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Lee Y, Ko D, Yoon J, Kim S. TMEM52B-derived peptides inhibit generation of soluble E-cadherin and EGFR activity to suppress colon cancer growth and early metastasis. J Transl Med 2025; 23:146. [PMID: 40025509 PMCID: PMC11874797 DOI: 10.1186/s12967-025-06075-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 01/02/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND Transmembrane protein 52B (TMEM52B) is a novel gene expressed widely in various normal human tissues; however, the biological function of TMEM52B in cancer remains largely unknown. Previously, we demonstrated that TMEM52B is a novel modulator of E-cadherin and EGFR activity, and that it has tumor suppressor-like activity using both experimental and clinical analyses. Here, we hypothesized that the extracellular domain (ECD) of TMEM52B may exert tumor-suppressing activity. METHODS We designed and evaluated the therapeutic potential of TMEM52B ECD-derived peptides in vitro and in vivo. The molecular mechanisms underlying the anti-cancer activity of the peptides were explored. RESULTS TMEM52B ECD-derived peptides reduced cancer cell survival, invasion, and anchorage-independent growth, which was accompanied by decreased phosphorylation of ERK1/2 and AKT. The peptides maintained intact E-cadherin at organized cell-cell junctions, leading to reduced β-catenin activity. They also inhibited generation of soluble E-cadherin and activation of EGFR by binding directly to the E-cadherin ECD and interfering with the interaction between soluble E-cadherin and EGFR. Peptides fused to the Fc domain of human IgG1 efficiently inhibited tumor growth in a colon cancer xenograft model and reduced survival of circulating tumor cells in an early metastasis model. CONCLUSIONS These results strongly suggest that TMEM52B ECD-derived peptides could provide a platform for the development of novel anti-cancer therapeutics and furnish a useful tool for exploring the function of TMEM52B in modulating the interplay between E-cadherin and EGFR.
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Affiliation(s)
- Yunhee Lee
- Korea Research Institute of Bioscience and Biotechnology, Microbiome Convergence Research Center, 125 Gwahak-ro, Yuseong-gu, Daejon, 34141, Korea
| | - Dongjoon Ko
- Korea Research Institute of Bioscience and Biotechnology, Microbiome Convergence Research Center, 125 Gwahak-ro, Yuseong-gu, Daejon, 34141, Korea
- Department of Functional Genomics, Korea University of Science and Technology, Daejon, 34113, Korea
| | - Junghwa Yoon
- Korea Research Institute of Bioscience and Biotechnology, Microbiome Convergence Research Center, 125 Gwahak-ro, Yuseong-gu, Daejon, 34141, Korea
| | - Semi Kim
- Korea Research Institute of Bioscience and Biotechnology, Microbiome Convergence Research Center, 125 Gwahak-ro, Yuseong-gu, Daejon, 34141, Korea.
- Department of Functional Genomics, Korea University of Science and Technology, Daejon, 34113, Korea.
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2
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Bhattacharya S. An empirical review on the resistance mechanisms of epidermal growth factor receptor inhibitors and predictive molecular biomarkers in colorectal cancer. Crit Rev Oncol Hematol 2023; 183:103916. [PMID: 36717006 DOI: 10.1016/j.critrevonc.2023.103916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/06/2022] [Accepted: 01/20/2023] [Indexed: 01/29/2023] Open
Abstract
Despite advances in cytotoxic treatments, colorectal cancer remains a leading cause of death. Metastatic colorectal cancer (mCRC) patients have a poor prognosis despite improved treatments and more prolonged median survival. Monoclonal antibodies like cetuximab and panitumumab target the epidermal growth factor receptor (EGFR). They play an essential role in the treatment of metastatic colorectal cancer (mCRC) due to their efficacy in multiple phase III clinical trials across multiple treatment lines. It was discovered that anti-EGFR moAbs were only effective for a small number of patients. Mutations in KRAS and NRAS have been identified as biomarkers of drug resistance. New molecular predictors and prognostic markers are used clinically. The K-Ras mutation is the first molecular marker of a lack of response to EGFR-targeted therapy in K-Ras-mutant patients. Validating predictive and prognostic markers will improve cancer treatments. This article examines molecular markers that can predict colorectal cancer prognosis.
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Affiliation(s)
- Sankha Bhattacharya
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra 425405, India.
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Basal VEGF-A and ACE Plasma Levels of Metastatic Colorectal Cancer Patients Have Prognostic Value for First-Line Treatment with Chemotherapy Plus Bevacizumab. Cancers (Basel) 2022; 14:cancers14133054. [PMID: 35804826 PMCID: PMC9265004 DOI: 10.3390/cancers14133054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/14/2022] [Accepted: 06/20/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Molecular biology knowledge has enabled the incorporation of targeted therapies, such as the anti-angiogenic drug bevacizumab, into combined chemotherapy regimens for the treatment of metastatic colorectal cancer. However, to date, there are no reliable useful biomarkers to predict the efficacy of this anti-angiogenic therapy. The objective of this prospective study was to evaluate potential circulating plasma biomarkers in mCRC patients prior to the start of first-line treatment with chemotherapy plus bevacizumab. We found that high VEGF-A and low ACE plasma levels were associated with poor OS after treatment. Moreover, a simple scoring system combining both biomarkers efficiently stratified patients into high- or low-risk groups, which allows the selection of patients for anti-angiogenic therapy. Abstract The identification of factors that respond to anti-angiogenic therapy would represent a significant advance in the therapeutic management of metastatic-colorectal-cancer (mCRC) patients. We previously reported the relevance of VEGF-A and some components of the renin–angiotensin-aldosterone system (RAAS) in the response to anti-angiogenic therapy in cancer patients. Therefore, this prospective study aims to evaluate the prognostic value of basal plasma levels of VEGF-A and angiotensin-converting enzyme (ACE) in 73 mCRC patients who were to receive bevacizumab-based therapies as a first-line treatment. We found that high basal VEGF-A plasma levels were significantly associated with worse overall survival (OS) and progression-free survival (FPS). On the other hand, low ACE levels were significantly associated with poor OS. Importantly, a simple scoring system combining the basal plasma levels of VEGF-A and ACE efficiently stratified mCRC patients, according to OS, into high-risk or low-risk groups, prior to their treatment with bevacizumab. In conclusion, our study supports that VEGF-A and ACE may be potential biomarkers for selecting those mCRC patients who will most benefit from receiving chemotherapy plus bevacizumab treatment in first-line therapy. Additionally, our data reinforce the notion of a close association between the RAAS and the anti-angiogenic response in cancer.
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Amano T, Iijima H, Shinzaki S, Tashiro T, Iwatani S, Tani M, Otake Y, Yoshihara T, Sugimoto A, Egawa S, Yamaguchi S, Kinoshita K, Araki M, Hirao M, Sakakibara Y, Hiyama S, Ogawa H, Nagaike K, Murata J, Komori M, Okuda Y, Kizu T, Tsujii Y, Hayashi Y, Inoue T, Takahashi H, Mizushima T, Morii E, Takehara T. Vascular endothelial growth factor-A is an Immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma. BMC Cancer 2021; 21:978. [PMID: 34465291 PMCID: PMC8406832 DOI: 10.1186/s12885-021-08724-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 08/22/2021] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, β-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.
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Affiliation(s)
- Takahiro Amano
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hideki Iijima
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Shinichiro Shinzaki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Taku Tashiro
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shuko Iwatani
- Department of Internal Medicine, Osaka Police Hospital, Osaka, Japan
| | - Mizuki Tani
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuriko Otake
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takeo Yoshihara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Aya Sugimoto
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan
| | - Satoshi Egawa
- Department of Internal Medicine, Osaka Police Hospital, Osaka, Japan
| | - Shinjiro Yamaguchi
- Department of Gastroenterology, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan
| | - Kazuo Kinoshita
- Department of Gastroenterology, Otemae Hospital, Osaka, Japan
| | - Manabu Araki
- Department of Gastroenterology, National Hospital Organization Osaka Minami Medical Center, Kawachinagano, Osaka, Japan
| | - Motohiro Hirao
- Department of Gastroenterology and Hepatology, Osaka Rosai Hospital, Sakai, Osaka, Japan
| | - Yuko Sakakibara
- Department of Gastroenterology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Satoshi Hiyama
- Department of Gastroenterology, Japan Community Healthcare Organization Osaka Hospital, Osaka, Japan
| | - Hiroyuki Ogawa
- Department of Gastroenterology, Nishinomiya Municipal Central Hospital, Nishinomiya, Hyogo, Japan
| | - Koji Nagaike
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, Suita, Osaka, Japan
| | - Jun Murata
- Department of Gastroenterology, Higashiosaka City Medical Center, Higashiosaka, Osaka, Japan
| | - Masato Komori
- Department of Gastroenterology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Hyogo, Japan
| | - Yorihide Okuda
- Department of Gastroenterology, Saiseikai Senri Hospital, Suita, Osaka, Japan
| | - Takashi Kizu
- Department of Gastroenterology, Yao Municipal Hospital, Yao, Osaka, Japan
| | - Yoshiki Tsujii
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yoshito Hayashi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takahiro Inoue
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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Chang Z, Huang R, Fu W, Li J, Ji G, Huang J, Shi W, Yin H, Wang W, Meng T, Huang Z, Wei Q, Qin H. The Construction and Analysis of ceRNA Network and Patterns of Immune Infiltration in Colon Adenocarcinoma Metastasis. Front Cell Dev Biol 2020; 8:688. [PMID: 32850813 PMCID: PMC7417319 DOI: 10.3389/fcell.2020.00688] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 07/06/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Colon adenocarcinoma (COAD) is a malignant and lethal tumor in digestive system and distance metastasis lead to poor prognosis. The metastasis-specific ceRNAs (competitive endogenous RNAs) and tumor-infiltrating immune cells might associate with tumor prognosis and distance metastasis. Nonetheless, few studies have concentrated on ceRNAs and Immune cells in COAD. METHODS The gene expression profile and clinical information of COAD were downloaded from TCGA and divided into two groups: primary tumors with or without distance metastasis. We applied comprehensive bioinformatics methods to analyze differential expression genes (DEGs) related to metastasis and establish the ceRNA networks. The Cox analysis and Lasso regression were utilized to screen the pivotal genes and prevent overfitting. Based on them, the prognosis prediction nomograms were established. The cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm was then applied to screen significant tumor immune-infiltrating cells associated with COAD metastasis and established another prognosis prediction model. Ultimately, co-expression analysis was applied to explore the relationship between key genes in ceRNA networks and significant immune cells. Multiple databases and preliminary clinical specimen validation were used to test the expressions of key biomarkers at the cellular and tissue levels. RESULTS We explored 1 significantly differentially expressed lncRNA, 1 significantly differentially expressed miRNA, 8 survival-related immune-infiltrating cells, 5 immune cells associated with distance metastasis. Besides, 3 pairs of important biomarkers associated with COAD metastasis were also identified: T cells follicular helper and hsa-miR-125b-5p (R = -0.200, P < 0.001), Macrophages M0 and hsa-miR-125b-5p (R = 0.170, P < 0.001) and Macrophages M0 and FAS (R = -0.370, P < 0.001). Multidimensional validation and preliminary clinical specimen validation also supported the results. CONCLUSION In this research, we found some significant ceRNAs (FAS and hsa-miR-125b-5p) and tumor-infiltrating immune cells (T cells follicular helper and Macrophages M0) might related to distance metastasis and prognosis of COAD. The nomograms could assist scientific and medical researchers in clinical management.
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Affiliation(s)
- Zhengyan Chang
- Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Runzhi Huang
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
- Tongji University School of Medicine, Tongji University, Shanghai, China
| | - Wanting Fu
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiehan Li
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guo Ji
- Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jinglei Huang
- Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Weijun Shi
- Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Huabin Yin
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Weifeng Wang
- Department of Central Laboratory, Shanghai Tenth People’s Hospital, Shanghai, China
| | - Tong Meng
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Zongqiang Huang
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qing Wei
- Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Huanlong Qin
- Department of Gastrointestinal Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
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Torén W, Ansari D, Andersson R. Immunohistochemical investigation of prognostic biomarkers in resected colorectal liver metastases: a systematic review and meta-analysis. Cancer Cell Int 2018; 18:217. [PMID: 30602942 PMCID: PMC6307223 DOI: 10.1186/s12935-018-0715-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 12/18/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Many studies have investigated the prognostic role of biomarkers in colorectal liver metastases (CRLM). However, no biomarker has been established in routine clinical practice. The aim of this study was to scrutinize the current literature for biomarkers evaluated by immunohistochemistry as prognostic markers in patients with resected CRLM. METHODS A systematic review was performed according to the PRISMA guidelines. Articles were identified in the PubMed database with selected search terms and by cross-references search. The REMARK quality criteria were applied. Markers were included if they reported the prognostic impact of immunohistochemical markers in a multivariable setting in relation to overall survival (OS). A meta-analysis was conducted when more than one original article provided survival data of a marker. RESULTS In total, 26 biomarkers were identified as independent significant markers for OS in resected CRLM. These biomarkers were found to be involved in multiple oncogenic signalling pathways that control cell growth, apoptosis, angiogenesis and evasion of immune detection. Among these biomarker candidates were Ki-67, EGFR, p53, hTERT, CD34, TSP-1, KISS1, Aurora kinase A and CDX2. CD34 and TSP-1 were reported as significantly associated with survival by more than one study and where therefore pooled in a meta-analysis. CONCLUSION A number of independent prognostic biomarkers for resected CRLM were identified. However, most markers were evaluated in a retrospective setting with small patient cohorts, without external validation. Large, prospective, multicentre studies with standardised methods are needed before biomarkers can translated into the clinic.
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Affiliation(s)
- William Torén
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, SE-221 85 Lund, Sweden
| | - Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, SE-221 85 Lund, Sweden
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Lund University and Skåne University Hospital, SE-221 85 Lund, Sweden
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7
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Abbas M, Faggian A, Sintali DN, Khan GJ, Naeem S, Shi M, Dingding C. Current and future biomarkers in gastric cancer. Biomed Pharmacother 2018; 103:1688-1700. [DOI: 10.1016/j.biopha.2018.04.178] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/24/2018] [Accepted: 04/24/2018] [Indexed: 02/06/2023] Open
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8
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de Bree E, Rovers KP, Stamatiou D, Souglakos J, Michelakis D, de Hingh IH. The evolving management of small bowel adenocarcinoma. Acta Oncol 2018; 57:712-722. [PMID: 29381126 DOI: 10.1080/0284186x.2018.1433321] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 01/22/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Small bowel adenocarcinoma (SBA) is rare despite the fact that the small bowel represents the longest part and has the largest surface of all alimentary tract sections. Its incidence is 50-fold lower than that of colorectal carcinoma. It is often diagnosed at an advanced stage due to atypical and late symptoms, its low index of suspicion, difficult endoscopic access and poor detection by radiological imaging, resulting in impaired outcome. Due to its rarity and being molecularly a unique intestinal cancer, data regarding its optimal management are relatively sparse. MATERIAL AND METHODS A PubMed search was performed to identify relevant manuscripts that were recently published. Emerging data regarding the pathogenesis, the diagnosis and the treatment of SBA that resulted from recent research are discussed in this comprehensive review. RESULTS Genomic analysis has demonstrated that SBA is a molecularly unique intestinal cancer. Double balloon enteroscopy and capsule endoscopy are novel techniques which may result in earlier diagnosis and consequently in improvement of the generally poor prognosis. For clinically localized disease, the quality of surgery has recently been defined, with removal of at least 8-10 lymph nodes correlating with improved prognosis. Moreover, adjuvant chemotherapy seems to improve outcome of stage III disease. The combination of a fluoropyrimidine and oxaliplatin appears to be the most effective systemic chemotherapy for disseminated disease. Genomic profiling can identify potentially targetable genomic alterations in a significant proportion of SBA patients. The role of administration of targeted agents or immune checkpoint inhibitors is still unknown and subject of ongoing clinical trials. In the common case of peritoneal metastases, recent studies have shown that cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy may be an attractive treatment option in selected patients. CONCLUSIONS SBA is a rare and unique malignancy, whose diagnostic approach and treatment are evolving, resulting in improved outcome.
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Affiliation(s)
- Eelco de Bree
- a Department of Surgical Oncology , Medical School of Crete University Hospital , Heraklion , Greece
| | - Koen P Rovers
- b Department of Surgical Oncology , Catharina Hospital , Eindhoven , The Netherlands
| | - Dimitris Stamatiou
- a Department of Surgical Oncology , Medical School of Crete University Hospital , Heraklion , Greece
| | - John Souglakos
- c Department of Medical Oncology and Laboratory of Translational Oncology , Medical School of Crete University Hospital , Heraklion , Greece
| | - Dimosthenis Michelakis
- a Department of Surgical Oncology , Medical School of Crete University Hospital , Heraklion , Greece
| | - Ignace H de Hingh
- b Department of Surgical Oncology , Catharina Hospital , Eindhoven , The Netherlands
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Bendardaf R, El-Serafi A, Syrjänen K, Collan Y, Pyrhönen S. The effect of vascular endothelial growth factor-1 expression on survival of advanced colorectal cancer patients. Libyan J Med 2018; 12:1290741. [PMID: 28245709 PMCID: PMC5345584 DOI: 10.1080/19932820.2017.1290741] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Colorectal cancer is third leading cause of cancer mortality. About 60% of patients had already developed metastasis at the time of diagnosis. Vascular endothelial growth factor (VEGF) is crucial for the development of neovascularization and hence metastasis. This study aimed at investigating the relation between the expression of VEGF in biopsies from surgically dissected colon cancer and the survival of those patients. Biopsies were collected from 86 patients with advanced colon cancer and sections were stained by immunohistochemistry for VEGF. Patients received chemotherapy after the operation and were followed up for disease progression and survival. The clinical data were statistically analyzed with respect to the immunohistochemistry results. The survival of the patients was significantly longer in the patients for whom biopsies showed negative or weak expression of VEGF in comparison to those with moderate to high expression (p-value = 0.04). The expression of VEGF was more frequent in the patients who died as a consequence of the disease in comparison to the 10-year survivors. In conclusion, VEGF could be related to the survival of the patients with colorectal carcinoma and should be considered as a predictor of the prognosis.
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Affiliation(s)
- Riyad Bendardaf
- a Department of Medical Oncology , University Sharjah Hospital , Sharjah , United Arab Emirates.,b College of Medicine , University of Sharjah , Sharjah , United Arab Emirates
| | - Ahmed El-Serafi
- b College of Medicine , University of Sharjah , Sharjah , United Arab Emirates.,c Faculty of Medicine , Suez Canal University , Ismailia , Egypt
| | - Kari Syrjänen
- d Turku University Hospital and University of Turku , Turku , Finland
| | - Yrjö Collan
- d Turku University Hospital and University of Turku , Turku , Finland
| | - Seppo Pyrhönen
- d Turku University Hospital and University of Turku , Turku , Finland
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Antoniou G, Lee ATJ, Huang PH, Jones RL. Olaratumab in soft tissue sarcoma - Current status and future perspectives. Eur J Cancer 2018; 92:33-39. [PMID: 29413687 DOI: 10.1016/j.ejca.2017.12.026] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/13/2017] [Accepted: 12/25/2017] [Indexed: 12/16/2022]
Abstract
Recent randomised phase II trial data have indicated that the addition of olaratumab, a novel monoclonal antibody against platelet-derived growth factor receptor alpha (PDGFRα), to doxorubicin confers an unprecedented improvement in overall survival to patients with anthracycline-naïve advanced soft tissue sarcoma. However, this result was disproportionate with progression-free survival and response rate, and consequently there are unanswered questions regarding the precise mechanism of action of olaratumab. While preclinical data show that olaratumab specifically inhibits PDGFRα-mediated oncogenic signalling with attendant anti-tumour effects, a lack of correlation between pharmacodynamics markers of PDGFRα inhibition and clinical benefit from olaratumab suggest other mechanisms beyond modulation of downstream PDGFRα molecular pathways. Proposed mechanisms of olaratumab activity include engagement of anti-tumour immune responses and alterations of the tumour stroma, but these require further evaluation. Meanwhile, the drug-specific contribution of cytotoxic agents to olaratumab-containing combinations has yet to be characterised. Ongoing and future preclinical and translational studies, coupled with the anticipated results of a phase III trial that has completed enrolment, should provide greater insight into the efficacy and mode of action of olaratumab in soft tissue sarcomas.
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Affiliation(s)
| | - Alexander T J Lee
- Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK; Institute of Cancer Research, Fulham Road, London, SW3 6JJ, UK
| | - Paul H Huang
- Institute of Cancer Research, Fulham Road, London, SW3 6JJ, UK
| | - Robin L Jones
- Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK; Institute of Cancer Research, Fulham Road, London, SW3 6JJ, UK.
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11
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Nandi D, Cheema PS, Jaiswal N, Nag A. FoxM1: Repurposing an oncogene as a biomarker. Semin Cancer Biol 2017; 52:74-84. [PMID: 28855104 DOI: 10.1016/j.semcancer.2017.08.009] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 08/08/2017] [Accepted: 08/23/2017] [Indexed: 12/16/2022]
Abstract
The past few decades have witnessed a tremendous progress in understanding the biology of cancer, which has led to more comprehensive approaches for global gene expression profiling and genome-wide analysis. This has helped to determine more sophisticated prognostic and predictive signature markers for the prompt diagnosis and precise screening of cancer patients. In the search for novel biomarkers, there has been increased interest in FoxM1, an extensively studied transcription factor that encompasses most of the hallmarks of malignancy. Considering the attractive potential of this multifarious oncogene, FoxM1 has emerged as an important molecule implicated in initiation, development and progression of cancer. Bolstered with the skill to maneuver the proliferation signals, FoxM1 bestows resistance to contemporary anti-cancer therapy as well. This review sheds light on the large body of literature that has accumulated in recent years that implies that FoxM1 neoplastic functions can be used as a novel predictive, prognostic and therapeutic marker for different cancers. This assessment also highlights the key features of FoxM1 that can be effectively harnessed to establish FoxM1 as a strong biomarker in diagnosis and treatment of cancer.
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Affiliation(s)
- Deeptashree Nandi
- Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India
| | - Pradeep Singh Cheema
- Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India
| | - Neha Jaiswal
- Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India
| | - Alo Nag
- Department of Biochemistry, University of Delhi South Campus, New Delhi, 110021, India.
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12
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Prediction of novel target genes and pathways involved in irinotecan-resistant colorectal cancer. PLoS One 2017; 12:e0180616. [PMID: 28749961 PMCID: PMC5531462 DOI: 10.1371/journal.pone.0180616] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 06/14/2017] [Indexed: 01/02/2023] Open
Abstract
Background Acquired drug resistance to the chemotherapeutic drug irinotecan (the active metabolite of which is SN-38) is one of the significant obstacles in the treatment of advanced colorectal cancer (CRC). The molecular mechanism or targets mediating irinotecan resistance are still unclear. It is urgent to find the irinotecan response biomarkers to improve CRC patients’ therapy. Methods Genetic Omnibus Database GSE42387 which contained the gene expression profiles of parental and irinotecan-resistant HCT-116 cell lines was used. Differentially expressed genes (DEGs) between parental and irinotecan-resistant cells, protein-protein interactions (PPIs), gene ontologies (GOs) and pathway analysis were performed to identify the overall biological changes. The most common DEGs in the PPIs, GOs and pathways were identified and were validated clinically by their ability to predict overall survival and disease free survival. The gene-gene expression correlation and gene-resistance correlation was also evaluated in CRC patients using The Cancer Genomic Atlas data (TCGA). Results The 135 DEGs were identified of which 36 were upregulated and 99 were down regulated. After mapping the PPI networks, the GOs and the pathways, nine genes (GNAS, PRKACB, MECOM, PLA2G4C, BMP6, BDNF, DLG4, FGF2 and FGF9) were found to be commonly enriched. Signal transduction was the most significant GO and MAPK pathway was the most significant pathway. The five genes (FGF2, FGF9, PRKACB, MECOM and PLA2G4C) in the MAPK pathway were all contained in the signal transduction and the levels of those genes were upregulated. The FGF2, FGF9 and MECOM expression were highly associated with CRC patients’ survival rate but not PRKACB and PLA2G4C. In addition, FGF9 was also associated with irinotecan resistance and poor disease free survival. FGF2, FGF9 and PRKACB were positively correlated with each other while MECOM correlated positively with FGF9 and PLA2G4C, and correlated negatively with FGF2 and PRKACB after doing gene-gene expression correlation. Conclusion Targeting the MAPK signal transduction pathway through the targeting of the FGF2, FGF9, MECOM, PLA2G4C and PRKACB might increase tumor responsiveness to irinotecan treatment.
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Au TH, Wang K, Stenehjem D, Garrido-Laguna I. Personalized and precision medicine: integrating genomics into treatment decisions in gastrointestinal malignancies. J Gastrointest Oncol 2017; 8:387-404. [PMID: 28736627 PMCID: PMC5506274 DOI: 10.21037/jgo.2017.01.04] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 11/21/2016] [Indexed: 12/19/2022] Open
Abstract
The advent of next generation sequencing (NGS) technologies has advanced our understanding of the intrinsic biology of different gastrointestinal (GI) tumor types. The use of novel, more efficient sequencing platforms has improved turnaround times of sequencing results. This is providing real time opportunities to put precision medicine to the test. A number of early phase clinical trials are testing targeted therapies in unique molecularly characterized subsets of patients (baskets). While basket studies are gaining momentum, treatment failures serve to remind us that shifting from a histology-driven to a histology-agnostic approach is unlikely to be a failure-free strategy for a number of tumor types as recently learnt from vemurafenib failure in BRAF mutated metastatic colorectal cancer (mCRC). GI malignancies are clinically and molecularly heterogeneous. Unfortunately, development of biomarkers of response to therapy as well as targeted therapies for GI adenocarcinomas has fallen behind compared to other malignancies. Trastuzumab is the only FDA approved targeted therapy for GI adenocarcinomas for which a biomarker of response (HER2 amplifications) is available. In addition, RAS mutations are known to predict lack of response to epidermal growth factor receptor (EGFR) inhibitors in advanced colorectal cancer (CRC) patients. However, NGS has recently revealed that a number of actionable genetic aberrations are present at low prevalence across different GI malignancies. Prospective randomized clinical trials will determine whether matching actionable aberration with targeted therapy will contribute to improve survival in patients with GI malignancies. Here, we review current evidence for targeted therapies in GI malignancies, as well as application and pitfalls of NGS including tissue testing and liquid biopsies.
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Affiliation(s)
- Trang H. Au
- Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake City, Utah, USA
| | - Kai Wang
- OrigiMed, Shanghai 200000, China
| | - David Stenehjem
- Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake City, Utah, USA
- Center for Investigational Therapeutics, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Ignacio Garrido-Laguna
- Center for Investigational Therapeutics, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA
- Division of Oncology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA
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Stanel SC, Sjöberg J, Salmonson T, Foggi P, Caleno M, Melchiorri D, Gravanis I, Tzogani K, Pignatti F. European Medicines Agency approval summary: Zaltrap for the treatment of patients with oxaliplatin-resistant metastatic colorectal cancer. ESMO Open 2017; 2:e000190. [PMID: 28761750 PMCID: PMC5519808 DOI: 10.1136/esmoopen-2017-000190] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 03/16/2017] [Indexed: 12/13/2022] Open
Abstract
On 1 February 2013, a marketing authorisation valid throughout the European Union was issued for aflibercept (Zaltrap) in combination with irinotecan/5-fluorouracil/folinic acid chemotherapy for the treatment of adults with metastatic colorectal cancer resistant to or progressive after an oxaliplatin-containing regimen. Aflibercept is a recombinant fusion protein which blocks the activation of vascular endothelial growth factor (VEGF) receptors and the proliferation of endothelial cells, acting as a soluble decoy receptor that binds to VEGF-A with higher affinity than its native receptors, as well as placental growth factor and VEGF-B. The use of aflibercept was studied in a randomised, double-blind, placebo-controlled phase III study, in patients with metastatic colorectal cancer (mCRC) who had previously been treated with an oxaliplatin-based treatment with or without prior bevacizumab. Aflibercept (n=612) was compared with placebo (n=614), both in combination with FOLFIRI (infusional fluorouracil, leucovorin and irinotecan). The primary endpoint of the study was overall survival (OS). The median OS in the intent-to-treat population was 13.5 months in subjects treated with aflibercept compared with 12.1 months for subjects in the control arm (stratified HR=0.817, 95% CI 0.714 to 0.935, stratified pvalue=0.0032). The frequency of adverse events was higher in the aflibercept arm compared with the placebo arm, reflecting the toxicity profile of anti-VEGF agents in combination with chemotherapy. This paper is based on the scientific review of the application leading to approval of aflibercept in the EU. The detailed scientific assessment report and product information for this product are available on the European Medicines Agency website (http://www.ema.europa.eu). Trial registration number NCT00561470, Results.
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Affiliation(s)
| | - Jan Sjöberg
- Läkemedelsverket, Medical Products Agency, Uppsala, Sweden
| | | | - Paolo Foggi
- Agenzia Italiana del Farmaco, Italian Medicines Agency, Rome, Italy
| | | | - Daniela Melchiorri
- Department of Physiology and Pharmacology, University of Roma "La Sapienza", Rome, Italy
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Ahn HM, Ryu J, Song JM, Lee Y, Kim HJ, Ko D, Choi I, Kim SJ, Lee JW, Kim S. Anti-cancer Activity of Novel TM4SF5-Targeting Antibodies through TM4SF5 Neutralization and Immune Cell-Mediated Cytotoxicity. Am J Cancer Res 2017; 7:594-613. [PMID: 28255353 PMCID: PMC5327636 DOI: 10.7150/thno.15629] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 08/04/2016] [Indexed: 11/05/2022] Open
Abstract
The transmembrane four L6 family member 5 (TM4SF5) protein is a novel molecular target for the prevention and treatment of hepatocellular carcinoma. TM4SF5 is highly expressed in liver, colon, esophageal, and pancreatic cancers and is implicated in tumor progression. Here, we screened monoclonal antibodies that specifically bound to the extracellular loop 2 (EC2) of TM4SF5 from a phage-displayed murine antibody (single-chain variable fragment; scFv) library. We constructed and characterized chimeric antibodies, Ab27 and Ab79, of scFv fused with Fc domain of human IgG1. The affinity (KD) of Ab27 and Ab79 for soluble EC2 was approximately 9.2 nM and 16.9 nM, respectively, as determined by surface plasmon resonance analysis. Ab27 and Ab79 efficiently bound to native TM4SF5 on the cell surface were internalized into the cancer cells, leading to a decrease in cell surface TM4SF5. Ab27 and Ab79 inhibited the proliferation and invasion of TM4SF5-positive liver and colon cancer cells and reduced FAK and c-Src phosphorylation. Ab27 and Ab79 also enhanced anoikis sensitivity and reduced survivin. Ab27 mediated antibody-dependent cell-mediated cytotoxicity in vitro. Ab27 and Ab79 efficiently inhibited tumor growth in a liver cancer xenograft model. These results strongly support the further development of Ab27 as a novel anti-cancer agent in the clinic.
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Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer. Sci Rep 2016; 6:34523. [PMID: 27739445 PMCID: PMC5064353 DOI: 10.1038/srep34523] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 09/15/2016] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths. Molecularly targeted therapies (e.g. bevacizumab) have improved survival rates but drug resistance ultimately develops and newer therapies are required. We identified quininib as a small molecule drug with anti-angiogenic activity using in vitro, ex vivo and in vivo screening models. Quininib (2-[(E)-2-(Quinolin-2-yl) vinyl] phenol), is a small molecule drug (molecular weight 283.75 g/mol), which significantly inhibited blood vessel development in zebrafish embryos (p < 0.001). In vitro, quininib reduced endothelial tubule formation (p < 0.001), cell migration was unaffected by quininib and cell survival was reduced by quininib (p < 0.001). Using ex vivo human CRC explants, quininib significantly reduced the secretions of IL-6, IL-8, VEGF, ENA-78, GRO-α, TNF, IL-1β and MCP-1 ex vivo (all values p < 0.01). Quininib is well tolerated in mice when administered at 50 mg/kg intraperitoneally every 3 days and significantly reduced tumour growth of HT-29-luc2 CRC tumour xenografts compared to vehicle control. In addition, quininib reduced the signal from a αvβ3 integrin fluorescence probe in tumours 10 days after treatment initiation, indicative of angiogenic inhibition. Furthermore, quininib reduced the expression of angiogenic genes in xenografted tumours. Collectively, these findings support further development of quininib as a novel therapeutic agent for CRC.
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Targeting TRAP1 as a downstream effector of BRAF cytoprotective pathway: a novel strategy for human BRAF-driven colorectal carcinoma. Oncotarget 2016; 6:22298-309. [PMID: 26084290 PMCID: PMC4673164 DOI: 10.18632/oncotarget.4263] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 06/01/2015] [Indexed: 12/13/2022] Open
Abstract
The HSP90 chaperone TRAP1 is translational regulator of BRAF synthesis/ubiquitination, since BRAF down-regulation, ERK signaling inhibition and delay of cell cycle progression occur upon TRAP1 silencing/inhibition. Since TRAP1 is upregulated in human colorectal carcinomas (CRCs) and involved in protection from apoptosis and as human BRAF-driven CRCs are poorly responsive to anticancer therapies, the relationship between TRAP1 regulation of mitochondrial apoptotic pathway and BRAF antiapoptotic signaling has been further evaluated. This study reports that BRAF cytoprotective signaling involves TRAP1-dependent inhibition of the mitochondrial apoptotic pathway. It is worth noting that BRAF and TRAP1 interact and that the activation of BRAF signaling results in enhanced TRAP1 serine-phosphorylation, a condition associated with resistance to apoptosis. Consistently, a BRAF dominant-negative mutant prevents TRAP1 serine phosphorylation and restores drug sensitivity in BRAFV600E CRC drug-resistant cells with high TRAP1 levels. In addition, TRAP1 targeting by the mitochondria-directed HSP90 chaperones inhibitor gamitrinib induces apoptosis and inhibits colony formation in BRAF-driven CRC cells. Thus, TRAP1 is a downstream effector of BRAF cytoprotective pathway in mitochondria and TRAP1 targeting may represent a novel strategy to improve the activity of proapoptotic agents in BRAF-driven CRC cells.
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High serum levels of interleukin-6 in patients with advanced or metastatic colorectal cancer: the effect on the outcome and the response to chemotherapy plus bevacizumab. Surg Today 2016; 47:483-489. [PMID: 27549777 DOI: 10.1007/s00595-016-1404-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 07/12/2016] [Indexed: 12/19/2022]
Abstract
PURPOSE We evaluated the relationship of the pretreatment serum IL-6 levels with the outcome and treatment response in patients with advanced or metastatic colorectal cancer (CRC) who underwent bevacizumab-containing chemotherapy. METHODS In this retrospective study, the pretreatment serum IL-6 and plasma vascular endothelial growth factor (VEGF) levels were measured in 113 patients with metastatic CRC. The cut-off values for these measurements, as determined by a receiver operating characteristic curve analysis, were 4.3 and 66 pg/mL, respectively. The median follow-up period was 19 months (range 1-40 months). Sixty-three patients had primary cancer, and 38 had a metachronous recurrence. Thirty patients underwent curative resection, and 71 underwent chemotherapy, 53 of whom received bevacizumab-containing chemotherapy. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier and multivariate Cox proportional hazards regression analyses. RESULTS The plasma VEGF levels and positive KRAS mutation status were not associated with the outcomes. However, high serum IL-6 levels were significantly associated with poorer OS and PFS in comparison to low serum IL-6 levels. A Cox proportional hazards regression analysis showed that high serum IL-6 levels were an independent risk factor for a poor outcome. CONCLUSION In patients with metastatic CRC, high pretreatment serum IL-6 levels were associated with a poor outcome and bevacizumab resistance.
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Glucose Transporter 1 (SLC2A1) and Vascular Endothelial Growth Factor A (VEGFA) Predict Survival After Resection of Colorectal Cancer Liver Metastasis. Ann Surg 2016; 263:138-45. [PMID: 25563886 DOI: 10.1097/sla.0000000000001109] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To investigate the individual and combined prognostic value of HIF1α, SLC2A1, and vascular endothelial growth factor A (VEGFA) in a multi-institutional cohort of patients with resected colorectal cancer liver metastasis (CRCLM). BACKGROUND In the majority of patients with CRCLM, resection seems not to be curative, despite its curative intent. Overexpression of hypoxia-inducible factor 1α (HIF1α), glucose transporter 1 (SLC2A1; also known as GLUT1), and VEGFA has been associated with tumor progression and poor prognosis of patients with colorectal cancer (CRC). METHODS Tissue microarrays were generated using CRCLM and patient-matched primary CRC from patients who underwent CRCLM resection between 1990 and 2010. Prognostic value of HIF1α, SLC2A1, and VEGFA was determined by immunohistochemistry. A 500-fold cross-validated hazard rate ratio (HRRav) for overall survival was calculated. RESULTS HIF1α, SLC2A1, and VEGFA expression could be evaluated in 328, 350, and 335 patients, respectively. High SLC2A1 expression was associated with good prognosis (HRRav, 0.67; P (HRR >1) < 0.01) and high VEGFA expression to poor prognosis (HRRav, 1.84; P (HRR < 1) = 0.02), also after multivariate analysis including established clinicopathological prognostic variables (HRRav, 0.67; P (HRR > 1) < 0.01 and HRRav, 1.50; P (HRR < 1) = 0.02, respectively). SLC2A1 showed prognostic value particularly in patients treated with systemic therapy (P < 0.01), whereas the prognostic value of VEGFA expression was mainly observed in patients not treated with systemic therapy (P < 0.01). Prognosis was especially poor in patients with both low SLC2A1 and high VEGFA expression (P < 0.01). HIF1α expression was not associated with survival. CONCLUSIONS SLC2A1 and VEGFA expression are prognostic molecular biomarkers for patients with CRCLM with added value to established clinicopathological variables.
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Chen Y, Shi Y, Lin J, Ye YB, Wang XJ, Chen G, Guo ZQ. Combined Analysis of EGFR and PTEN Status in Patients With KRAS Wild-Type Metastatic Colorectal Cancer. Medicine (Baltimore) 2015; 94:e1698. [PMID: 26448020 PMCID: PMC4616741 DOI: 10.1097/md.0000000000001698] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
To determine the relationship between the expression of phosphatase and tensin homologue (PTEN) and epidermal growth factor receptor (EGFR) in metastatic colorectal cancer (mCRC) and the clinical outcome of cetuximab-containing chemotherapy. A total of 158 consecutive mCRC patients with wild-type KRAS status who received chemotherapy with or without cetuximab, and for whom tumor tissue was available, were enrolled. The EGFR and PTEN expression was determined by immunohistochemistry (IHC). A total of 158 mCRC patients with wild-type KRAS status were enrolled in the study; 51 patients received chemotherapy combined with cetuximab, 107 patients received chemotherapy alone. Patients who received chemotherapy combined with cetuximab had longer overall survival (OS) compared with patients who received chemotherapy alone. High EGFR expression was detected in 60 patients (38.0%), while normal PTEN expression was detected in 60 patients (59.5%). The PTEN status was significantly related with the histological grade. For patients who received chemotherapy combined with cetuximab the median OS of patients with high-expression of EGFR was longer than the OS of patients with low EGRF expression; 25.0 versus 19.0 months, P = 0.002. For patient with normal PTEN the median OS were longer than the median OS for patients with loss of PTEN; 24.0 versus 19.0 months, P = 0.026. The overall response rate (ORR) had a borderline association with EGFR and PTEN expression (P = 0.055 and 0.048, respectively). In a multivariate analysis, ECOG PS, EGFR status, chemotherapy ± cetuximab, and the interaction of EGFR or PTEN and chemotherapy ± cetuximab were independent prognostic factors for OS. Our findings show that chemotherapy combined with cetuximab demonstrated encouraging antitumor activity for mCRC patients with wild-type KRAS status. Especially, those who have high EGFR expression or normal PTEN expression were more likely to benefit from such a treatment strategy. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.
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Affiliation(s)
- Yu Chen
- From the Department of Medical Oncology, Fujian Provincial Cancer Hospital, Fujian Medical University Teaching Hospital (YC, JL, X-JW, Z-QG); The Union Clinical Medical College of Fujian Medical University (YC); Department of Molecular Pathology, Fujian Provincial Cancer Hospital, Fujian Medical University Teaching Hospital (YS, GC); Laboratory of Immuno-Oncology, Fujian Provincial Cancer Hospital, Fujian Medical University Teaching Hospital (YBY); and Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian Province, People's Republic of China (YBY, GC)
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Akkad J, Bochum S, Martens UM. Personalized treatment for colorectal cancer: novel developments and putative therapeutic strategies. Langenbecks Arch Surg 2015; 400:129-43. [DOI: 10.1007/s00423-015-1276-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 01/23/2015] [Indexed: 01/14/2023]
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Gong B, Liu WW, Nie WJ, Li DF, Xie ZJ, Liu C, Liu YH, Mei P, Li ZJ. MiR-21/RASA1 axis affects malignancy of colon cancer cells via RAS pathways. World J Gastroenterol 2015; 21:1488-97. [PMID: 25663768 PMCID: PMC4316091 DOI: 10.3748/wjg.v21.i5.1488] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Revised: 08/28/2014] [Accepted: 09/30/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To determine how the oncogene miR-21 regulates the RAS signaling pathways and affects colon cancer cell behaviors. METHODS RAS p21 GTPase activating protein 1 (RASA1) protein expression in six colon cancer cell lines was assessed by Western blot. Colon cancer RKO cells were chosen for transfection because they are KRAS wild type colon cancer cells whose RASA1 expression is significantly decreased. RKO cells were transfected with vectors overexpressing or down-regulating either miR-21 or RASA1. Furthermore, a luciferase reporter assay was used to determine whether RASA1 is a gene target of miR-21. Then, changes in mRNA and protein levels of RASA1, RAS-GTP, and other components of the RAS signaling pathways were assessed in transfected RKO cells by real-time quantitative reverse transcription-polymerase chain reaction, Western blot and immunoprecipitation. Finally, cell proliferation, apoptosis, invasion, and tumor formation ability were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye assay, flow cytometry, transwell assay, and animal experiment, respectively. RESULTS RASA1 protein levels were significantly decreased in RKO cells compared with the other 5 colon cancer cell lines, and RASA1 was confirmed as a target gene of miR-21. Interestingly, RASA1 mRNA and protein levels in pre-miR-21-LV (up-regulation of miR-21) cells were lower than those in anti-miR-21-LV (down-regulation of miR-21) cells (P < 0.05). In addition, pre-miR-21-LV or siRASA1 (down-regulation of RASA1) cells showed higher cell proliferation, reduced apoptosis, increased expression of RAS-GTP, p-AKT, Raf-1, KRAS, and p-ERK1/2, and higher invasion and tumor formation ability, compared with control, anti-miR-21-LV or pcDNA3.1-RASA1 (up-regulation of RASA1) cells (P < 0.05). CONCLUSION RASA1 is a target gene of miR-21, which promotes malignant behaviors of RKO cells through regulation of RASA1 expression.
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Mohamed Suhaimi NA, Foong YM, Lee DYS, Phyo WM, Cima I, Lee EXW, Goh WL, Lim WY, Chia KS, Kong SL, Gong M, Lim B, Hillmer AM, Koh PK, Ying JY, Tan MH. Non-invasive sensitive detection of KRAS and BRAF mutation in circulating tumor cells of colorectal cancer patients. Mol Oncol 2015; 9:850-60. [PMID: 25605225 DOI: 10.1016/j.molonc.2014.12.011] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Revised: 12/22/2014] [Accepted: 12/27/2014] [Indexed: 12/28/2022] Open
Abstract
Characterization of genetic alterations in tumor biopsies serves as useful biomarkers in prognosis and treatment management. Circulating tumor cells (CTCs) obtained non-invasively from peripheral blood could serve as a tumor proxy. Using a label-free CTC enrichment strategy that we have established, we aimed to develop sensitive assays for qualitative assessment of tumor genotype in patients. Blood consecutively obtained from 44 patients with local and advanced colorectal cancer and 18 healthy donors were enriched for CTCs using a size-based microsieve technology. To screen for CTC mutations, we established high-resolution melt (HRM) and allele-specific PCR (ASPCR) KRAS-codon 12/13- and BRAF-codon 600- specific assays, and compared the performance with pyrosequencing and Sanger sequencing. For each patient, the resulting CTC genotypes were compared with matched tumor and normal tissues. Both HRM and ASPCR could detect as low as 1.25% KRAS- or BRAF-mutant alleles. HRM detected 14/44 (31.8%) patients with KRAS mutation in CTCs and 5/44 (11.3%) patients having BRAF mutation in CTCs. ASPCR detected KRAS and BRAF mutations in CTCs of 10/44 (22.7%) and 1/44 (2.3%) patients respectively. There was an increased detection of mutation in blood using these two methods. Comparing tumor tissues and CTCs mutation status using HRM, we observed 84.1% concordance in KRAS genotype (p = 0.000129, Fishers' exact test; OR = 38.7, 95% CI = 4.05-369) and 90.9% (p = 0.174) concordance in BRAF genotype. Our results demonstrate that CTC enrichment, coupled with sensitive mutation detection methods, may allow rapid, sensitive and non-invasive assessment of tumor genotype.
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Affiliation(s)
| | - Yu Miin Foong
- Institute of Bioengineering and Nanotechnology, Singapore
| | | | - Wai Min Phyo
- Institute of Bioengineering and Nanotechnology, Singapore
| | - Igor Cima
- Institute of Bioengineering and Nanotechnology, Singapore
| | | | - Wei Lin Goh
- Fortis Surgical Hospital Singapore, Singapore
| | - Wei-Yen Lim
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Kee Seng Chia
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | | | - Min Gong
- Genome Institute of Singapore, Singapore
| | - Bing Lim
- Genome Institute of Singapore, Singapore
| | | | - Poh Koon Koh
- Institute of Bioengineering and Nanotechnology, Singapore; Fortis Surgical Hospital Singapore, Singapore
| | - Jackie Y Ying
- Institute of Bioengineering and Nanotechnology, Singapore
| | - Min-Han Tan
- Institute of Bioengineering and Nanotechnology, Singapore; National Cancer Centre Singapore, Singapore.
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Chabu C, Xu T. Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth. Development 2014; 141:4729-39. [PMID: 25411211 DOI: 10.1242/dev.108092] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Oncogenic mutations in Ras deregulate cell death and proliferation to cause cancer in a significant number of patients. Although normal Ras signaling during development has been well elucidated in multiple organisms, it is less clear how oncogenic Ras exerts its effects. Furthermore, cancers with oncogenic Ras mutations are aggressive and generally resistant to targeted therapies or chemotherapy. We identified the exocytosis component Sec15 as a synthetic suppressor of oncogenic Ras in an in vivo Drosophila mosaic screen. We found that oncogenic Ras elevates exocytosis and promotes the export of the pro-apoptotic ligand Eiger (Drosophila TNF). This blocks tumor cell death and stimulates overgrowth by activating the JNK-JAK-STAT non-autonomous proliferation signal from the neighboring wild-type cells. Inhibition of Eiger/TNF exocytosis or interfering with the JNK-JAK-STAT non-autonomous proliferation signaling at various steps suppresses oncogenic Ras-mediated overgrowth. Our findings highlight important cell-intrinsic and cell-extrinsic roles of exocytosis during oncogenic growth and provide a new class of synthetic suppressors for targeted therapy approaches.
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Affiliation(s)
- Chiswili Chabu
- Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536, USA
| | - Tian Xu
- Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536, USA
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Stein A, Bokemeyer C. How to select the optimal treatment for first line metastatic colorectal cancer. World J Gastroenterol 2014; 20:899-907. [PMID: 24574764 PMCID: PMC3921543 DOI: 10.3748/wjg.v20.i4.899] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 10/27/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
Choice of first line treatment for patients with metastatic colorectal cancer (mCRC) is based on tumour and patient related factors and molecular information for determination of individual treatment aim and thus treatment intensity. Recent advances (e.g., extended RAS testing) enable tailored patient assignment to the most beneficial treatment approach. Besides fluoropyrimidines, irinotecan and oxaliplatin, a broad variety of molecular targeting agents are currently available, e.g., anti-angiogenic agents (bevacizumab) and epidermal growth factor receptor (EGFR) antibodies (cetuximab, panitumumab) for first line treatment of mCRC. Although some combinations should be avoided (e.g., oral or bolus fluoropyrimidines, oxaliplatin and EGFR antibodies), treatment options range from single agent to highly effective four-drug regimen. Preliminary data comparing EGFR antibodies and bevacizumab, both with chemotherapy, seem to favour EGFR antibodies in RAS wildtype disease. However, choosing the most appropriate treatment approach for mCRC patients remains a complex issue, with numerous open questions.
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Pakladok T, Hosseinzadeh Z, Almilaji A, Lebedeva A, Shumilina E, Alesutan I, Lang F. Up-regulation of hERG K⁺ channels by B-RAF. PLoS One 2014; 9:e87457. [PMID: 24475291 PMCID: PMC3903650 DOI: 10.1371/journal.pone.0087457] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 12/26/2013] [Indexed: 11/19/2022] Open
Abstract
Human ether-a-go-go related-gene K⁺ channels (hERG) participate in the regulation of tumor cell proliferation and apoptosis. HERG channel activity is up-regulated by growth factors. Kinases sensitive to growth factor signaling include the serine/threonine protein kinase B-RAF. The present study thus explored whether B-RAF influences hERG channel expression and activity. To this end, hERG channels were expressed in Xenopus oocytes with or without wild-type B-RAF, hERG channel activity was determined utilizing dual-electrode voltage clamp and hERG protein abundance in the cell membrane was analyzed utilizing confocal microscopy as well as chemiluminescence. Moreover, in rhabdomyosarcoma RD cells the effect of B-RAF inhibitor PLX-4720 on hERG-mediated current was quantified by whole-cell patch clamp and hERG cell surface protein abundance by utilizing biotinylation of cell surface proteins as well as flow cytometry. As a result, co-expression of wild-type B-RAF in hERG-expressing Xenopus oocytes significantly increased hERG channel activity and hERG channel protein abundance in the cell membrane. Treatment for 24 hours of B-RAF and hERG-expressing Xenopus oocytes with B-RAF inhibitor PLX-4720 (10 µM) significantly decreased hERG-mediated current and hERG cell surface expression. Similarly, in rhabdomyosarcoma RD cells, treatment for 24 hours with B-RAF inhibitor PLX-4720 significantly decreased hERG cell membrane protein abundance and hERG-mediated current. In conclusion, B-RAF is a powerful regulator of hERG channel activity and cell surface hERG protein abundance.
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Affiliation(s)
| | | | - Ahmad Almilaji
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - Aleksandra Lebedeva
- Department of Physiology, University of Tübingen, Tübingen, Germany
- Department of Immunology, Institute of Experimental Medicine, St. Petersburg, Russia
| | | | - Ioana Alesutan
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - Florian Lang
- Department of Physiology, University of Tübingen, Tübingen, Germany
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Leiphrakpam PD, Agarwal E, Mathiesen M, Haferbier KL, Brattain MG, Chowdhury S. In vivo analysis of insulin-like growth factor type 1 receptor humanized monoclonal antibody MK-0646 and small molecule kinase inhibitor OSI-906 in colorectal cancer. Oncol Rep 2013; 31:87-94. [PMID: 24173770 PMCID: PMC3868504 DOI: 10.3892/or.2013.2819] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 09/20/2013] [Indexed: 01/15/2023] Open
Abstract
The development and characterization of effective anticancer drugs against colorectal cancer (CRC) is of urgent need since it is the second most common cause of cancer death. The study was designed to evaluate the effects of two IGF-1R antagonists, MK-0646, a recombinant fully humanized monoclonal antibody and OSI-906, a small molecule tyrosine kinase inhibitor on CRC cells. Xenograft study was performed on IGF-1R-dependent CRC cell lines for analyzing the antitumor activity of MK-0646 and OSI-906. Tumor proliferation and apoptosis were assessed using Ki67 and TUNEL assays, respectively. We also performed in vitro characterization of MK-0646 and OSI-906 treatment on CRC cells to identify mechanisms associated with drug-induced cell death. Exposure of the GEO and CBS tumor xenografts to MK-0646 or OSI-906 led to a decrease in tumor growth. TUNEL analysis showed an increase of approximately 45-55% in apoptotic cells in both MK-0646 and OSI-906 treated tumor samples. We report the novel finding that treatment with IGF-1R antagonists led to downregulation of X-linked inhibitor of apoptosis (XIAP) protein involved in cell survival and inhibition of cell death. In conclusion, IGF-1R antagonists (MK-0646 and OSI-906) demonstrated single agent inhibition of subcutaneous CRC xenograft growth. This was coupled to pro-apoptotic effects resulting in downregulation of XIAP and inhibition of cell survival. We report a novel mechanism by which MK-0646 and OSI-906 elicits cell death in vivo and in vitro. Moreover, these results indicate that MK-0646 and OSI-906 may be potential anticancer candidates for the treatment of patients with IGF-1R-dependent CRC.
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Affiliation(s)
- Premila D Leiphrakpam
- Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA
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28
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Cohn AL, Tabernero J, Maurel J, Nowara E, Sastre J, Chuah BYS, Kopp MV, Sakaeva DD, Mitchell EP, Dubey S, Suzuki S, Hei YJ, Galimi F, McCaffery I, Pan Y, Loberg R, Cottrell S, Choo SP. A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer. Ann Oncol 2013; 24:1777-1785. [PMID: 23510984 DOI: 10.1093/annonc/mdt057] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Targeted agents presently available for mutant KRAS metastatic colorectal cancer (mCRC) are bevacizumab and aflibercept. We evaluated the efficacy and safety of conatumumab (an agonistic monoclonal antibody against human death receptor 5) and ganitumab (a monoclonal antibody against the type 1 insulin-like growth factor receptor) combined with standard FOLFIRI chemotherapy as a second-line treatment in patients with mutant KRAS mCRC. PATIENTS AND METHODS Patients with mutant KRAS metastatic adenocarcinoma of the colon or rectum refractory to fluoropyrimidine- and oxaliplatin-based chemotherapy were randomized 1 : 1 : 1 to receive intravenous FOLFIRI plus conatumumab 10 mg/kg (Arm A), ganitumab 12 mg/kg (Arm B), or placebo (Arm C) Q2W. The primary end point was progression-free survival (PFS). RESULTS In total, 155 patients were randomized. Median PFS in Arms A, B, and C was 6.5 months (HR, 0.69; P = 0.147), 4.5 months (HR, 1.01; P = 0.998), and 4.6 months, respectively; median overall survival was 12.3 months (HR, 0.89; P = 0.650), 12.4 months (HR, 1.27; P = 0.357), and 12.0 months; and objective response rate was 14%, 8%, and 2%. The most common grade ≥3 adverse events in Arms A/B/C included neutropenia (30%/25%/18%) and diarrhea (18%/2%/10%). CONCLUSIONS Conatumumab, but not ganitumab, plus FOLFIRI was associated with a trend toward improved PFS. Both combinations had acceptable toxicity.
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Affiliation(s)
- A L Cohn
- Rocky Mountain Cancer Center, Denver, USA.
| | - J Tabernero
- Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona
| | - J Maurel
- Medical Oncology Department, Hospital Clinic de Barcelona, Barcelona, Spain
| | - E Nowara
- Maria Skodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - J Sastre
- Hospital Clinico San Carlos, Servicio de Oncologíca Medíca, Madrid, and Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid, Spain
| | - B Y S Chuah
- Department of Internal Medicine, National University Hospital, Singapore, Singapore
| | - M V Kopp
- Samara Regional Oncology Dispensary, Samara
| | - D D Sakaeva
- Clinical Oncology Dispensary of the Republic of Bashkortostan, Ufa, Russia
| | - E P Mitchell
- Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia
| | - S Dubey
- Amgen Inc., South San Francisco
| | | | | | | | | | | | | | | | - S-P Choo
- Medical Oncology, National Cancer Centre Singapore, Singapore
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Zenonos K, Kyprianou K. RAS signaling pathways, mutations and their role in colorectal cancer. World J Gastrointest Oncol 2013; 5:97-101. [PMID: 23799159 PMCID: PMC3682174 DOI: 10.4251/wjgo.v5.i5.97] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Revised: 03/26/2013] [Accepted: 04/11/2013] [Indexed: 02/05/2023] Open
Abstract
Two of the main cellular pathways in which the RAS protein operates are the mitogen-activated protein kinases (MAPK) and phosphoinositide-3 kinase (PI3K) pathways. In a normal cell, these are important in controlling several functions, such as cell growth and survival. It becomes self-evident that these events will be disrupted in a malignant cell with a deregulated MAPK or PI3K pathway. Mutations in genes involved in these pathways and interacting with RAS, as well as RAS itself will be discussed. The second part of this review concentrates on how crucial RAS signaling is in colorectal cancer progression, with references to treatment response and prognosis when RAS or other related mutations are present.
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Orr Gandy KA, Adada M, Canals D, Carroll B, Roddy P, Hannun YA, Obeid LM. Epidermal growth factor-induced cellular invasion requires sphingosine-1-phosphate/sphingosine-1-phosphate 2 receptor-mediated ezrin activation. FASEB J 2013; 27:3155-66. [PMID: 23629860 DOI: 10.1096/fj.13-228460] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Ezrin, radixin, and moesin (ERM) proteins link cortical actin to the plasma membrane and coordinate cellular events that require cytoskeletal rearrangement, including cell division, migration, and invasion. While ERM proteins are involved in many important cellular events, the mechanisms regulating their function are not completely understood. Our laboratory previously identified reciprocal roles for the sphingolipids ceramide and sphingosine-1-phosphate (S1P) in the regulation of ERM proteins. We recently showed that ceramide-induced activation of PP1α leads to dephosphorylation and inactivation of ERM proteins, while S1P results in phosphorylation and activation of ERM proteins. Following these findings, we aimed to examine known inducers of the SK/S1P pathway and evaluate their ability to regulate ERM proteins. We examined EGF, a known inducer of the SK/S1P pathway, for its ability to regulate the ERM family of proteins. We found that EGF induces ERM c-terminal threonine phosphorylation via activation of the SK/S1P pathway, as this was prevented by siRNA knockdown or pharmacological inhibition of SK. Using pharmacological, as well as genetic, knockdown approaches, we determined that EGF induces ERM phosphorylation via activation of S1PR2. In addition, EGF led to cell polarization in the form of lamellipodia, and this occurred through a mechanism involving S1PR2-mediated phosphorylation of ezrin T567. EGF-induced cellular invasion was also found to be dependent on S1PR2-induced T567 ezrin phosphorylation, such that S1PR2 antagonist, JTE-013, and expression of a dominant-negative ezrin mutant prevented cellular invasion toward EGF. In this work, a novel mechanism of EGF-stimulated invasion is unveiled, whereby S1P-mediated activation of S1PR2 and phosphorylation of ezrin T567 is required.
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Affiliation(s)
- K Alexa Orr Gandy
- Department of Molecular and Cellular Biology and Pathobiology, Medical University of South Carolina, Charleston, South Carolina, USA
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Raina K, Agarwal C, Wadhwa R, Serkova NJ, Agarwal R. Energy deprivation by silibinin in colorectal cancer cells: a double-edged sword targeting both apoptotic and autophagic machineries. Autophagy 2013; 9:697-713. [PMID: 23445752 DOI: 10.4161/auto.23960] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Small molecules with the potential to initiate different types of programmed cell death could be useful 'adjunct therapy' where current anticancer modalities fail to generate significant activity due to a defective apoptotic machinery or resistance of cancer cells to the specific death mechanism induced by that treatment. The current study identified silibinin, for the first time, as one such natural agent, having dual efficacy against colorectal cancer (CRC) cells. First, silibinin rapidly induced oxidative stress in CRC SW480 cells due to reactive oxygen species (ROS) generation with a concomitant dissipation of mitchondrial potential (ΔΨm) and cytochrome c release leading to mild apoptosis as a biological effect. However, with increased exposure to silibinin, cytoplasmic vacuolization intensified within the cells followed by sequestration of the organelles, which inhibits the further release of cytochrome c. Interestingly, this decrease in apoptotic response correlated with increased autophagic events as evidenced by tracking the dynamics of LC3-II within the cells. Mechanistic studies revealed that silibinin strongly inhibited PIK3CA-AKT-MTOR but activated MAP2K1/2-MAPK1/3 pathways for its biological effects. Corroborating these effects, endoplasmic reticulum stress was generated and glucose uptake inhibition as well as energy restriction were induced by silibinin, thus, mimicking starvation-like conditions. Further, the cellular damage to tumor cells by silibinin was severe and irreparable due to sustained interference in essential cellular processes such as mitochondrial metabolism, phospholipid and protein synthesis, suggesting that silibinin harbors a deadly 'double-edged sword' against CRC cells thereby further advocating its clinical effectiveness against this malignancy.
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Affiliation(s)
- Komal Raina
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Bustin SA, Murphy J. RNA biomarkers in colorectal cancer. Methods 2013; 59:116-25. [DOI: 10.1016/j.ymeth.2012.10.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Revised: 09/28/2012] [Accepted: 10/04/2012] [Indexed: 02/08/2023] Open
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Conte B, Kopetz S. Challenges and strategies for identifying biomarkers for colorectal cancer. COLORECTAL CANCER 2013; 2:487-489. [PMID: 25598846 DOI: 10.2217/crc.13.65] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- Bruno Conte
- Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 426, Houston, TX 77030, USA
| | - Scott Kopetz
- Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 426, Houston, TX 77030, USA
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Kara O, Duman BB, Kara B, Erdogan S, Parsak CK, Sakman G. Analysis of PTEN, VEGF, HER2 and P53 Status in Determining Colorectal Cancer Benefit from Bevacizumab Therapy. Asian Pac J Cancer Prev 2012; 13:6397-401. [DOI: 10.7314/apjcp.2012.13.12.6397] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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35
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Bagai R, Ma PC. The Role of the Insulin-like Growth Factor-1 Receptor (IGF-1R), Phosphatase and Tensin Homolog (PTEN), c-Met, and the PI3-Kinase Pathway in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2012. [DOI: 10.1007/s11888-012-0139-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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36
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Bettstetter M, Berezowska S, Keller G, Walch A, Feuchtinger A, Slotta-Huspenina J, Feith M, Drecoll E, Höfler H, Langer R. Epidermal growth factor receptor, phosphatidylinositol-3-kinase catalytic subunit/PTEN, and KRAS/NRAS/BRAF in primary resected esophageal adenocarcinomas: loss of PTEN is associated with worse clinical outcome. Hum Pathol 2012; 44:829-36. [PMID: 23158210 DOI: 10.1016/j.humpath.2012.08.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 07/31/2012] [Accepted: 08/02/2012] [Indexed: 01/18/2023]
Abstract
Alterations of the epidermal growth factor receptor (EGFR) can be observed in a significant subset of esophageal adenocarcinomas (EACs), and targeted therapy against EGFR may become an interesting approach for the treatment of these tumors. Mutations of KRAS, NRAS, BRAF, and phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) and deregulation of PTEN expression influence the responsiveness against anti-EGFR therapy in colorectal carcinomas. We investigated the prevalence of these events in a collection of 117 primary resected EACs, correlated the findings with EGFR expression and amplification, and determined their clinicopathologic impact. KRAS mutations were detected in 4 (3%) of 117 tumors (3× G12D and 1 G12V mutation). One tumor had a PIK3CA E545K mutation. Neither NRAS nor BRAF mutations were detected. Sixteen (14%) of 117 cases were negative for PTEN expression, determined by immunohistochemistry. Loss of PTEN was observed predominantly in advanced tumor stages (P = .004). There was no association between PTEN and EGFR status. Loss of PTEN was associated with shorter overall and disease-free survival (P < .001 each) and also an independent prognostic factor in multivariate analysis (P = .015). EGFR status had no prognostic impact in this case collection. In summary, loss of PTEN can be detected in a significant subset of EAC and is associated with an aggressive phenotype. Therefore, PTEN may be useful as a prognostic biomarker. In contrast, mutations of RAS/RAF/PIK3CA appear only very rarely, if at all, in EAC. A possible predictive role of PTEN in anti-EGFR treatment warrants further investigations, whereas determination of RAS/RAF/PIK3CA mutations may only have a minor impact in this context.
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Affiliation(s)
- Marcus Bettstetter
- Teilgemeinschaftspraxis Molekularpathologie Südbayern, D-81675 Munich, Germany
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Prognostic Impact of del(17p) and del(22q) as assessed by interphase FISH in sporadic colorectal carcinomas. PLoS One 2012; 7:e42683. [PMID: 22912721 PMCID: PMC3422354 DOI: 10.1371/journal.pone.0042683] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2011] [Accepted: 07/11/2012] [Indexed: 12/11/2022] Open
Abstract
Background Most sporadic colorectal cancer (sCRC) deaths are caused by metastatic dissemination of the primary tumor. New advances in genetic profiling of sCRC suggest that the primary tumor may contain a cell population with metastatic potential. Here we compare the cytogenetic profile of primary tumors from liver metastatic versus non-metastatic sCRC. Methodology/Principal Findings We prospectively analyzed the frequency of numerical/structural abnormalities of chromosomes 1, 7, 8, 13, 14, 17, 18, 20, and 22 by iFISH in 58 sCRC patients: thirty-one non-metastatic (54%) vs. 27 metastatic (46%) disease. From a total of 18 probes, significant differences emerged only for the 17p11.2 and 22q11.2 chromosomal regions. Patients with liver metastatic sCRC showed an increased frequency of del(17p11.2) (10% vs. 67%;p<.001) and del(22q11.2) (0% vs. 22%;p = .02) versusnon-metastatic cases. Multivariate analysis of prognostic factors for overall survival (OS) showed that the only clinical and cytogenetic parameters that had an independent adverse impact on patient outcome were the presence of del(17p) with a 17p11.2 breakpoint and del(22q11.2). Based on these two cytogenetic variables, patients were classified into three groups: low- (no adverse features), intermediate- (one adverse feature) and high-risk (two adverse features)- with significantly different OS rates at 5-years (p<.001): 92%, 53% and 0%, respectively. Conclusions/Significance Our results unravel the potential implication of del(17p11.2) in sCRC patients with liver metastasis as this cytogenetic alteration appears to be intrinsically related to an increased metastatic potential and a poor outcome, providing additional prognostic information to that associated with other cytogenetic alterations such as del(22q11.2). Additional prospective studies in larger series of patients would be required to confirm the clinical utility of the new prognostic markers identified.
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Clarke SJ, Karapetis CS, Gibbs P, Pavlakis N, Desai J, Michael M, Tebbutt NC, Price TJ, Tabernero J. Overview of biomarkers in metastatic colorectal cancer: tumour, blood and patient-related factors. Crit Rev Oncol Hematol 2012; 85:121-35. [PMID: 22762963 DOI: 10.1016/j.critrevonc.2012.06.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Revised: 05/31/2012] [Accepted: 06/07/2012] [Indexed: 02/07/2023] Open
Abstract
During the last 20 years there have been major therapeutic developments in colorectal cancer (CRC) with the introduction of multiple novel therapeutic agents into routine clinical practice. This has improved survival in both the adjuvant and advanced disease settings. However, improvements have come with substantial increases in expense to the community and potential toxicity to the patient. There has been substantial research to identify tumour factors in CRC that predict treatment response and survival outcomes. This research has identified clinically useful predictive biomarkers to aid clinical decision making, such as the presence or absence of KRAS gene mutations which can determine the benefit of using epidermal growth factor receptor (EGFR) inhibiting antibodies. However, less attention has been paid to the identification and impact of predictive patient-derived factors such as age, gender and the presence of comorbid conditions or evidence of a systemic inflammatory response. In this article, the current concepts of tumour and patient-related predictive factors in CRC management are reviewed.
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Affiliation(s)
- Stephen J Clarke
- Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia.
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40
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Kanthan R, Senger JL, Kanthan SC. Molecular events in primary and metastatic colorectal carcinoma: a review. PATHOLOGY RESEARCH INTERNATIONAL 2012; 2012:597497. [PMID: 22997602 PMCID: PMC3357597 DOI: 10.1155/2012/597497] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2011] [Accepted: 02/23/2012] [Indexed: 12/13/2022]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease, developing through a multipathway sequence of events guided by clonal selections. Pathways included in the development of CRC may be broadly categorized into (a) genomic instability, including chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP), (b) genomic mutations including suppression of tumour suppressor genes and activation of tumour oncogenes, (c) microRNA, and (d) epigenetic changes. As cancer becomes more advanced, invasion and metastases are facilitated through the epithelial-mesenchymal transition (EMT), with additional genetic alterations. Despite ongoing identification of genetic and epigenetic markers and the understanding of alternative pathways involved in the development and progression of this disease, CRC remains the second highest cause of malignancy-related mortality in Canada. The molecular events that underlie the tumorigenesis of primary and metastatic colorectal carcinoma are detailed in this manuscript.
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Affiliation(s)
- Rani Kanthan
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada S7N 0W8
- Royal University Hospital, Room 2868 G-Wing, 103 Hospital Drive, Saskatoon, SK, Canada S7N 0W8
| | - Jenna-Lynn Senger
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada S7N 0W8
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Hamfjord J, Stangeland AM, Hughes T, Skrede ML, Tveit KM, Ikdahl T, Kure EH. Differential expression of miRNAs in colorectal cancer: comparison of paired tumor tissue and adjacent normal mucosa using high-throughput sequencing. PLoS One 2012; 7:e34150. [PMID: 22529906 PMCID: PMC3328481 DOI: 10.1371/journal.pone.0034150] [Citation(s) in RCA: 131] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2011] [Accepted: 02/23/2012] [Indexed: 12/19/2022] Open
Abstract
We present the results of a global study of dysregulated miRNAs in paired samples of normal mucosa and tumor from eight patients with colorectal cancer. Although there is existing data of miRNA contribution to colorectal tumorigenesis, these studies are typically small to medium scale studies of cell lines or non-paired tumor samples. The present study is to our knowledge unique in two respects. Firstly, the normal and adjacent tumor tissue samples are paired, thus taking into account the baseline differences between individuals when testing for differential expression. Secondly, we use high-throughput sequencing, thus enabling a comprehensive survey of all miRNAs expressed in the tissues. We use Illumina sequencing technology to perform sequencing and two different tools to statistically test for differences in read counts per gene between samples: edgeR when using the pair information and DESeq when ignoring this information, i.e., treating tumor and normal samples as independent groups. We identify 37 miRNAs that are significantly dysregulated in both statistical approaches, 19 down-regulated and 18 up-regulated. Some of these miRNAs are previously published as potential regulators in colorectal adenocarcinomas such as miR-1, miR-96 and miR-145. Our comprehensive survey of differentially expressed miRNAs thus confirms some existing findings. We have also discovered 16 dysregulated miRNAs, which to our knowledge have not previously been associated with colorectal carcinogenesis: the following significantly down-regulated miR-490-3p, -628-3p/-5p, -1297, -3151, -3163, -3622a-5p, -3656 and the up-regulated miR-105, -549, -1269, -1827, -3144-3p, -3177, -3180-3p, -4326. Although the study is preliminary with only eight patients included, we believe the results add to the present knowledge on miRNA dysregulation in colorectal carcinogenesis. As such the results would serve as a robust training set for validation of potential biomarkers in a larger cohort study. Finally, we also present data supporting the hypothesis that there are differences in miRNA expression between adenocarcinomas and neuroendocrine tumors of the colon.
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Affiliation(s)
- Julian Hamfjord
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Astrid M. Stangeland
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Timothy Hughes
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Martina L. Skrede
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Kjell M. Tveit
- Department of Oncology, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Tone Ikdahl
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Elin H. Kure
- Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
- Department of Pathology, Oslo University Hospital, Oslo, Norway
- Department of Environmental and Health Studies, Faculty of Arts and Sciences, Telemark University College, Bø, Norway
- * E-mail:
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Abstract
Biomarkers reflective of the molecular and genetic heterogeneity in colorectal cancers now guide certain aspects of clinical management and offer great potential for enrichment, stratification, and identification of novel therapeutic targets in drug development. Using case-based examples, this article reviews biomarkers that have an established role in the clinical management of colorectal cancer: mismatch repair protein testing and KRAS and BRAF mutational analysis. A selection of biomarkers undergoing validation for future clinical application is presented, and the dynamic and challenging interface between biomarkers in research and clinical practice is discussed.
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Glimelius B, Cavalli-Björkman N. Metastatic colorectal cancer: current treatment and future options for improved survival. Medical approach--present status. Scand J Gastroenterol 2012; 47:296-314. [PMID: 22242568 DOI: 10.3109/00365521.2012.640828] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Metastatic colorectal cancer has a poor prognosis, and the majority of patients are left with palliative measures. The development seen using medical treatments are reviewed. MATERIAL AND METHODS A systematic approach to the literature-based evidence of effects from palliative chemotherapy and targeted drugs was aimed at. RESULTS The continuous improvements during the past 20-25 years have been documented in several large conclusive trials. At the end of the 1980s, the evidence that chemotherapy should be used at all was very limited, whereas presently most patients can be offered three lines of chemotherapy with or without a targeted drug based upon good scientific evidence. Median survival in trials has gradually improved from about 6 months to above 24 months in the most recent trials. Survival in the populations has, however, not improved to the same extent. Several important issues remain to be solved, such as the best sequence of treatments, what regimens to use in various situations, when to start and when to stop if a response is seen, whether cure may be possible in a small subset of patients, and socioeconomic issues. Integration of surgery and other local methods have further improved outcome for some individuals, but must be fine-tuned. CONCLUSIONS Progress has been rapid in advanced colorectal cancer. This is likely a result of well-designed trials in collaboration between academy and industry, showing a great interest in the disease. A multi-professional approach and future collaborations may hopefully introduce new treatment concepts, further improving outcome.
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Affiliation(s)
- Bengt Glimelius
- Department of Radiology, Oncology and Radiation Science, University of Uppsala, Uppsala, Sweden.
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Zhang D, Jiang H, Wang Y, Ma J. Pentoxifylline inhibits hepatic stellate cells proliferation via the Raf/ERK pathway. APMIS 2012; 120:572-81. [PMID: 22716212 DOI: 10.1111/j.1600-0463.2011.02868.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Accepted: 12/19/2011] [Indexed: 12/31/2022]
Abstract
Pentoxifylline (PTX), which is a xanthine derivative, is a well-known suppressor of tumor necrosis factor-alpha (TNF-alpha) production in inflammatory cells and has also been shown to inhibit collagen synthesis in hepatic stellate cells (HSCs) in vitro. The present study aimed to evaluate the effects of PTX on proliferation in HSCs as mediated by the Raf/MEK/extracellular-signal-regulated kinase (ERK) signaling pathway. The rat hepatic stellate cell line T6 and activated primary rat HSCs were used in this study. The proliferation rate of the cells treated with 1 mM PTX significantly decreased compared with that of the control in T6 cells (78.3 ± 6.03% at 12 h, 61.0 ± 7.55% at 24 h, and 44.7 ± 2.08% at 48 h, p < 0.05). PTX (1 mM) also decreased the fraction of the HSC population in the S and G2/M-phases of the cell cycle in primary activated rat HSCs. The Raf-1 inhibitor GW5074 and the ERK inhibitor U0126 had inhibitory effects that were similar to those of PTX on HSC proliferation. In addition, PTX inhibited the phosphorylation of Raf-1 (p-Raf-1) and ERK (p-ERK) in a dose- and time-dependent manner in HSCs. These data provide evidence that PTX suppresses HSC proliferation via the Raf/MEK/ERK pathway.
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Affiliation(s)
- Di Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, China
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Nowsheen S, Aziz K, Panayiotidis MI, Georgakilas AG. Molecular markers for cancer prognosis and treatment: have we struck gold? Cancer Lett 2011; 327:142-52. [PMID: 22120674 DOI: 10.1016/j.canlet.2011.11.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Revised: 11/16/2011] [Accepted: 11/17/2011] [Indexed: 12/22/2022]
Abstract
The last decade has witnessed an emerging role for molecular or biochemical markers indicating a specific cellular mechanism or tissue function, often called 'biomarkers'. Biomarkers such as altered DNA, proteins and inflammatory cytokines are critical in cancer research and strategizing treatment in the clinic. In this review we look at the application of biological indicators to cancer research and highlight their roles in cancer detection and treatment. With technological advances in gene expression, genomic and proteomic analysis, biomarker discovery is expanding fast. We focus on some of the predominantly used markers in different types of malignancies, their advantages, and their limitations. Finally we conclude by looking at the future of biomarkers, their utility in the tumorigenic studies, and the progress towards personalized treatment strategies.
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Affiliation(s)
- Somaira Nowsheen
- Department of Radiation Oncology, University of Alabama at Birmingham Comprehensive Cancer Center, 35294, USA
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Wang Z, Yuan X, Jiao N, Zhu H, Zhang Y, Tong J. CDH13 and FLBN3 gene methylation are associated with poor prognosis in colorectal cancer. Pathol Oncol Res 2011; 18:263-70. [PMID: 21796503 DOI: 10.1007/s12253-011-9437-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Accepted: 07/07/2011] [Indexed: 12/17/2022]
Abstract
The aim of this study was to identify potential epigenetic prognostic biomarkers for colorectal cancer (CRC) in the Chinese population. The methylation status of five tumor suppressor genes (CDH13, DLEC1, FBLN3, hMHL1 and RUNX3) was determined using manual microdissection followed by methylation-specific PCR in 85 paired CRC specimens and adjacent normal tissue. The results showed that methylation frequencies in cancerous tissues were 31.8% for CDH13, 37.6% for DLEC1, 38.8% for FBLN3, 22.4% for hMHL1 and 27.1% for RUNX3, all of which were significantly higher than in corresponding normal tissue. Furthermore, CDH13 methylation was associated with poor differentiation (P = 0.019) and tended to be predominant in advanced stages (P = 0.084); FBLN3 methylation was associated with advanced stages (P = 0.027) and lymph node metastasis (P = 0.029). Accordingly, the methylation status of CDH13 (P = 0.022), FBLN3 (P = 0.008), CDH13 and/or FBLN3 (P = 0.001) predicted adverse overall survival in CRC, while hMHL1 methylation showed a protective role in survival (P = 0.046). Cox proportional hazard models further indicated that CDH13 and/or FBLN3 methylation, but not that of hMHL1, was an independent prognostic factor for CRC. In conclusion, we found CDH13 and FBLN3 gene methylation are potential biomarkers for poor prognosis in CRC.
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Affiliation(s)
- Zhu Wang
- Department of Oncology, Yangzhou No.1 People's Hospital, The second Clinical School of Yangzhou University, Number 368, Mid Hanjiang Road, Yangzhou, 225009, China.
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Cordero OJ, Imbernon M, Chiara LD, Martinez-Zorzano VS, Ayude D, de la Cadena MP, Rodriguez-Berrocal FJ. Potential of soluble CD26 as a serum marker for colorectal cancer detection. World J Clin Oncol 2011; 2:245-61. [PMID: 21773075 PMCID: PMC3139035 DOI: 10.5306/wjco.v2.i6.245] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Revised: 03/28/2011] [Accepted: 04/05/2011] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is characterized by a low survival rate even though the basis for colon cancer development, which involves the evolution of adenomas to carcinoma, is known. Moreover, the mortality rates continue to rise in economically transitioning countries although there is the opportunity to intervene in the natural history of the adenoma–cancer sequence through risk factors, screening, and treatment. Screening in particular accounted for most of the decline in colorectal cancer mortality achieved in the USA during the period 1975-2000. Patients show a better prognosis when the neoplasm is diagnosed early. Among the variety of screening strategies, the methods range from invasive and costly procedures such as colonoscopy to more low-cost and non-invasive tests such as the fecal occult blood test (guaiac and immunochemical). As a non-invasive biological serum marker would be of great benefit because of the performance of the test, several biomarkers, including cytologic assays, DNA and mRNA, and soluble proteins, have been studied. We found that the soluble CD26 (sCD26) concentration is diminished in serum of colorectal cancer patients compared to healthy donors, suggesting the potential utility of a sCD26 immunochemical detection test for early diagnosis. sCD26 originates from plasma membrane CD26 lacking its transmembrane and cytoplasmic domains. Some 90%–95% of sCD26 has been associated with serum dipeptidyl peptidase IV (DPP-IV) activity. DPP-IV, assigned to the CD26 cluster, is a pleiotropic enzyme expressed mainly on epithelial cells and lymphocytes. Our studies intended to validate this test for population screening to detect colorectal cancer and advanced adenomas are reviewed here.
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Affiliation(s)
- Oscar J Cordero
- Oscar J Cordero, Monica Imbernon, Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, School of Biology, CIBUS Building, Campus Vida, 15782 Santiago de Compostela, Spain
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