubular adenocarcinoma and 10.8% had mucinous adenocarcinoma. The prevalence rates of KRAS, NRAS, BRAF, PIK3CA, TP53, APC, SMAD, FBXW7 mutations in Arab population were 44.4%, 4%, 4%, 13.1%, 52.5%, 27.3%, 2% and 3% respectively. Compared to 48.4%, 4%, 4%, 12.1%, 47.5%, 24.2%, 11.1% and 0% respectively in matched Western population. Associations between these mutations and patient clinicopathological features were not statistically significant. CONCLUSIONS This is the first study to report comprehensive hotspot mutations using NGS in Arab patients with CRC. The frequency of KRAS, NRAS, BRAF, TP53, APC and PIK3CA mutations were similar to reported frequencies in Western population except SMAD4 that had a lower frequency and higher frequency of FBXW7 mutation.
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Affiliation(s)
- Humaid O Al-Shamsi
- Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA;; Khalifa Bin Zayed Al Nahyan Foundation, Abu Dhabi, United Arab Emirates;; Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jeremy Jones
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Yazan Fahmawi
- Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ibrahim Dahbour
- Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Aziz Tabash
- Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Reham Abdel-Wahab
- Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA;; Clinical Oncology Department, Assiut University, Assiut, Egypt
| | - Ahmed O S Abousamra
- Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Kenna R Shaw
- Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lianchun Xiao
- Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Manal M Hassan
- Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Benjamin R Kipp
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Amr S Soliman
- Department of Epidemiology, the University of Nebraska Medical Center, Omaha, Nebraska, USA
| | | | - Robert A Wolff
- Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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19
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Li WM, Hu TT, Zhou LL, Feng YM, Wang YY, Fang J. Highly sensitive detection of the PIK3CA (H1047R) mutation in colorectal cancer using a novel PCR-RFLP method. BMC Cancer 2016; 16:454. [PMID: 27405731 PMCID: PMC4941018 DOI: 10.1186/s12885-016-2493-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 06/28/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The PIK3CA (H1047R) mutation is considered to be a potential predictive biomarker for EGFR-targeted therapies. In this study, we developed a novel PCR-PFLP approach to detect the PIK3CA (H1047R) mutation in high effectiveness. METHODS A 126-bp fragment of PIK3CA exon-20 was amplified by PCR, digested with FspI restriction endonuclease and separated by 3 % agarose gel electrophoresis for the PCR-RFLP analysis. The mutant sequence of the PIK3CA (H1047R) was spiked into the corresponding wild-type sequence in decreasing ratios for sensitivity analysis. Eight-six cases of formalin-fixed paraffin-embedded colorectal cancer (CRC) specimens were subjected to PCR-RFLP to evaluate the applicability of the method. RESULTS The PCR-RFLP method had a capability to detect as litter as 0.4 % of mutation, and revealed 16.3 % of the PIK3CA (H1047R) mutation in 86 CRC tissues, which was significantly higher than that discovered by DNA sequencing (9.3 %). A positive association between the PIK3CA (H1047R) mutation and the patients' age was first found, except for the negative relationship with the degree of tumor differentiation. In addition, the highly sensitive detection of a combinatorial mutation of PIK3CA, KRAS and BRAF was achieved using individual PCR-RFLP methods. CONCLUSIONS We developed a sensitive, simple and rapid approach to detect the low-abundance PIK3CA (H1047R) mutation in real CRC specimens, providing an effective tool for guiding cancer targeted therapy.
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Affiliation(s)
- Wan-Ming Li
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Ting-Ting Hu
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Lin-Lin Zhou
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Yi-Ming Feng
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Yun-Yi Wang
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, People's Republic of China
| | - Jin Fang
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, People's Republic of China.
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20
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miRs-134 and -370 function as tumor suppressors in colorectal cancer by independently suppressing EGFR and PI3K signalling. Sci Rep 2016; 6:24720. [PMID: 27095166 PMCID: PMC4837379 DOI: 10.1038/srep24720] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 04/04/2016] [Indexed: 01/07/2023] Open
Abstract
Growth factor receptor signalling plays a central and critical role in colorectal cancer. Most importantly, the EGFR signalling cascade involving PI3K/AKT/mTOR and Raf/MEK/ERK pathways are particularly relevant, since they are commonly activated in several cancer entities, including colorectal cancer. In this study, we show that miRs-134 and -370 are both capable of regulating these pathways by targeting EGFR and PIK3CA. In three different colorectal cancer cell lines (DLD1, HCT-116 and RKO), suppression of EGFR and PIK3CA through the enhanced expression of miR-134 or -370 led to a suppression of the key molecules of the PI3K/AKT/mTOR pathway. Furthermore, overexpression of miR-134 or -370 resulted in a significant reduction of cell proliferation, colony formation, migration, invasion and in-vivo tumor growth and metastasis. Concurrent experiments with small interfering RNAs targeting the prime targets show that our selected miRNAs exert a greater functional influence and affect more downstream molecules than is seen with silencing of the individual proteins. Taken together, these data indicate that miRs-134 and -370 are potential tumour suppressor miRNAs and could play a fundamental role in suppressing colorectal cancer tumorigenesis through their ability to co-ordinately regulate EGFR signalling cascade by independently targeting EGFR and PIK3CA.
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21
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BRAF, PIK3CA, and HER2 Oncogenic Alterations According to KRAS Mutation Status in Advanced Colorectal Cancers with Distant Metastasis. PLoS One 2016; 11:e0151865. [PMID: 26991109 PMCID: PMC4798471 DOI: 10.1371/journal.pone.0151865] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 03/04/2016] [Indexed: 02/08/2023] Open
Abstract
Background Anti-EGFR antibody–based treatment is an important therapeutic strategy for advanced colorectal cancer (CRC); despite this, several mutations—including KRAS, BRAF, and PIK3CA mutations, and HER2 amplification—are associated with the mechanisms underlying the development of resistance to anti-EGFR therapy. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC. Methods KRAS, BRAF, and PIK3CA mutations were determined by Cobas real-time polymerase chain reaction (PCR) in 191 advanced CRC patients with distant metastasis. Microsatellite instability (MSI) status was determined by a fragmentation assay and HER2 amplification was assessed by silver in situ hybridization. In addition, KRAS mutations were investigated by the Sanger sequencing method in 97 of 191 CRC cases. Results Mutations in KRAS, BRAF, and PIK3CA were found in 104 (54.5%), 6 (3.1%), and 25 (13.1%) cases of advanced CRC, respectively. MSI-high status and HER2 amplification were observed in 3 (1.6%) and 16 (8.4%) cases, respectively. PIK3CA mutations were more frequently found in KRAS mutant type (18.3%) than KRAS wild type (6.9%) (P = 0.020). In contrast, HER2 amplifications and BRAF mutations were associated with KRAS wild type with borderline significance (P = 0.052 and 0.094, respectively). In combined analyses with KRAS, BRAF and HER2 status, BRAF mutations or HER2 amplifications were associated with the worst prognosis in the wild type KRAS group (P = 0.004). When comparing the efficacy of detection methods, the results of real time PCR analysis revealed 56 of 97 (57.7%) CRC cases with KRAS mutations, whereas Sanger sequencing revealed 49 cases (50.5%). Conclusions KRAS mutations were found in 54.5% of advanced CRC patients. Our results support that subgrouping using PIK3CA and BRAF mutation or HER2 amplification status, in addition to KRAS mutation status, is helpful for managing advanced CRC patients.
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22
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Neumann JHL, Jung A, Kirchner T. [Molecular pathology of colorectal cancer]. DER PATHOLOGE 2016; 36:137-44. [PMID: 25777075 DOI: 10.1007/s00292-015-0005-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In recent years, several predictive and prognostic biomarkers have been established in colorectal cancer (CRC). The RAS-mutation status is widely applied in the daily routine diagnostic as predictive biomarker for treatment with EGFR-inhibitors. A BRAF- mutation has no predictive value in this context. The detection of high-grade microsatellite instability (MSI-H) is a predictive biomarker for response to 5-Fluoruracil-monotherapy. Prognostic biomarkers in CRC are the MSI-status and the mutational status of BRAF. According to the current WHO classification poorly and undifferentiated CRC and MSI-associated special morphological subtypes are molecular graded depending on their MSI-status. The detection of a BRAF-mutation in the context of microsatellite stability (MSS) is associated with a very poor prognosis and thus represents the most aggressive molecular subtype of CRC. In patients with positive Bethesda criteria a stepwise immunohistochemical and molecular diagnostic scheme is proposed.
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Affiliation(s)
- J H L Neumann
- Pathologisches Institut, Ludwig-Maximilians-Universität München, Thalkirchner Straße 36, 80337, München, Deutschland,
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23
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Papagiorgis PC. Segmental distribution of some common molecular markers for colorectal cancer (CRC): influencing factors and potential implications. Tumour Biol 2016; 37:5727-34. [PMID: 26842924 DOI: 10.1007/s13277-016-4913-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 01/25/2016] [Indexed: 02/07/2023] Open
Abstract
Proximal and distal colorectal cancers (CRCs) are regarded as distinct disease entities, evolving through different genetic pathways and showing multiple clinicopathological and molecular differences. Segmental distribution of some common markers (e.g., KRAS, EGFR, Ki-67, Bcl-2, COX-2) is clinically important, potentially affecting their prognostic or predictive value. However, this distribution is influenced by a variety of factors such as the anatomical overlap of tumorigenic molecular events, associations of some markers with other clinicopathological features (stage and/or grade), and wide methodological variability in markers' assessment. All these factors represent principal influences followed by intratumoral heterogeneity and geographic variation in the frequency of detection of particular markers, whereas the role of other potential influences (e.g., pre-adjuvant treatment, interaction between markers) remains rather unclear. Better understanding and elucidation of the various influences may provide a more accurate picture of the segmental distribution of molecular markers in CRC, potentially allowing the application of a novel patient stratification for treatment, based on particular molecular profiles in combination with tumor location.
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24
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Stahler A, Heinemann V, Giessen-Jung C, Crispin A, Schalhorn A, Stintzing S, Fischer von Weikersthal L, Vehling-Kaiser U, Stauch M, Quietzsch D, Held S, von Einem JC, Holch J, Neumann J, Kirchner T, Jung A, Modest DP. Influence of mRNA expression of epiregulin and amphiregulin on outcome of patients with metastatic colorectal cancer treated with 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as first-line treatment (FIRE 1-trial). Int J Cancer 2015; 138:739-46. [PMID: 26284333 DOI: 10.1002/ijc.29807] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 07/07/2015] [Accepted: 08/03/2015] [Indexed: 12/22/2022]
Abstract
Our aim was to investigate the impact of EREG and AREG mRNA expression (by RT-qPCR) in patients with metastatic colorectal cancer (mCRC). In addition, epidermal growth factor receptor (EGFR) expression (by immunohistochemistry) as well as RAS-and PIK3CA-mutations (by pyrosequencing) were assessed. Tumors of 208 mCRC patients receiving 5-fluorouracil/leucovorin plus irinotecan (FUFIRI) or irinotecan plus oxaliplatin (mIROX) within the FIRE-1 trial were analyzed for mutations. Molecular characteristics were correlated with response, progression-free survival (PFS), overall survival (OS). mRNA expression was evaluated using ROC-analysis in 192 tumors (AREG high n = 31 vs. low n = 161; EREG high n = 89 vs. low n = 103). High versus low AREG expression was associated with PFS of 10.0 versus 8.0 months (HR = 0.62, 95% CI: 0.402-0.940, p = 0.03) and OS of 24.6 versus 18.7 months (HR = 0.72, 95% CI: 0.476-1.078, p = 0.11). High versus low EREG expression correlated with prolonged PFS (9.4 vs. 6.8 months, HR = 0.62, 95% CI: 0.460-0.846, p = 0.002) and OS (25.8 vs. 15.5 months, HR = 0.48, 95% CI: 0.351-0.657, p < 0.001). The positive prognostic effect of high EREG expression was confirmed in a multivariate analysis and was neither affected by EGFR expression nor by mutations of RAS- and PIK3CA-genes. EREG expression appears as an independent prognostic marker in patients with mCRC receiving first-line irinotecan-based chemotherapy.
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Affiliation(s)
- A Stahler
- Department of Medicine III And Comprehensive Cancer Centre, University Hospital Grosshadern, University of Munich, Germany.,Institute of Pathology, University of Munich, Germany
| | - V Heinemann
- Department of Medicine III And Comprehensive Cancer Centre, University Hospital Grosshadern, University of Munich, Germany.,DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - C Giessen-Jung
- Department of Medicine III And Comprehensive Cancer Centre, University Hospital Grosshadern, University of Munich, Germany
| | - A Crispin
- Institute of Medical Informatics, Biometry, and Epidemiology, University of Munich, Germany
| | - A Schalhorn
- Department of Medicine III And Comprehensive Cancer Centre, University Hospital Grosshadern, University of Munich, Germany
| | - S Stintzing
- Department of Medicine III And Comprehensive Cancer Centre, University Hospital Grosshadern, University of Munich, Germany.,DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | | | | | - M Stauch
- Onkologische Schwerpunktpraxis in Kronach, Ambulantes Zentrum Für Hämatologie Und Onkologie, Kronach, Germany
| | | | - S Held
- ClinAssess GmbH, Leverkusen, Germany
| | - J C von Einem
- Department of Medicine III And Comprehensive Cancer Centre, University Hospital Grosshadern, University of Munich, Germany
| | - J Holch
- Department of Medicine III And Comprehensive Cancer Centre, University Hospital Grosshadern, University of Munich, Germany
| | - J Neumann
- Institute of Pathology, University of Munich, Germany.,DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - T Kirchner
- Institute of Pathology, University of Munich, Germany.,DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - A Jung
- Institute of Pathology, University of Munich, Germany.,DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - D P Modest
- Department of Medicine III And Comprehensive Cancer Centre, University Hospital Grosshadern, University of Munich, Germany.,DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
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25
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Beyer K, Altendorf-Hofmann A, Chen Y, Bickel K, Petersen I. KRAS and aneusomy of chromosomes 4, 10 and 12 in colorectal carcinomas. Pathol Res Pract 2015; 211:646-51. [DOI: 10.1016/j.prp.2015.05.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2015] [Revised: 05/10/2015] [Accepted: 05/20/2015] [Indexed: 01/17/2023]
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26
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Raja M, Zverev M, Seipel K, Williams GT, Clarke AR, Shaw PHS. Assessment of the In Vivo Activity of PI3K and MEK Inhibitors in Genetically Defined Models of Colorectal Cancer. Mol Cancer Ther 2015. [PMID: 26206338 DOI: 10.1158/1535-7163.mct-15-0223] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The objective of tailoring medicines for cancer patients according to the molecular profile of their disease holds great promise for the improvement of cancer therapy. Nevertheless, this approach has been limited, in part, due to the lack of predictive and informative preclinical studies. Herein, we describe an assessment of the therapeutic potential of targeting PI3K/mTOR and MAPK signaling in genetically defined mouse models of colorectal cancer mirroring disease subtypes targeted for novel therapy in the FOCUS4 trial. Our studies demonstrate that dual PI3K/mTOR inhibition is highly effective in invasive adenocarcinoma models characterized by combinatorial mutations in Apc and Pten; Apc and Kras; and Apc, Pten and Kras. MEK inhibition was effective in the combinatorial Apc and Kras setting, but had no impact in either Apc Pten mutants or in Apc Pten Kras triple mutants. Furthermore, we describe the importance of scheduling for combination studies and show that although no additional benefit is gained in Apc Pten mice, combination of PI3K/mTOR and MAPK inhibition leads to an additive benefit in survival in Apc Kras mice and a synergistic increase in survival in Apc Pten Kras mice. This is the first study using robust colorectal cancer genetically engineered mouse models to support the validity of PI3K/mTOR and MEK inhibitors as tailored therapies for colorectal cancer and highlight the potential importance of drug scheduling in the clinic.
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Affiliation(s)
- Meera Raja
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Matt Zverev
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, United Kingdom
| | - Katja Seipel
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, United Kingdom. University Hospital Bern, Bern, Switzerland
| | | | - Alan R Clarke
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, United Kingdom.
| | - Paul H S Shaw
- European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, United Kingdom
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27
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Michl M, Heinemann V, Jung A, Engel J, Kirchner T, Neumann J. Expression of cancer stem cell markers in metastatic colorectal cancer correlates with liver metastasis, but not with metastasis to the central nervous system. Pathol Res Pract 2015; 211:601-9. [PMID: 26092596 DOI: 10.1016/j.prp.2015.05.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Revised: 04/29/2015] [Accepted: 05/21/2015] [Indexed: 01/05/2023]
Abstract
INTRODUCTION In colorectal cancer (CRC), metastatic spread is supposed to be mainly driven by tumor cells with stem cell features. Only about 1% of all CRC patients develop metastasis to the central nervous system (CNS). The present study intended to analyze the correlation between the expression of cancer stem cell markers and patterns of liver or CNS metastases. MATERIAL AND METHODS Immunohistochemistry for β-catenin, CD133, CD44 and the mismatch-repair markers hMLH1 and hMSH2 was applied to primary specimen of two CRC cohorts with CNS (n=29) and exclusive liver metastasis (n=36). Furthermore, mutation analysis for KRAS exon 2 and BRAF exon 15 was performed. RESULTS The expression of nuclear β-catenin, CD44 and CD133 was associated with the development of liver metastasis, but not of CNS metastasis. CD133 expression was absent in CRC with solitary CNS metastasis. Combination of cancer stem cell markers revealed high discriminatory power for the prediction of different patterns of distant spread. KRAS mutation was more frequently detected in patients with CNS metastasis, but the mutational status of KRAS and BRAF failed to show correlation with clinico-pathological data or the results of immunohistochemistry. CONCLUSIONS This study demonstrates that deregulation of Wnt/β-catenin-signaling and high-grade expression of cancer stem cell markers correlate with metastasis to the liver, but not to the CNS. These data implicate that in CRC other mechanisms than deregulation of Wnt/β-catenin-signaling and acquisition of cancer stemness are required for formation of CNS metastasis.
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Affiliation(s)
- Marlies Michl
- Department of Medical Oncology, Klinikum Grosshadern and Comprehensive Cancer Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Volker Heinemann
- Department of Medical Oncology, Klinikum Grosshadern and Comprehensive Cancer Center, Ludwig-Maximilians-Universität München, Munich, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Andreas Jung
- German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Jutta Engel
- Munich Cancer Registry (MCR), Klinikum Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany; Institute of Medical Informatics, Biometry and Epidemiology (IBE), Ludwig-Maximilians-Universität München, Munich, Germany
| | - Thomas Kirchner
- German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Jens Neumann
- Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany.
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28
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Ormanns S, Neumann J, Horst D, Kirchner T, Jung A. WNT signaling and distant metastasis in colon cancer through transcriptional activity of nuclear β-Catenin depend on active PI3K signaling. Oncotarget 2015; 5:2999-3011. [PMID: 24930890 PMCID: PMC4102786 DOI: 10.18632/oncotarget.1626] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
We determined whether active PI3K signaling together with nuclear accumulation of β-Catenin is necessary to fully activate canonical WNT signaling and examined the association of both signaling pathways with colon cancer progression. Using reporter gene assays we examined the activation of β-Catenin mediated transcription upon PI3K inhibition with or without β-Catenin nuclear accumulation. Ectopically induced as well as constitutively active WNT signaling strictly required PI3K activity whereas PI3K inhibition had no effect on β-Catenin subcellular localization but impaired β-Catenin binding to WNT target gene promoters and decreased WNT target gene expression. Transcriptional activity of nuclear β-Catenin depended on active PI3K signaling as nuclear accumulation of β-Catenin failed to induce WNT reporter gene transcription upon PI3K inhibition. PI3K dependend transcriptional transactivation of β-Catenin relies on events beyond phosphorylation at the AKT target site serine 552, as S552D-phosphomimetic β-Catenin mutants were unable to restore WNT signaling when inhibiting PI3K. To study the prognostic value of PI3K pathway activation (activating PIK3CA mutations or loss of PTEN expression) and nuclear β-Catenin expression, both variables were determined in 55 matched pairs of primary right sided colon cancer cases with or without distant metastasis. Activating mutations in the PIK3CA gene or loss of PTEN expression did not correlate with distant metastasis while high nuclear β-Catenin expression combined with activation of the PI3K pathway identified cases in which distant metastasis had occurred. Activation of the PI3K pathway was not associated with nuclear β-Catenin expression. We conclude that the transcriptional activity of nuclear β-Catenin depends on PI3K activity. However, PI3K on its own does not affect β-Catenin subcellular localization. Both factors synergize for full WNT signaling activity and are associated with distant metastasis in colon cancer. Thus, the detection of high nuclear β-Catenin expression and simultaneous PI3K pathway activation identifies colon cancer patients with a high risk for distant metastasis.
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Affiliation(s)
- Steffen Ormanns
- Institute of Pathology, Ludwig Maximilians Universität, Munich, Germany
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29
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Danielsen SA, Eide PW, Nesbakken A, Guren T, Leithe E, Lothe RA. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochim Biophys Acta Rev Cancer 2014; 1855:104-21. [PMID: 25450577 DOI: 10.1016/j.bbcan.2014.09.008] [Citation(s) in RCA: 173] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 09/07/2014] [Indexed: 12/16/2022]
Abstract
PI3K/AKT signaling leads to reduced apoptosis, stimulates cell growth and increases proliferation. Under normal conditions, PI3K/AKT activation is tightly controlled and dependent on both extracellular growth signals and the availability of amino acids and glucose. Genetic aberrations leading to PI3K/AKT hyper-activation are observed at considerable frequency in all major nodes in most tumors. In colorectal cancer the most commonly observed pathway changes are IGF2 overexpression, PIK3CA mutations and PTEN mutations and deletions. Combined, these alterations are found in about 40% of large bowel tumors. In addition, but not mutually exclusive to these, KRAS mutations are observed at a similar frequency. There are however additional, less frequent and more poorly understood events that may also push the PI3K/AKT pathway into overdrive and thus promote malignant growth. Here we discuss aberrations of components at the genetic, epigenetic, transcriptional, post-transcriptional, translational and post-translational level where perturbations may drive excessive PI3K/AKT signaling. Integrating multiple molecular levels will advance our understanding of this cancer critical circuit and more importantly, improve our ability to pharmacologically target the pathway in view of clonal development, tumor heterogeneity and drug resistance mechanisms. In this review, we revisit the PI3K/AKT pathway cancer susceptibility syndromes, summarize the known aberrations at the different regulatory levels and the prognostic and predictive values of these alterations in colorectal cancer.
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Affiliation(s)
- Stine Aske Danielsen
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Peter Wold Eide
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Arild Nesbakken
- K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
| | - Tormod Guren
- K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Edward Leithe
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Ragnhild A Lothe
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
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30
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Guéguinou M, Gambade A, Félix R, Chantôme A, Fourbon Y, Bougnoux P, Weber G, Potier-Cartereau M, Vandier C. Lipid rafts, KCa/ClCa/Ca2+ channel complexes and EGFR signaling: Novel targets to reduce tumor development by lipids? BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2014; 1848:2603-20. [PMID: 25450343 DOI: 10.1016/j.bbamem.2014.10.036] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 10/15/2014] [Accepted: 10/22/2014] [Indexed: 12/29/2022]
Abstract
Membrane lipid rafts are distinct plasma membrane nanodomains that are enriched with cholesterol, sphingolipids and gangliosides, with occasional presence of saturated fatty acids and phospholipids containing saturated acyl chains. It is well known that they organize receptors (such as Epithelial Growth Factor Receptor), ion channels and their downstream acting molecules to regulate intracellular signaling pathways. Among them are Ca2+ signaling pathways, which are modified in tumor cells and inhibited upon membrane raft disruption. In addition to protein components, lipids from rafts also contribute to the organization and function of Ca2+ signaling microdomains. This article aims to focus on the lipid raft KCa/ClCa/Ca2+ channel complexes that regulate Ca2+ and EGFR signaling in cancer cells, and discusses the potential modification of these complexes by lipids as a novel therapeutic approach in tumor development. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
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Affiliation(s)
- Maxime Guéguinou
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Audrey Gambade
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Romain Félix
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Aurélie Chantôme
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Yann Fourbon
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Philippe Bougnoux
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France; Centre HS Kaplan, CHRU Tours, Tours F-37032, France
| | - Günther Weber
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Marie Potier-Cartereau
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France
| | - Christophe Vandier
- Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours F-37032, France; Université François Rabelais, Tours F-37032, France.
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Nummela P, Saarinen L, Thiel A, Järvinen P, Lehtonen R, Lepistö A, Järvinen H, Aaltonen LA, Hautaniemi S, Ristimäki A. Genomic profile of pseudomyxoma peritonei analyzed using next-generation sequencing and immunohistochemistry. Int J Cancer 2014; 136:E282-9. [DOI: 10.1002/ijc.29245] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Revised: 08/29/2014] [Accepted: 09/16/2014] [Indexed: 02/06/2023]
Affiliation(s)
- Pirjo Nummela
- Genome-Scale Biology Research Program, Research Programs Unit; University of Helsinki; Helsinki Finland
| | - Lilli Saarinen
- Genome-Scale Biology Research Program, Research Programs Unit; University of Helsinki; Helsinki Finland
| | - Alexandra Thiel
- Genome-Scale Biology Research Program, Research Programs Unit; University of Helsinki; Helsinki Finland
| | - Petrus Järvinen
- Department of Surgery; Helsinki University Central Hospital; Helsinki Finland
- Department of Urology; Helsinki University Central Hospital; Helsinki Finland
| | - Rainer Lehtonen
- Genome-Scale Biology Research Program, Research Programs Unit; University of Helsinki; Helsinki Finland
| | - Anna Lepistö
- Department of Surgery; Helsinki University Central Hospital; Helsinki Finland
| | - Heikki Järvinen
- Department of Surgery; Helsinki University Central Hospital; Helsinki Finland
| | - Lauri A Aaltonen
- Genome-Scale Biology Research Program, Research Programs Unit; University of Helsinki; Helsinki Finland
- Department of Medical Genetics; University of Helsinki; Helsinki Finland
| | - Sampsa Hautaniemi
- Genome-Scale Biology Research Program, Research Programs Unit; University of Helsinki; Helsinki Finland
| | - Ari Ristimäki
- Genome-Scale Biology Research Program, Research Programs Unit; University of Helsinki; Helsinki Finland
- Division of Pathology and Genetics; HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki; Helsinki Finland
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Bisht S, Ahmad F, Sawaimoon S, Bhatia S, Das BR. Molecular spectrum of KRAS, BRAF, and PIK3CA gene mutation: determination of frequency, distribution pattern in Indian colorectal carcinoma. Med Oncol 2014; 31:124. [PMID: 25073438 DOI: 10.1007/s12032-014-0124-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2014] [Accepted: 07/05/2014] [Indexed: 12/20/2022]
Abstract
Molecular evaluation of KRAS, BRAF, and PIK3CA mutation has become an important part in colorectal carcinoma evaluation, and their alterations may determine the therapeutic response to anti-EGFR therapy. The current study demonstrates the evaluation of KRAS, BRAF, and PIK3CA mutation using direct sequencing in 204 samples. The frequency of KRAS, BRAF, and PIK3CA mutations was 23.5, 9.8, and 5.9 %, respectively. Five different substitution mutations at KRAS codon 12 (G12S, G12D, G12A, G12V, and G12C) and one substitution type at codon 13 (G13D) were observed. KRAS mutations were significantly higher in patients who were >50 years, and were associated with moderate/poorly differentiated tumors and adenocarcinomas. All mutations in BRAF gene were of V600E type, which were frequent in patients who were ≤ 50 years. Unlike KRAS mutations, BRAF mutations were more frequent in well-differentiated tumors and right-sided tumors. PIK3CA-E545K was the most recurrent mutation while other mutations detected were T544I, Q546R, H1047R, G1049S, and D1056N. No significant association of PIK3CA mutation with age, tumor differentiation, location, and other parameters was noted. No concomitant mutation of KRAS and BRAF mutations was observed, while, interestingly, five cases showed concurrent mutation of KRAS and PIK3CA mutations. In conclusion, to our knowledge, this is the first study to evaluate the PIK3CA mutation in Indian CRC patients. The frequency of KRAS, BRAF, and PIK3CA was similar to worldwide reports. Furthermore, identification of molecular markers has unique strengths, and can provide insights into the pathogenic process and help optimize personalized prevention and therapy.
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Affiliation(s)
- Swati Bisht
- Research and Development, SRL Limited, Plot No 1, Prime Square Building, S.V. Road, Goregaon (W), Mumbai, 400062, India
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33
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Raj N, Saltz L. Biologic agents in the treatment of colorectal cancer: an update. COLORECTAL CANCER 2014. [DOI: 10.2217/crc.14.26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY Biologic agents are drugs that are made by living organisms. A number of these agents are now routinely used in the treatment of metastatic colorectal cancer. These biologic agents block aspects of specific signaling pathways. They are commonly presumed to have a more selective and targeted action in comparison to cytotoxic chemotherapy, although this assumption is not always borne out by data. These agents were developed with the goal of reducing the use of cytotoxic chemotherapy and thereby reducing the associated toxicities, however they are most commonly used concurrently with cytotoxics, and so the older toxicities often remain. This paper will provide a critical overview of the biologic agents that are currently used in the management of metastatic colorectal cancer, focusing on VEGF and the EGF receptor inhibitors. The rationale behind the use of these biologic agents, including the clinical trials incorporating these agents, will be discussed, and the toxicities associated with these agents will also be reviewed.
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Affiliation(s)
- Nitya Raj
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, New York, NY 10128, USA
| | - Leonard Saltz
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, New York, NY 10128, USA
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34
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Davies EJ, Marsh Durban V, Meniel V, Williams GT, Clarke AR. PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine. J Pathol 2014; 233:27-38. [PMID: 24293351 DOI: 10.1002/path.4312] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 11/22/2013] [Accepted: 11/26/2013] [Indexed: 12/15/2022]
Abstract
Mutation or loss of the genes PTEN and KRAS have been implicated in human colorectal cancer (CRC), and have been shown to co-occur despite both playing a role in the PI3' kinase (PI3'K) pathway. We investigated the role of these genes in intestinal tumour progression in vivo, using genetically engineered mouse models, with the aim of generating more representative models of human CRC. Intestinal-specific deletion of Pten and activation of an oncogenic allele of Kras was induced in wild-type (WT) mice and mice with a predisposition to adenoma development (Apc(fl/+) ). The animals were euthanized when they became symptomatic of a high tumour burden. Histopathological examination of the tissues was carried out, and immunohistochemistry used to characterize signalling pathway activation. Mutation of Pten and Kras resulted in a significant life-span reduction of mice predisposed to adenomas. Invasive adenocarcinoma was observed in these animals, with evidence of activation of the PI3'K pathway but no metastasis. However, mutation of Pten and Kras in WT animals not predisposed to adenomas led to perturbed homeostasis of the intestinal epithelium and the development of hyperplastic polyps, dysplastic sessile serrated adenomas and metastasizing adenocarcinomas with serrated features. These studies demonstrate synergism between Pten and Kras mutations in intestinal tumour progression, in an autochthonous and immunocompetent murine model, with potential application to preclinical drug testing. In particular, they show that Pten and Kras mutations alone predispose mice to the spectrum of serrated lesions that reflect the serrated pathway of CRC progression in humans.
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Affiliation(s)
- Emma J Davies
- Cardiff School of Biosciences, Cardiff University, UK
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35
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Stintzing S, Lenz HJ. A small cog in a big wheel: PIK3CA mutations in colorectal cancer. J Natl Cancer Inst 2013; 105:1775-6. [PMID: 24231451 DOI: 10.1093/jnci/djt330] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Sebastian Stintzing
- Affiliation of authors: USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA (SS, H-JL)
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