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Puzzo M, De Santo M, Morelli C, Leggio A, Catalano S, Pasqua L. Colorectal Cancer: Current and Future Therapeutic Approaches and Related Technologies Addressing Multidrug Strategies Against Multiple Level Resistance Mechanisms. Int J Mol Sci 2025; 26:1313. [PMID: 39941081 PMCID: PMC11818749 DOI: 10.3390/ijms26031313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/31/2025] [Accepted: 02/01/2025] [Indexed: 02/16/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and is associated with a poor prognosis. The mutation profile and related involved pathways of CRC have been, in broad terms, analyzed. The main current therapeutic approaches have been comprehensively reviewed here, and future possible therapeu-tic options and related technologies have been perspectively presented. The complex scenario represented by the multiple-level resistance mechanism in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, is discussed. Examples of engineered therapeutic approaches from the literature along with a drug combination tested in clinical trials are discussed. The encouraging results observed with the latter combination (the BEACON clinical trial), totally free from chemotherapy, prompted the authors to imagine a future possible nanotechnology-assisted therapeutic approach for bypassing multiple-level resistance mechanisms, hopefully allowing, in principle, a complete biological cancer remission.
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Affiliation(s)
- Marianna Puzzo
- Laboratory of Clinical, Biomolecular and Genetic Analyses Unit, Annunziata Hospital, 87100 Cosenza, Italy; (M.P.); (S.C.)
| | - Marzia De Santo
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Catia Morelli
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Antonella Leggio
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Stefania Catalano
- Laboratory of Clinical, Biomolecular and Genetic Analyses Unit, Annunziata Hospital, 87100 Cosenza, Italy; (M.P.); (S.C.)
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
| | - Luigi Pasqua
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
- Department of Environmental Engineering, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy
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Díaz del Arco C, Fernández Aceñero MJ, Ortega Medina L. Liquid biopsy for gastric cancer: Techniques, applications, and future directions. World J Gastroenterol 2024; 30:1680-1705. [PMID: 38617733 PMCID: PMC11008373 DOI: 10.3748/wjg.v30.i12.1680] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/01/2024] [Accepted: 03/08/2024] [Indexed: 03/28/2024] Open
Abstract
After the study of circulating tumor cells in blood through liquid biopsy (LB), this technique has evolved to encompass the analysis of multiple materials originating from the tumor, such as nucleic acids, extracellular vesicles, tumor-educated platelets, and other metabolites. Additionally, research has extended to include the examination of samples other than blood or plasma, such as saliva, gastric juice, urine, or stool. LB techniques are diverse, intricate, and variable. They must be highly sensitive, and pre-analytical, patient, and tumor-related factors significantly influence the detection threshold, diagnostic method selection, and potential results. Consequently, the implementation of LB in clinical practice still faces several challenges. The potential applications of LB range from early cancer detection to guiding targeted therapy or immunotherapy in both early and advanced cancer cases, monitoring treatment response, early identification of relapses, or assessing patient risk. On the other hand, gastric cancer (GC) is a disease often diagnosed at advanced stages. Despite recent advances in molecular understanding, the currently available treatment options have not substantially improved the prognosis for many of these patients. The application of LB in GC could be highly valuable as a non-invasive method for early diagnosis and for enhancing the management and outcomes of these patients. In this comprehensive review, from a pathologist's perspective, we provide an overview of the main options available in LB, delve into the fundamental principles of the most studied techniques, explore the potential utility of LB application in the context of GC, and address the obstacles that need to be overcome in the future to make this innovative technique a game-changer in cancer diagnosis and treatment within clinical practice.
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Affiliation(s)
- Cristina Díaz del Arco
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
| | - M Jesús Fernández Aceñero
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
| | - Luis Ortega Medina
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
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Gene Expression Analysis of Immune Regulatory Genes in Circulating Tumour Cells and Peripheral Blood Mononuclear Cells in Patients with Colorectal Carcinoma. Int J Mol Sci 2023; 24:ijms24055051. [PMID: 36902476 PMCID: PMC10003441 DOI: 10.3390/ijms24055051] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/21/2023] [Accepted: 03/02/2023] [Indexed: 03/09/2023] Open
Abstract
Information regarding genetic alterations of driver cancer genes in circulating tumour cells (CTCs) and their surrounding immune microenvironment nowadays can be employed as a real-time monitoring platform for translational applications such as patient response to therapeutic targets, including immunotherapy. This study aimed to investigate the expression profiling of these genes along with immunotherapeutic target molecules in CTCs and peripheral blood mononuclear cells (PBMCs) in patients with colorectal carcinoma (CRC). Expression of p53, APC, KRAS, c-Myc, and immunotherapeutic target molecules PD-L1, CTLA-4, and CD47 in CTCs and PBMCs were analysed by qPCR. Their expression in high versus low CTC-positive patients with CRC was compared and clinicopathological correlations between these patient groups were analysed. CTCs were detected in 61% (38 of 62) of patients with CRC. The presence of higher numbers of CTCs was significantly correlated with advanced cancer stages (p = 0.045) and the subtypes of adenocarcinoma (conventional vs. mucinous, p = 0.019), while being weakly correlated with tumour size (p = 0.051). Patients with lower numbers of CTCs had higher expression of KRAS. Higher KRAS expression in CTCs was negatively correlated with tumour perforation (p = 0.029), lymph node status (p = 0.037), distant metastasis (p = 0.046) and overall staging (p = 0.004). CTLA-4 was highly expressed in both CTCs and PBMCs. In addition, CTLA-4 expression was positively correlated with KRAS (r = 0.6878, p = 0.002) in the enriched CTC fraction. Dysregulation of KRAS in CTCs might evade the immune system by altering the expression of CTLA-4, providing new insights into the selection of therapeutic targets at the onset of the disease. Monitoring CTCs counts, as well as gene expression profiling of PBMCs, can be helpful in predicting tumour progression, patient outcome and treatment.
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Copy Number Variations as Determinants of Colorectal Tumor Progression in Liquid Biopsies. Int J Mol Sci 2023; 24:ijms24021738. [PMID: 36675253 PMCID: PMC9866722 DOI: 10.3390/ijms24021738] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/09/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
Over the years, increasing evidence has shown that copy number variations (CNVs) play an important role in the pathogenesis and prognosis of Colorectal Cancer (CRC). Colorectal adenomas are highly prevalent lesions, but only 5% of these adenomas ever progress to carcinoma. This review summarizes the different CNVs associated with adenoma-carcinoma CRC progression and with CRC staging. Characterization of CNVs in circulating free-RNA and in blood-derived exosomes augers well with the potential of using such assays for patient management and early detection of metastasis. To overcome the limitations related to tissue biopsies and tumor heterogeneity, using CNVs to characterize tumor-derived materials in biofluids provides less invasive sampling methods and a sample that collectively represents multiple tumor sites in heterogeneous samples. Liquid biopsies provide a source of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), tumor-derived exosomes (TDE), circulating free RNA, and non-coding RNA. This review provides an overview of the current diagnostic and predictive models from liquid biopsies.
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Born J, Hendricks A, Hauser C, Egberts JH, Becker T, Röder C, Sebens S. Detection of Marker Associated with CTC in Colorectal Cancer in Mononuclear Cells of Patients with Benign Inflammatory Intestinal Diseases. Cancers (Basel) 2021; 14:cancers14010047. [PMID: 35008210 PMCID: PMC8750406 DOI: 10.3390/cancers14010047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Colorectal carcinoma (CRC) is one of the most frequent cancers in western countries, and non-invasive methods for early detection are still needed. Circulating tumor cells (CTC) in blood of CRC patients have been proven as prognostic and predictive biomarker; however, the suitability of CTC-associated markers for early CRC detection and discrimination from benign diseases has not been analyzed. Thus, this study investigated whether CTC-associated markers can also be detected in the blood of patients with benign inflammatory intestinal disease (IID) or whether they are specific for malignancy. The detection rate of CK20 and DEFA5 clearly differed in diseased patients and healthy controls, while LAD1 and PLS3 was found in all samples but with clear qualitative differences in gene expression. No association between inflammation severity and CTC marker expression was found in IID patients. Finally, PLS3 was identified to be a suitable marker for differentiation between malignant and non-malignant intestinal diseases or healthy controls. Abstract Colorectal carcinoma (CRC) belongs to the most common tumor entities in western countries. Circulating tumor cells (CTC) in blood of CRC patients are a powerful prognostic and predictive biomarker. However, whether CTC-associated markers can also be used for early CRC detection and discrimination from benign diseases is not known. This study investigated the presence of CTC-associated markers CK20, PLS3, LAD1, and DEFA5 in blood of patients with benign inflammatory intestinal disease (IID) and their correlation with malignancy. The detection rate of CK20 and DEFA5 significantly differed between diseased patients and healthy controls. LAD1 and PLS3 were detected in all samples with clear differences in gene expression. DEFA5 expression was higher in CRC and IID patients compared to healthy donors, while CK20 and PLS3 were lower in CRC compared to IID patients or healthy controls. Overall, all CTC-associated markers were detectable in blood of IID patients, but not correlating with inflammation severity. Finally, PLS3 emerged as a suitable marker for differentiation between malignant and non-malignant intestinal diseases or healthy controls, however its suitability for early CRC detection needs to be further validated.
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Affiliation(s)
- Johanna Born
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, Building U30 Entrance 1, 24105 Kiel, Germany; (J.B.); (C.R.)
| | - Alexander Hendricks
- Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105 Kiel, Germany; (A.H.); (C.H.); (J.-H.E.); (T.B.)
| | - Charlotte Hauser
- Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105 Kiel, Germany; (A.H.); (C.H.); (J.-H.E.); (T.B.)
| | - Jan-Hendrik Egberts
- Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105 Kiel, Germany; (A.H.); (C.H.); (J.-H.E.); (T.B.)
| | - Thomas Becker
- Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, Building C, 24105 Kiel, Germany; (A.H.); (C.H.); (J.-H.E.); (T.B.)
| | - Christian Röder
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, Building U30 Entrance 1, 24105 Kiel, Germany; (J.B.); (C.R.)
| | - Susanne Sebens
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3, Building U30 Entrance 1, 24105 Kiel, Germany; (J.B.); (C.R.)
- Correspondence: ; Tel.: +49-431-500-30501
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Jiang M, Jin S, Han J, Li T, Shi J, Zhong Q, Li W, Tang W, Huang Q, Zong H. Detection and clinical significance of circulating tumor cells in colorectal cancer. Biomark Res 2021; 9:85. [PMID: 34798902 PMCID: PMC8605607 DOI: 10.1186/s40364-021-00326-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/27/2021] [Indexed: 02/08/2023] Open
Abstract
Histopathological examination (biopsy) is the "gold standard" for the diagnosis of colorectal cancer (CRC). However, biopsy is an invasive method, and due to the temporal and spatial heterogeneity of the tumor, a single biopsy cannot reveal the comprehensive biological characteristics and dynamic changes of the tumor. Therefore, there is a need for new biomarkers to improve CRC diagnosis and to monitor and treat CRC patients. Numerous studies have shown that "liquid biopsy" is a promising minimally invasive method for early CRC detection. A liquid biopsy mainly samples circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), microRNA (miRNA) and extracellular vesicles (EVs). CTCs are malignant cells that are shed from the primary tumors and/or metastases into the peripheral circulation. CTCs carry information on both primary tumors and metastases that can reflect dynamic changes in tumors in a timely manner. As a promising biomarker, CTCs can be used for early disease detection, treatment response and disease progression evaluation, disease mechanism elucidation, and therapeutic target identification for drug development. This review will discuss currently available technologies for plasma CTC isolation and detection, their utility in the management of CRC patients and future research directions.
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Affiliation(s)
- Miao Jiang
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, NO.1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Shuiling Jin
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, NO.1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Jinming Han
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, NO.1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Tong Li
- BGI College, Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052, Henan, China
| | - Jianxiang Shi
- BGI College, Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052, Henan, China.,Precision Medicine Center, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052, China
| | - Qian Zhong
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, NO.1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Wen Li
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, NO.1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Wenxue Tang
- Departments of Otolaryngology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China.
| | - Qinqin Huang
- Academy of medical science, Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Hong Zong
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, NO.1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China.
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Clinical Significance of Circulating Tumor Cell Induced Epithelial-Mesenchymal Transition in Patients with Metastatic Colorectal Cancer by Single-Cell RNA-Sequencing. Cancers (Basel) 2021; 13:cancers13194862. [PMID: 34638346 PMCID: PMC8507666 DOI: 10.3390/cancers13194862] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/18/2021] [Accepted: 09/25/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Circulating tumor cells (CTCs) are a prognostic marker in patients with metastatic colorectal cancer (mCRC). However, little is known about the characterization of CTCs in mCRC at the single-cell level using RNA sequencing. The purpose of this study was to validate the capability to detect and isolate single CTCs for single-cell RNA sequencing (scRNA-seq) and to identify clinical significance at a single CTC level. METHODS Single CTCs from 27 mCRC patients were collected by CTC-FIND, which is comprised of filter separation and immunomagnetic depletion to collect ultra-pure CTC samples. To address tumor heterogeneity, CTCs were collected without relying on any traditional CTC markers, such as epithelial and mesenchymal cell antigens, and were undertaken by scRNA-seq using SMART-Seq v4. RESULTS We identified 59 single CTCs which were classified into four groups by epithelial, epithelial-mesenchymal transition (EMT) and stem cell-related gene expression. Patients receiving second or later-line treatment who had EMT gene expressing CTCs had a significantly shorter PFS and OS. CONCLUSIONS Exploiting CTC-FIND with SMART-Seq v4 showed that scRNA-seq of CTCs may shed new insight into tumor heterogeneity of mCRC and that the presence of CTCs expressing EMT-related genes at the single-cell level could have prognostic value in mCRC patients.
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Carissimi F, Barbaglia MN, Salmi L, Ciulli C, Roccamatisi L, Cordaro G, Mallela VR, Minisini R, Leone BE, Donadon M, Torzilli G, Pirisi M, Romano F, Famularo S. Finding the seed of recurrence: Hepatocellular carcinoma circulating tumor cells and their potential to drive the surgical treatment. World J Gastrointest Surg 2021; 13:967-978. [PMID: 34621473 PMCID: PMC8462072 DOI: 10.4240/wjgs.v13.i9.967] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/25/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
The treatment for hepatocellular carcinoma (HCC) relies on liver resection, which is, however, burdened by a high rate of recurrence after surgery, up to 60% at 5 years. No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient. Recently liquid biopsy has shown interesting results in diagnosis, prognosis and treatment allocation strategies in other types of cancers, since its ability to identify circulating tumor cells (CTCs) derived from the primary tumor. Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC. In fact, after being modified by the epithelial-mesenchymal transition, CTCs circulate as “seeds” in peripheral blood, then reach the target organ as dormant cells which could be subsequently “awakened” and activated, and then initiate metastasis. Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections, particularly in the case of microvascular invasion, which has been recently pointed as a histological sign of the spread of those cells. Thus, their presence, also in the early stages, may justify the recurrence event also in the contest of liver transplant. Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics. Moreover, it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies, and in perspective, it could also become a new method to allocate organs for transplantation, according to the risk of relapse after liver transplant. The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC, highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice.
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Affiliation(s)
- Francesca Carissimi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | | | - Livia Salmi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Cristina Ciulli
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Linda Roccamatisi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Giuseppe Cordaro
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
| | - Venkata Ramana Mallela
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Biagio Eugenio Leone
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Unit of Pathology, San Gerardo Hospital, Monza 20900, Italy
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara 28100, Italy
| | - Fabrizio Romano
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Department of Medicine and Surgery, University of Milan-Bicocca, Monza 20900, Italy
| | - Simone Famularo
- School of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Italy
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Brar B, Ranjan K, Palria A, Kumar R, Ghosh M, Sihag S, Minakshi P. Nanotechnology in Colorectal Cancer for Precision Diagnosis and Therapy. FRONTIERS IN NANOTECHNOLOGY 2021. [DOI: 10.3389/fnano.2021.699266] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most frequently occurring tumor in the human population. CRCs are usually adenocarcinomatous and originate as a polyp on the inner wall of the colon or rectum which may become malignant in the due course of time. Although the therapeutic options of CRC are limited, the early diagnosis of CRC may play an important role in preventive and therapeutic interventions to decrease the mortality rate. The CRC-affected tissues exhibit several molecular markers that may be exploited as the novel strategy to develop newer approaches for the treatment of the disease. Nanotechnology consists of a wide array of innovative and astonishing nanomaterials with both diagnostics and therapeutic potential. Several nanomaterials and nano formulations such as Carbon nanotubes, Dendrimer, Liposomes, Silica Nanoparticles, Gold nanoparticles, Metal-organic frameworks, Core-shell polymeric nano-formulations, Nano-emulsion System, etc can be used to targeted anticancer drug delivery and diagnostic purposes in CRC. The light-sensitive photosensitizer drugs loaded gold and silica nanoparticles can be used to diagnose as well as the killing of CRC cells by the targeted delivery of anticancer drugs to cancer cells. This review is focused on the recent advancement of nanotechnology in the diagnosis and treatment of CRC.
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Obermayr E, Reiner A, Brandt B, Braicu EI, Reinthaller A, Loverix L, Concin N, Woelber L, Mahner S, Sehouli J, Vergote I, Zeillinger R. The Long-Term Prognostic Significance of Circulating Tumor Cells in Ovarian Cancer-A Study of the OVCAD Consortium. Cancers (Basel) 2021; 13:cancers13112613. [PMID: 34073412 PMCID: PMC8198007 DOI: 10.3390/cancers13112613] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/20/2021] [Accepted: 05/22/2021] [Indexed: 01/19/2023] Open
Abstract
INTRODUCTION We previously reported the prognostic impact of circulating tumor cells (CTCs) in a multicenter study on minimal residual disease in primary ovarian cancer. With additional follow-up data, we evaluated the combined CTC approach (CTCscombo), in particular for the patients who had survived more than five years. MATERIAL AND METHODS Blood samples taken at baseline and six months after adjuvant treatment (follow-up) were assessed by quantitative PCR (qPCR) measuring PPIC transcripts and immunofluorescent staining (IF). A positive result with either IF or qPCR was classified as CTCcombo-positive. Further, PPIC was assessed in the primary tumor tissue. RESULTS The concordance of IF and qPCR was 65% at baseline and 83% after treatment. Results showed that 50.5% of the baseline and 29.5% of the follow-up samples were CTCcombo-positive. CTCscombo after treatment were associated with increased mortality after adjusting for FIGO stage (HR 2.574, 95% CI: 1.227-5.398, p = 0.012), a higher risk of recurrence after adjusting for peritoneal carcinosis (HR 4.068, 95% CI: 1.948-8.498, p < 0.001), and increased mortality after five survived years. DISCUSSION The two-sided analytical approach revealed CTC subpopulations associated with ovarian cancer progression and may illuminate a potential treatment-related shift in molecular phenotypes. That approach can identify patients who have elevated risk of recurrence and death due to ovarian cancer and who may require risk-adapted treatment strategies.
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Affiliation(s)
- Eva Obermayr
- Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria; (A.R.); (R.Z.)
- Correspondence:
| | - Angelika Reiner
- Department of Pathology, Klinikum Donaustadt, 1090 Vienna, Austria;
| | - Burkhard Brandt
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
- Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Elena Ioana Braicu
- Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité, Universitätsmedizin Berlin, 13353 Berlin, Germany; (E.I.B.); (J.S.)
| | - Alexander Reinthaller
- Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria; (A.R.); (R.Z.)
| | - Liselore Loverix
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, University Hospitals Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (L.L.); (I.V.)
| | - Nicole Concin
- Department of Obstetrics and Gynecology, Innsbruck Medical University, 6020 Innsbruck, Austria;
| | - Linn Woelber
- Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (L.W.); (S.M.)
| | - Sven Mahner
- Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (L.W.); (S.M.)
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Jalid Sehouli
- Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité, Universitätsmedizin Berlin, 13353 Berlin, Germany; (E.I.B.); (J.S.)
| | - Ignace Vergote
- Division of Gynecological Oncology, Department of Obstetrics and Gynecology, University Hospitals Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (L.L.); (I.V.)
| | - Robert Zeillinger
- Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria; (A.R.); (R.Z.)
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11
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Yuan X, Yi M, Dong B, Chu Q, Wu K. Prognostic significance of KRT19 in Lung Squamous Cancer. J Cancer 2021; 12:1240-1248. [PMID: 33442422 PMCID: PMC7797641 DOI: 10.7150/jca.51179] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 12/04/2020] [Indexed: 12/11/2022] Open
Abstract
Backgroud: Keratin 19 (KRT19) is the intermediate filament that constitutes the cytoskeleton and regulates cell-cycle and cell death. Objective: We aimed to assess whether KRT19 was involved in lung cancer development. Methods: The expression of KRT19 in lung cancer was evaluated from mRNA expression on open databse and protein abundance on tumor tissue array. Results: Using open microarray gene expression datasets and differential expression analysis, we found that KRT19 was upregulated in lung cancer compared with normal tissue. Further analysis suggested that KRT19 mRNA expression was correlated with tumor progression and overall survival in lung cancer patients. As KRT19 was overexpressed in adenocarcinoma (AC) and squamous cell carcinoma (SCC), we examined the prognostic value of KRT19 protein abundance by tissue microarray (TMA). The results suggested that protein expression of KRT19 was significantly associated with overall survival of SCC. Conclusions: Giving the prognostic role of KRT19 in lung cancer, KRT19 could be considered as an potential molecular marker in lung cancer, especially in SCC.
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Affiliation(s)
- Xun Yuan
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China
| | - Bing Dong
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, P.R. China.,Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
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12
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Hamid FB, Gopalan V, Matos M, Lu CT, Lam AKY. Genetic Heterogeneity of Single Circulating Tumour Cells in Colorectal Carcinoma. Int J Mol Sci 2020; 21:ijms21207766. [PMID: 33092235 PMCID: PMC7589365 DOI: 10.3390/ijms21207766] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/10/2020] [Accepted: 10/18/2020] [Indexed: 12/11/2022] Open
Abstract
The aim of the present study was to isolate and investigate the genetic heterogeneities in single circulating tumour cells (CTCs) from patients with colorectal carcinoma (CRC). Twenty-eight single CTCs were collected from eight patients with CRC using a negative immunomagnetic enrichment method. After validation with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene expression in 3 colon cancer cell lines, a panel of 19 genes were used to analyse the single CTCs (n = 28), primary colorectal carcinoma tissues (n = 8) and colon carcinoma cells (n = 6) using real-time qPCR. Genetic heterogeneities were assessed by comparing gene expression profiles of single CTCs from the different patients and in the same patient, respectively. Genetic profiling of the single CTCs showed extensive heterogeneities of the selected genes among the CTCs. Hierarchical clustering analyses exhibited two clusters of CTCs with differentially expressed genes, which highlighted different modifications from the primary carcinomas. Further, the genetic heterogeneities were observed between different patients or in the same patient. Finally, AKT1 expression was significantly (p = 0.0129) higher in single CTCs from CRC of advanced pathological stages (III or IV) CRC than in CTCs from CRC of early stages (I or II). Our findings suggest that single-cell genetic analysis can monitor the genetic heterogeneities and guide the personalised therapeutic targets in clinical sectors.
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Affiliation(s)
- Faysal Bin Hamid
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia;
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia;
- Correspondence: (V.G.); (A.K.L.)
| | - Marco Matos
- Oncology, Gold Coast University Hospital, Gold Coast, QLD 4215, Australia;
| | - Cu-Tai Lu
- Colorectal Surgery, Gold Coast University Hospital, Gold Coast, QLD 4215, Australia;
| | - Alfred King-yin Lam
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia;
- Correspondence: (V.G.); (A.K.L.)
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13
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Histopathological growth patterns and positive margins after resection of colorectal liver metastases. HPB (Oxford) 2020; 22:911-919. [PMID: 31735649 PMCID: PMC7888172 DOI: 10.1016/j.hpb.2019.10.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 08/23/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Histopathological growth patterns (HGPs) of colorectal liver metastases (CRLM) may be an expression of biological tumour behaviour impacting the risk of positive resection margins. The current study aimed to investigate whether the non-desmoplastic growth pattern (non-dHGP) is associated with a higher risk of positive resection margins after resection of CRLM. METHODS All patients treated surgically for CRLM between January 2000 and March 2015 at the Erasmus MC Cancer Institute and between January 2000 and December 2012 at the Memorial Sloan Kettering Cancer Center were considered for inclusion. RESULTS Of all patients (n = 1302) included for analysis, 13% (n = 170) had positive resection margins. Factors independently associated with positive resection margins were the non-dHGP (odds ratio (OR): 1.79, 95% confidence interval (CI): 1.11-2.87, p = 0.016) and a greater number of CRLM (OR: 1.15, 95% CI: 1.08-1.23 p < 0.001). Both positive resection margins (HR: 1.41, 95% CI: 1.13-1.76, p = 0.002) and non-dHGP (HR: 1.57, 95% CI: 1.26-1.95, p < 0.001) were independently associated with worse overall survival. CONCLUSION Patients with non-dHGP are at higher risk of positive resection margins. Despite this association, both positive resection margins and non-dHGP are independent prognostic indicators of worse overall survival.
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14
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Tieng FYF, Baharudin R, Abu N, Mohd Yunos RI, Lee LH, Ab Mutalib NS. Single Cell Transcriptome in Colorectal Cancer-Current Updates on Its Application in Metastasis, Chemoresistance and the Roles of Circulating Tumor Cells. Front Pharmacol 2020; 11:135. [PMID: 32174835 PMCID: PMC7056698 DOI: 10.3389/fphar.2020.00135] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 01/31/2020] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is among the most common cancer worldwide, a challenge for research, and a model for studying the molecular mechanisms involved in its development. Previously, bulk transcriptomics analyses were utilized to classify CRC based on its distinct molecular and clinicopathological features for prognosis and diagnosis of patients. The introduction of single-cell transcriptomics completely turned the table by enabling the examination of the expression levels of individual cancer cell within a single tumor. In this review, we highlighted the importance of these single-cell transcriptomics analyses as well as suggesting circulating tumor cells (CTCs) as the main focus of single-cell RNA sequencing. Characterization of these cells might reveal the intratumoral heterogeneity present in CRC while providing critical insights into cancer metastasis. To summarize, we believed the analysis of gene expression patterns of CTC from CRC at single-cell resolution holds the potential to provide key information for identification of prognostic and diagnostic markers as well as the development of precise and personalized cancer treatment.
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Affiliation(s)
- Francis Yew Fu Tieng
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Rashidah Baharudin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Ryia-Illani Mohd Yunos
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Learn-Han Lee
- Novel Bacteria and Drug Discovery Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Subang Jaya, Malaysia
| | - Nurul-Syakima Ab Mutalib
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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15
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Matsusaka S, Hanna DL, Ning Y, Yang D, Cao S, Berger MD, Miyamoto Y, Suenaga M, Dan S, Mashima T, Seimiya H, Zhang W, Lenz HJ. Epidermal growth factor receptor mRNA expression: A potential molecular escape mechanism from regorafenib. Cancer Sci 2020; 111:441-450. [PMID: 31821662 PMCID: PMC7004533 DOI: 10.1111/cas.14273] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 11/28/2019] [Accepted: 12/02/2019] [Indexed: 02/04/2023] Open
Abstract
Regorafenib has improved the survival of patients with refractory metastatic colorectal cancer (mCRC), yet the mechanisms of inherited or acquired resistance are not well understood. A total of 50 patients with refractory mCRC were enrolled. Circulating tumor cell (CTC) enumeration was carried out at baseline, day 21 after initiation of regorafenib, and at the time of progression of disease (PD) using the CellSearch System (Veridex LLC, NJ, USA). Poly(A) mRNA was extracted from CTCs, and gene expression of epithelial and epithelial‐mesenchymal transition markers was analyzed by a multiplex‐PCR based DNA Chip. Patients with fewer than 3 CTCs at baseline and day 21 had a longer progression‐free survival than those with 3 or more CTCs (3.3 vs 2.0 months, P = .008 and 3.3 vs 2.0 months, P = .004, respectively). Patients with fewer than 3 CTCs at baseline and day 21 had a longer overall survival (OS) than those with 3 or more CTCs (10.0 vs 4.6 months, P < .001 and 8.7 vs 3.8 months, P = .003, respectively). In multivariable analysis, CTC counts remained significantly associated with OS at baseline and day 21 (P = .019 and P = .028). Circulating tumor cell EGFR gene expression was upregulated at day 21 and/or PD in 64% of patients. Patients had significantly increased EGFR expression at PD compared to baseline (P = .041) and at day 21 and/or PD compared to baseline (P = .004). Our findings suggest that CTC count and EGFR expression could be useful markers of regorafenib efficacy and outcomes. Upregulation of CTC EGFR expression might be a molecular escape mechanism under regorafenib therapy.
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Affiliation(s)
- Satoshi Matsusaka
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.,Department of Clinical Research and Regional Innovation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Diana L Hanna
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yan Ning
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Dongyun Yang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Shu Cao
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Martin D Berger
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yuji Miyamoto
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Mitsukuni Suenaga
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.,Department of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tetsuo Mashima
- Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroyuki Seimiya
- Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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16
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Vafaei S, Fattahi F, Ebrahimi M, Janani L, Shariftabrizi A, Madjd Z. Common molecular markers between circulating tumor cells and blood exosomes in colorectal cancer: a systematic and analytical review. Cancer Manag Res 2019; 11:8669-8698. [PMID: 31576171 PMCID: PMC6768129 DOI: 10.2147/cmar.s219699] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022] Open
Abstract
Nearly half of patients with colorectal cancer (CRC), the third leading cause of cancer deaths worldwide, are diagnosed in the late stages of the disease. Appropriate treatment is not applied in a timely manner and nearly 90% of the patients who experience metastasis ultimately die. Timely detection of CRC can increase the five-year survival rate of patients. Existing histopathological and molecular classifications are insufficient for prediction of metastasis, which limits approaches to treatment. Detection of reliable cancer-related biomarkers can improve early diagnosis, prognosis, and treatment response prediction and recurrence risk. Circulating tumor cells (CTCs) and exosomes in peripheral blood can be used in a liquid biopsy to assess the status of a tumor. Exosomes are abundant and available in all fluids of the body, have a high half-life and are released by most cells. Tumor-derived exosomes are released from primary tumors or CTCs with selective cargo that represents the overall tumor. The current systematic review highlights new trends and approaches in the detection of CRC biomarkers to determine tumor signatures using CTC and exosomes. When these are combined, they could be used to guide molecular pathology and can revolutionize detection tools. Relevant observational studies published until July 24, 2019 which evaluated the expression of tumor markers in CTCs and exosomes were searched in PubMed, Scopus, Embase, and ISI Web of Science databases. The extracted biomarkers were analyzed using String and EnrichR tools.
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Affiliation(s)
- Somayeh Vafaei
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Fahimeh Fattahi
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Leila Janani
- Department of Biostatistics, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | | | - Zahra Madjd
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
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17
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de Kruijff IE, Sieuwerts AM, Onstenk W, Kraan J, Smid M, Van MN, van der Vlugt-Daane M, Hoop EOD, Mathijssen RHJ, Lolkema MP, de Wit R, Hamberg P, Meulenbeld HJ, Beeker A, Creemers GJ, Martens JWM, Sleijfer S. Circulating Tumor Cell Enumeration and Characterization in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Cabazitaxel. Cancers (Basel) 2019; 11:cancers11081212. [PMID: 31434336 PMCID: PMC6721462 DOI: 10.3390/cancers11081212] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 08/15/2019] [Accepted: 08/16/2019] [Indexed: 02/07/2023] Open
Abstract
(1) Background: Markers identifying which patients with metastatic, castration-resistant prostate cancer (mCRPC) will benefit from cabazitaxel therapy are currently lacking. Therefore, the aim of this study was to identify markers associated with outcome to cabazitaxel therapy based on counts and gene expression profiles of circulating tumor cells (CTCs). (2) Methods: From 120 mCRPC patients, CellSearch enriched CTCs were obtained at baseline and after 6 weeks of cabazitaxel therapy. Furthermore, 91 genes associated with prostate cancer were measured in mRNA of these CTCs. (3) Results: In 114 mCRPC patients with an evaluable CTC count, the CTC count was independently associated with poor progression-free survival (PFS) and overall survival (OS) in multivariable analysis with other commonly used variables associated with outcome in mCRPC (age, prostate specific antigen (PSA), alkaline phosphatase, lactate dehydrogenase (LDH), albumin, hemoglobin), together with alkaline phosphatase and hemoglobin. A five-gene expression profile was generated to predict for outcome to cabazitaxel therapy. However, even though this signature was associated with OS in univariate analysis, this was not the case in the multivariate analysis for OS nor for PFS. (4) Conclusion: The established five-gene expression profile in CTCs was not independently associated with PFS nor OS. However, along with alkaline phosphatase and hemoglobin, CTC-count is independently associated with PFS and OS in mCRPC patients who are treated with cabazitaxel.
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Affiliation(s)
- Ingeborg E de Kruijff
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Anieta M Sieuwerts
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Wendy Onstenk
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Jaco Kraan
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Marcel Smid
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Mai N Van
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Michelle van der Vlugt-Daane
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Esther Oomen-de Hoop
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Ron H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Martijn P Lolkema
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Ronald de Wit
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Paul Hamberg
- Department of Medical Oncology, Franciscus Gasthuis & Vlietland, 3045 PM Rotterdam, The Netherlands
| | - Hielke J Meulenbeld
- Department of Medical Oncology, Gelre Ziekenhuizen, 7334 DZ Apeldoorn, The Netherlands
| | - Aart Beeker
- Department of Medical Oncology, Spaarne Gasthuis, 2134 TM Hoofddorp, The Netherlands
| | - Geert-Jan Creemers
- Department of Medical Oncology, Catharina Ziekenhuis, 5623 EJ Eindhoven, The Netherlands
| | - John W M Martens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
| | - Stefan Sleijfer
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
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18
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Pan F, Li W, Yang W, Yang XY, Liu S, Li X, Zhao X, Ding H, Qin L, Pan Y. Anterior gradient 2 as a supervisory marker for tumor vessel normalization induced by anti-angiogenic treatment. Oncol Lett 2018; 16:3083-3091. [PMID: 30127899 PMCID: PMC6096224 DOI: 10.3892/ol.2018.8996] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 05/14/2018] [Indexed: 12/11/2022] Open
Abstract
Anti-angiogenic therapy provides transient tumor vascular normalization, which results in a window of opportunity for improvement of radio- or chemotherapy. Biomarkers indicating this window are required for rationalizing anti-angiogenesis. Anterior gradient 2 (AGR2), the majority of which is secreted from tumor cells, is an easily detected plasma protein. In the present study, it was demonstrated that AGR2 could be applied as a biomarker for the supervision of vascular normalization during anti-angiogenic treatment with gold nanoparticles (AuNPs). Nude mice inoculated with SW620 human colorectal cancer cells were treated with AuNPs. Vessel density, pericyte coverage, vessel permeability, tumor hypoxia, tumor growth and AGR2 secretion were detected following treatment with AuNPs at days 0, 4, 6, 9 and 14. Tumor volume and vessel density were reduced, whereas pericyte coverage was increased, and hypoxia and vessel permeability were improved between days 6–9; however, these improvements decreased by day 14, revealing a time frame for tumor vascular normalization, namely days 4–9, during treatment with AuNPs in mice. AGR2 levels in tumor tissues and plasma were significantly low at day 9, along with vascular normalization; therefore, AGR2 can be used as a potential marker for monitoring tumor vascular normalization during anti-angiogenic treatment.
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Affiliation(s)
- Fan Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Wei Li
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Wende Yang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Xiao-Yan Yang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Shuhao Liu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Xin Li
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Xiaoxu Zhao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Hui Ding
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Li Qin
- Department of Histology and Embryology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Yunlong Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
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19
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Burz C, Pop VV, Buiga R, Daniel S, Samasca G, Aldea C, Lupan I. Circulating tumor cells in clinical research and monitoring patients with colorectal cancer. Oncotarget 2018; 9:24561-24571. [PMID: 29849961 PMCID: PMC5966258 DOI: 10.18632/oncotarget.25337] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 04/24/2018] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer remains a frequent disease to which screening and target therapy exist, but despite this is still marked by a high mortality rate. Even though radical surgery may be performed in many cases, patients relapse with metastatic disease. Circulating tumor cells were incriminated for tumor recurrence, that's why vigorous research started on their field. Owning prognostic and predictive value, it was revealed their usefulness in disease monitoring. Moreover, they may serve as liquid biopsies for genetic tests in cases where tissue biopsy is contraindicated or cannot be performed. In spite of these advantages, they were not included in clinical guidelines, despite CellSearch and many other detection methods were developed to ease the identification of circulating tumor cells. This review highlights the implication of circulating tumor cells in metastasis cascade, intrinsic tumor cells mechanisms and correlations with clinical parameters along with their utility for medical practice and detection techniques.
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Affiliation(s)
- Claudia Burz
- Iuliu Hatieganu University of Medicine and Pharmacy, Department Of Immunology and Allergology, Cluj-Napoca, Romania.,Ion Chiricuta Institute of Oncology, Cluj-Napoca, Romania
| | - Vlad-Vasile Pop
- Iuliu Hatieganu University of Medicine and Pharmacy, Department Of Immunology and Allergology, Cluj-Napoca, Romania
| | - Rares Buiga
- Ion Chiricuta Institute of Oncology, Cluj-Napoca, Romania
| | - Sur Daniel
- Iuliu Hatieganu University of Medicine and Pharmacy, Department Of Immunology and Allergology, Cluj-Napoca, Romania.,Ion Chiricuta Institute of Oncology, Cluj-Napoca, Romania
| | - Gabriel Samasca
- Iuliu Hatieganu University of Medicine and Pharmacy, Department Of Immunology and Allergology, Cluj-Napoca, Romania.,Emergency Hospital for Children, Cluj-Napoca, Romania
| | - Cornel Aldea
- Emergency Hospital for Children, Cluj-Napoca, Romania
| | - Iulia Lupan
- Babeş-Bolyai University, Department of Molecular Biology and Biotehnology, Cluj-Napoca, Romania.,Institute of Interdisciplinary Research in Bio-Nano-Sciences, Cluj-Napoca, Romania
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20
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Mellert H, Foreman T, Jackson L, Maar D, Thurston S, Koch K, Weaver A, Cooper S, Dupuis N, Sathyanarayana UG, Greer J, Hahn W, Shelton D, Stonemetz P, Pestano GA. Development and Clinical Utility of a Blood-Based Test Service for the Rapid Identification of Actionable Mutations in Non-Small Cell Lung Carcinoma. J Mol Diagn 2018; 19:404-416. [PMID: 28433077 DOI: 10.1016/j.jmoldx.2016.11.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 11/15/2016] [Accepted: 11/28/2016] [Indexed: 10/19/2022] Open
Abstract
Nearly 80% of cancer patients do not have genetic mutation results available at initial oncology consultation; up to 25% of patients begin treatment before receiving their results. These factors hinder the ability to pursue optimal treatment strategies. This study validates a blood-based genome-testing service that provides accurate results within 72 hours. We focused on targetable variants in advanced non-small cell lung carcinoma-epidermal growth factor receptor gene (EGFR) variant L858R, exon 19 deletion (ΔE746-A750), and T790M; GTPase Kirsten ras gene (KRAS) variants G12C/D/V; and echinoderm microtubule associated protein like and 4 anaplastic lymphoma receptor tyrosine kinase fusion (EML4-ALK) transcripts 1/2/3. Test development included method and clinical validation using samples from donors with (n = 219) or without (n = 30) cancer. Clinical sensitivity and specificity for each variant ranged from 78.6% to 100% and 94.2% to 100%, respectively. We also report on 1643 non-small cell lung carcinoma samples processed in our CLIA-certified laboratory. Mutation results were available within 72 hours for 94% of the tests evaluated. We detected 10.5% mutations for EGFR sensitizing (n = 2801 samples tested), 13.8% mutations for EGFR resistance (n = 1055), 13.2% mutations in KRAS (n = 3477), and 2% mutations for EML4-ALK fusion (n = 304). This rapid, highly sensitive, and actionable blood-based assay service expands testing options and supports faster treatment decisions.
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Affiliation(s)
| | | | | | - Dianna Maar
- Bio-Rad Digital Biology Center, Pleasanton, California
| | | | | | | | | | | | | | | | | | - Dawne Shelton
- Bio-Rad Digital Biology Center, Pleasanton, California
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21
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Riethdorf S, O'Flaherty L, Hille C, Pantel K. Clinical applications of the CellSearch platform in cancer patients. Adv Drug Deliv Rev 2018; 125:102-121. [PMID: 29355669 DOI: 10.1016/j.addr.2018.01.011] [Citation(s) in RCA: 166] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 01/12/2018] [Accepted: 01/15/2018] [Indexed: 12/29/2022]
Abstract
The CellSearch® system (CS) enables standardized enrichment and enumeration of circulating tumor cells (CTCs) that are repeatedly assessable via non-invasive "liquid biopsy". While the association of CTCs with poor clinical outcome for cancer patients has clearly been demonstrated in numerous clinical studies, utilizing CTCs for the identification of therapeutic targets, stratification of patients for targeted therapies and uncovering mechanisms of resistance is still under investigation. Here, we comprehensively review the current benefits and drawbacks of clinical CTC analyses for patients with metastatic and non-metastatic tumors. Furthermore, the review focuses on approaches beyond CTC enumeration that aim to uncover therapeutically relevant antigens, genomic aberrations, transcriptional profiles and epigenetic alterations of CTCs at a single cell level. This characterization of CTCs may shed light on the heterogeneity and genomic landscapes of malignant tumors, an understanding of which is highly important for the development of new therapeutic strategies.
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22
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Onstenk W, Sieuwerts AM, Mostert B, Lalmahomed Z, Bolt-de Vries JB, van Galen A, Smid M, Kraan J, Van M, de Weerd V, Ramírez-Moreno R, Biermann K, Verhoef C, Grünhagen DJ, IJzermans JNM, Gratama JW, Martens JWM, Foekens JA, Sleijfer S. Molecular characteristics of circulating tumor cells resemble the liver metastasis more closely than the primary tumor in metastatic colorectal cancer. Oncotarget 2018; 7:59058-59069. [PMID: 27340863 PMCID: PMC5312295 DOI: 10.18632/oncotarget.10175] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 05/29/2016] [Indexed: 12/21/2022] Open
Abstract
Background CTCs are a promising alternative for metastatic tissue biopsies for use in precision medicine approaches. We investigated to what extent the molecular characteristics of circulating tumor cells (CTCs) resemble the liver metastasis and/or the primary tumor from patients with metastatic colorectal cancer (mCRC). Results The CTC profiles were concordant with the liver metastasis in 17/23 patients (74%) and with the primary tumor in 13 patients (57%). The CTCs better resembled the liver metastasis in 13 patients (57%), and the primary tumor in five patients (22%). The strength of the correlations was not associated with clinical parameters. Nine genes (CDH1, CDH17, CDX1, CEACAM5, FABP1, FCGBP, IGFBP3, IGFBP4, and MAPT) displayed significant differential expressions, all of which were downregulated, in CTCs compared to the tissues in the 23 patients. Patients and Methods Patients were retrospectively selected from a prospective study. Using the CellSearch System, CTCs were enumerated and isolated just prior to liver metastasectomy. A panel of 25 CTC-specific genes was measured by RT-qPCR in matching CTCs, primary tumors, and liver metastases. Spearman correlation coefficients were calculated and considered as continuous variables with r=1 representing absolute concordance and r= -1 representing absolute discordance. A cut-off of r>0.1 was applied in order to consider profiles to be concordant. Conclusions In the majority of the patients, CTCs reflected the molecular characteristics of metastatic cells better than the primary tumors. Genes involved in cell adhesion and epithelial-to-mesenchymal transition were downregulated in the CTCs. Our results support the use of CTC characterization as a liquid biopsy for precision medicine.
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Affiliation(s)
- Wendy Onstenk
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - Anieta M Sieuwerts
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - Bianca Mostert
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - Zarina Lalmahomed
- Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Joan B Bolt-de Vries
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - Anne van Galen
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - Marcel Smid
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - Jaco Kraan
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - Mai Van
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - Vanja de Weerd
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - Raquel Ramírez-Moreno
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - Katharina Biermann
- Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Cornelis Verhoef
- Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Dirk J Grünhagen
- Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jan W Gratama
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - John W M Martens
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - John A Foekens
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
| | - Stefan Sleijfer
- Erasmus MC Cancer Institute, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, The Netherlands
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Bredemeier M, Edimiris P, Mach P, Kubista M, Sjöback R, Rohlova E, Kolostova K, Hauch S, Aktas B, Tewes M, Kimmig R, Kasimir-Bauer S. Gene Expression Signatures in Circulating Tumor Cells Correlate with Response to Therapy in Metastatic Breast Cancer. Clin Chem 2017; 63:1585-1593. [PMID: 28778937 DOI: 10.1373/clinchem.2016.269605] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 07/05/2017] [Indexed: 12/12/2022]
Abstract
Abstract
BACKGROUND
Circulating tumor cells (CTCs) are thought to be an ideal surrogate marker to monitor disease progression in metastatic breast cancer (MBC). We investigated the prediction of treatment response in CTCs of MBC patients on the basis of the expression of 46 genes.
METHODS
From 45 MBC patients and 20 healthy donors (HD), 2 × 5 mL of blood was collected at the time of disease progression (TP0) and at 2 consecutive clinical staging time points (TP1 and TP2) to proceed with the AdnaTest EMT-2/StemCellSelectTM (QIAGEN). Patients were grouped into (a) responder (R) and non-responder (NR) at TP1 and (b) overall responder (OR) and overall non-responder (ONR) at TP2. A 46-gene PCR assay was used for preamplification and high-throughput gene expression profiling. Data were analyzed by use of GenEx (MultiD) and SAS.
RESULTS
The CTC positivity was defined by the four-gene signature (EPCAM, KRT19, MUC1, ERBB2 positivity). Fourteen genes were identified as significantly differentially expressed between CTC+ and CTC− patients (KRT19, FLT1, EGFR, EPCAM, GZMM, PGR, CD24, KIT, PLAU, ALDH1A1, CTSD, MKI67, TWIST1, and ERBB2). KRT19 was highly expressed in CTC+ patients and ADAM17 in the NR at TP1. A significant differential expression of 4 genes (KRT19, EPCAM, CDH1, and SCGB2A2) was observed between OR and ONR when stratifying the samples into CTC+ or CTC−.
CONCLUSIONS
ADAM17 could be a key marker in distinguishing R from NR, and KRT19 was powerful in identifying CTCs.
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Affiliation(s)
- Maren Bredemeier
- Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany
| | - Philippos Edimiris
- Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany
| | - Pawel Mach
- Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany
| | - Mikael Kubista
- TATAA Biocenter, Goeteborg, Sweden
- Institute of Biotechnology CAS, Prague, Czech Republic
| | | | | | - Katarina Kolostova
- Department of Laboratory Genetics, University Hospital Kralovske Vinohrady, Prague, Czech Republic
| | | | - Bahriye Aktas
- Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany
| | - Mitra Tewes
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - Rainer Kimmig
- Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany
| | - Sabine Kasimir-Bauer
- Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany
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24
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Grillet F, Bayet E, Villeronce O, Zappia L, Lagerqvist EL, Lunke S, Charafe-Jauffret E, Pham K, Molck C, Rolland N, Bourgaux JF, Prudhomme M, Philippe C, Bravo S, Boyer JC, Canterel-Thouennon L, Taylor GR, Hsu A, Pascussi JM, Hollande F, Pannequin J. Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture. Gut 2017; 66:1802-1810. [PMID: 27456153 PMCID: PMC5595103 DOI: 10.1136/gutjnl-2016-311447] [Citation(s) in RCA: 150] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 06/20/2016] [Accepted: 06/22/2016] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full. DESIGN Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells. RESULTS Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both in vitro and in vivo. Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds. CONCLUSIONS Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine. CLINICAL TRIAL REGISTRATION ClinicalTrial.gov NCT01577511.
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Affiliation(s)
- Fanny Grillet
- Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France,Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France,Université de Montpellier, UMR5203, Montpellier, France
| | - Elsa Bayet
- Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France,Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France,Université de Montpellier, UMR5203, Montpellier, France
| | - Olivia Villeronce
- Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France,Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France,Université de Montpellier, UMR5203, Montpellier, France
| | - Luke Zappia
- Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
| | - Ebba Louise Lagerqvist
- Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France,Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France,Université de Montpellier, UMR5203, Montpellier, France
| | - Sebastian Lunke
- Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
| | | | - Kym Pham
- Department of Pathology, University of Melbourne, Parkville, Victoria, Australia,Center for Translational Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Christina Molck
- Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
| | | | | | | | | | - Sophie Bravo
- Laboratoire de Biochimie, CHU Carémeau, Nîmes, France
| | | | | | - Graham Roy Taylor
- Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
| | - Arthur Hsu
- Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
| | - Jean Marc Pascussi
- Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France,Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France,Université de Montpellier, UMR5203, Montpellier, France
| | - Frédéric Hollande
- Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France,Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France,Université de Montpellier, UMR5203, Montpellier, France,Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
| | - Julie Pannequin
- Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France,Institut National de la Santé et de la Recherche Médicale, U661, Montpellier, France,Université de Montpellier, UMR5203, Montpellier, France
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25
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Tohti M, Li J, Tang C, Wen G, Abdujilil A, Yizim P, Ma C. Serum AGR2 as a useful biomarker for pituitary adenomas. Clin Neurol Neurosurg 2017; 154:19-22. [PMID: 28092730 DOI: 10.1016/j.clineuro.2017.01.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 12/12/2016] [Accepted: 01/07/2017] [Indexed: 11/18/2022]
Abstract
OBJECTIVE This study aims to evaluate whether the serum Anterior Gradient-2 (AGR2) can be used as a potential biomarker screening in the diagnosis of Pituitary adenomas(PAs). PATIENTS AND METHODS The serum AGR2 protein levels were preoperatively measured in 163 PA patients, 43 patients with other sellar lesions excluding PAs, 7 patients with prostate cancer as a positive control and 20 normal people(10 female and 10 male) using Enzyme-Linked ImmunoSorbent Assay (ELISA). Differences in the serum AGR2 level between different groups were analyzed for statistical significance with a Mann-Whitney U test. RESULTS The data showed that serum AGR2 level was significantly higher in the serum of PA patients (250.10±79.14ng/ml) than the patients with other sellar lesions (220.84±79.62ng/ml, P=0.017) and normal people (163.67±50.38ng/ml, P <0.001). Receiver operating characteristic (ROC) curve analysis was used. The detected area under the curve (AUC) was 0.835. The calculated optimal cut-off point for AGR2 level in serum samples was 158.63ng/ml (Youden index=0.564). The sensitivity was 91.4% and the specificity was 65.0%. Despite the variety of PA clinical features, the serum level of AGR2 are definite in PAs, although there may be a difference between male or female patients. CONCLUSION Our data suggests AGR2 as a potential biomarker for the diagnosis of PAs.
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Affiliation(s)
- Mamatemin Tohti
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, China; Department of Neurosurgery, The People's Hospital of Xinjiang Uygur Autonomous Region, 91 Tianchi Road, Urumqi, 830001, China
| | - Junyang Li
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, China
| | - Chao Tang
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, China
| | - Guodao Wen
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, China
| | - Abdukeyum Abdujilil
- Department of Neurosurgery, The People's Hospital of Xinjiang Uygur Autonomous Region, 91 Tianchi Road, Urumqi, 830001, China
| | - Parhat Yizim
- Department of Neurosurgery, The People's Hospital of Xinjiang Uygur Autonomous Region, 91 Tianchi Road, Urumqi, 830001, China
| | - Chiyuan Ma
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, China.
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26
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van der Stok EP, Spaander MCW, Grünhagen DJ, Verhoef C, Kuipers EJ. Surveillance after curative treatment for colorectal cancer. Nat Rev Clin Oncol 2016; 14:297-315. [DOI: 10.1038/nrclinonc.2016.199] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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27
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Beije N, Helmijr JC, Weerts MJ, Beaufort CM, Wiggin M, Marziali A, Verhoef C, Sleijfer S, Jansen MP, Martens JW. Somatic mutation detection using various targeted detection assays in paired samples of circulating tumor DNA, primary tumor and metastases from patients undergoing resection of colorectal liver metastases. Mol Oncol 2016; 10:1575-1584. [PMID: 28949453 PMCID: PMC5423131 DOI: 10.1016/j.molonc.2016.10.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 08/04/2016] [Accepted: 10/03/2016] [Indexed: 12/21/2022] Open
Abstract
Assessing circulating tumor DNA (ctDNA) is a promising method to evaluate somatic mutations from solid tumors in a minimally-invasive way. In a group of twelve metastatic colorectal cancer (mCRC) patients undergoing liver metastasectomy, from each patient DNA from cell-free DNA (cfDNA), the primary tumor, metastatic liver tissue, normal tumor-adjacent colon or liver tissue, and whole blood were obtained. Investigated was the feasibility of a targeted NGS approach to identify somatic mutations in ctDNA. This targeted NGS approach was also compared with NGS preceded by mutant allele enrichment using synchronous coefficient of drag alteration technology embodied in the OnTarget assay, and for selected mutations with digital PCR (dPCR). All tissue and cfDNA samples underwent IonPGM sequencing for a CRC-specific 21-gene panel, which was analyzed using a standard and a modified calling pipeline. In addition, cfDNA, whole blood and normal tissue DNA were analyzed with the OnTarget assay and with dPCR for specific mutations in cfDNA as detected in the corresponding primary and/or metastatic tumor tissue. NGS with modified calling was superior to standard calling and detected ctDNA in the cfDNA of 10 patients harboring mutations in APC, ATM, CREBBP, FBXW7, KRAS, KMT2D, PIK3CA and TP53. Using this approach, variant allele frequencies in plasma ranged predominantly from 1 to 10%, resulting in limited concordance between ctDNA and the primary tumor (39%) and the metastases (55%). Concordance between ctDNA and tissue markedly improved when ctDNA was evaluated for KRAS, PIK3CA and TP53 mutations by the OnTarget assay (80%) and digital PCR (93%). Additionally, using these techniques mutations were observed in tumor-adjacent tissue with normal morphology in the majority of patients, which were not observed in whole blood. In conclusion, in these mCRC patients with oligometastatic disease NGS on cfDNA was feasible, but had limited sensitivity to detect all somatic mutations present in tissue. Digital PCR and mutant allele enrichment before NGS appeared to be more sensitive to detect somatic mutations.
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Affiliation(s)
- Nick Beije
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jean C. Helmijr
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Marjolein J.A. Weerts
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Corine M. Beaufort
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | | | - Cornelis Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Stefan Sleijfer
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Maurice P.H.M. Jansen
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - John W.M. Martens
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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28
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Swennenhuis JF, van Dalum G, Zeune LL, Terstappen LWMM. Improving the CellSearch® system. Expert Rev Mol Diagn 2016; 16:1291-1305. [PMID: 27797592 DOI: 10.1080/14737159.2016.1255144] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The CellSearch® CTC test enumerates tumor cells present in 7.5 ml blood of cancer patients. improvements, extensions and different utilities of the cellsearch system are discussed in this paper. Areas covered: This paper describes work performed with the CellSearch system, which go beyond the normal scope of the test. All results from searches with the search term 'CellSearch' from Web of Science and PubMed were categorized and discussed. Expert commentary: The CellSearch Circulating Tumor Cell test captures and identifies tumor cells in blood that are associated with poor clinical outcome. How to best use CTC in clinical practice is being explored in many clinical trials. The ability to extract information from the CTC to guide therapy will expand the potential clinical utility of CTC.
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Affiliation(s)
- J F Swennenhuis
- a Medical Cell BioPhysics , University of Twente , Enschede , The Netherlands
| | - G van Dalum
- a Medical Cell BioPhysics , University of Twente , Enschede , The Netherlands
| | - L L Zeune
- a Medical Cell BioPhysics , University of Twente , Enschede , The Netherlands
| | - L W M M Terstappen
- a Medical Cell BioPhysics , University of Twente , Enschede , The Netherlands
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29
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van der Stok EP, Smid M, Sieuwerts AM, Vermeulen PB, Sleijfer S, Ayez N, Grünhagen DJ, Martens JWM, Verhoef C. mRNA expression profiles of colorectal liver metastases as a novel biomarker for early recurrence after partial hepatectomy. Mol Oncol 2016; 10:1542-1550. [PMID: 27692894 DOI: 10.1016/j.molonc.2016.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 08/31/2016] [Accepted: 09/12/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Identification of specific risk groups for recurrence after surgery for isolated colorectal liver metastases (CRLM) remains challenging due to the heterogeneity of the disease. Classical clinicopathologic parameters have limited prognostic value. The aim of this study was to identify a gene expression signature measured in CRLM discriminating early from late recurrence after partial hepatectomy. METHODS CRLM from two patient groups were collected: I) with recurrent disease ≤12 months after surgery (N = 33), and II) without recurrences and disease free for ≥36 months (N = 30). The patients were clinically homogeneous; all had a low clinical risk score (0-2) and did not receive (neo-) adjuvant chemotherapy. Total RNA was hybridised to Illumina arrays, and processed for analysis. A leave-one-out cross validation (LOOCV) analysis was performed to identify a prognostic gene expression signature. RESULTS LOOCV yielded an 11-gene profile with prognostic value in relation to recurrent disease ≤12 months after partial hepatectomy. This signature had a sensitivity of 81.8%, with a specificity of 66.7% for predicting recurrences (≤12 months) versus no recurrences for at least 36 months after surgery (X2 P < 0.0001). CONCLUSION The current study yielded an 11-gene signature at mRNA level in CRLM discriminating early from late or no relapse after partial hepatectomy.
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Affiliation(s)
- E P van der Stok
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
| | - M Smid
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - A M Sieuwerts
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - P B Vermeulen
- Translational Cancer Research Group, Sint-Augustinus (GZA Hospitals) & CORE (Antwerp University), Oosterveldlaan 24, 2610 Wilrijk-Antwerp, Belgium
| | - S Sleijfer
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - N Ayez
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands
| | - D J Grünhagen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands
| | - J W M Martens
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - C Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands
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30
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Ignatiadis M, Lee M, Jeffrey SS. Circulating Tumor Cells and Circulating Tumor DNA: Challenges and Opportunities on the Path to Clinical Utility. Clin Cancer Res 2016; 21:4786-800. [PMID: 26527805 DOI: 10.1158/1078-0432.ccr-14-1190] [Citation(s) in RCA: 268] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Recent technological advances have enabled the detection and detailed characterization of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in blood samples from patients with cancer. Often referred to as a "liquid biopsy," CTCs and ctDNA are expected to provide real-time monitoring of tumor evolution and therapeutic efficacy, with the potential for improved cancer diagnosis and treatment. In this review, we focus on these opportunities as well as the challenges that should be addressed so that these tools may eventually be implemented into routine clinical care.
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Affiliation(s)
- Michail Ignatiadis
- Department of Medical Oncology and Breast Cancer Translational Research Laboratory J. C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Mark Lee
- Google[x] Life Sciences, Google, Inc, Mountain View, California
| | - Stefanie S Jeffrey
- Department of Surgery, Stanford University School of Medicine, Stanford, California.
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31
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Viswanath B, Kim S, Lee K. Recent insights into nanotechnology development for detection and treatment of colorectal cancer. Int J Nanomedicine 2016; 11:2491-504. [PMID: 27330292 PMCID: PMC4898029 DOI: 10.2147/ijn.s108715] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The global incidence of colorectal cancer (CRC) is 1.3 million cases. It is the third most frequent cancer in males and females. Most CRCs are adenocarcinomas and often begin as a polyp on the inner wall of the rectum or colon. Some of these polyps become malignant, eventually. Detecting and removing these polyps in time can prevent CRC. Therefore, early diagnosis of CRC is advantageous for preventive and instant action interventions to decrease the mortality rates. Nanotechnology has been enhancing different methods for the detection and treatment of CRCs, and the research has provided hope within the scientific community for the development of new therapeutic strategies. This review presents the recent development of nanotechnology for the detection and treatment of CRC.
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Affiliation(s)
- Buddolla Viswanath
- Department of Bionanotechnology, Gachon University, Gyeonggi-Do, Republic of Korea
| | - Sanghyo Kim
- Department of Bionanotechnology, Gachon University, Gyeonggi-Do, Republic of Korea
| | - Kiyoung Lee
- Division of Endocrinology and Metabolism, Gachon University Gil Hospital, Incheon, Republic of Korea
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32
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Lianidou ES. Gene expression profiling and DNA methylation analyses of CTCs. Mol Oncol 2016; 10:431-42. [PMID: 26880168 DOI: 10.1016/j.molonc.2016.01.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 01/19/2016] [Accepted: 01/25/2016] [Indexed: 01/26/2023] Open
Abstract
A variety of molecular assays have been developed for CTCs detection and molecular characterization. Molecular assays are based on the nucleic acid analysis in CTCs and are based on total RNA isolation and subsequent mRNA quantification of specific genes, or isolation of genomic DNA that can be for DNA methylation studies and mutation analysis. This review is mainly focused on gene expression and methylation studies in CTCs in various types of cancer.
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Affiliation(s)
- Evi S Lianidou
- Analysis of Circulating Tumor Cells Lab, Lab of Analytical Chemistry, Department of Chemistry, University of Athens, 15771, Greece.
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33
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Monocyte Activation in Immunopathology: Cellular Test for Development of Diagnostics and Therapy. J Immunol Res 2016; 2016:4789279. [PMID: 26885534 PMCID: PMC4739459 DOI: 10.1155/2016/4789279] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 12/20/2015] [Accepted: 12/21/2015] [Indexed: 12/14/2022] Open
Abstract
Several highly prevalent human diseases are associated with immunopathology. Alterations in the immune system are found in such life-threatening disorders as cancer and atherosclerosis. Monocyte activation followed by macrophage polarization is an important step in normal immune response to pathogens and other relevant stimuli. Depending on the nature of the activation signal, macrophages can acquire pro- or anti-inflammatory phenotypes that are characterized by the expression of distinct patterns of secreted cytokines and surface antigens. This process is disturbed in immunopathologies resulting in abnormal monocyte activation and/or bias of macrophage polarization towards one or the other phenotype. Such alterations could be used as important diagnostic markers and also as possible targets for the development of immunomodulating therapy. Recently developed cellular tests are designed to analyze the phenotype and activity of living cells circulating in patient's bloodstream. Monocyte/macrophage activation test is a successful example of cellular test relevant for atherosclerosis and oncopathology. This test demonstrated changes in macrophage activation in subclinical atherosclerosis and breast cancer and could also be used for screening a panel of natural agents with immunomodulatory activity. Further development of cellular tests will allow broadening the scope of their clinical implication. Such tests may become useful tools for drug research and therapy optimization.
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34
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Mostert B, Sieuwerts AM, Bolt-de Vries J, Kraan J, Lalmahomed Z, van Galen A, van der Spoel P, de Weerd V, Ramírez-Moreno R, Smid M, Verhoef C, IJzermans JNM, Gratama JW, Sleijfer S, Foekens JA, Martens JWM. mRNA expression profiles in circulating tumor cells of metastatic colorectal cancer patients. Mol Oncol 2015; 9:920-32. [PMID: 25655581 DOI: 10.1016/j.molonc.2015.01.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 12/05/2014] [Accepted: 01/02/2015] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION The molecular characterization of circulating tumor cells (CTCs) is a promising tool for the repeated and non-invasive evaluation of predictive and prognostic factors. Challenges associated with CTC characterization using the only FDA approved method for CTC enumeration, the CellSearch technique, include the presence of an excess of leukocytes in CTC-enriched blood fractions. Here we aimed to identify colorectal tumor-specific gene expression levels in the blood of patients with and without detectable CTCs according to CellSearch criteria. MATERIALS AND METHODS Blood of 30 healthy donors (HDs) and 142 metastatic colorectal cancer (mCRC) patients was subjected to CellSearch CTC enumeration and isolation. In all samples, 95 mRNAs were measured by reverse transcriptase quantitative PCR (RT-qPCR). HD blood samples and patient samples with three or more CTCs were compared to identify CTC-specific mRNAs. Patient samples without detectable CTCs were separately analyzed. RESULTS Thirty-four CTC-specific mRNAs were higher expressed in patients with ≥3 CTCs compared with HDs (Mann-Whitney U-test P < 0.05). Among patients without detectable CTCs, a HD-unlike subgroup was identified which could be distinguished from HDs by the expression of epithelial genes such as KRT19, KRT20 and AGR2. Also, in an independent patient set, a similar HD-unlike group could be identified among the patients without detectable CTCs according to the CellSearch system. CONCLUSION Extensive molecular characterization of colorectal CTCs is feasible and a subgroup of patients without detectable CTCs according to CellSearch criteria bears circulating tumor load, which may have clinical consequences. This CTC-specific gene panel for mCRC patients may enable the exploration of CTC characterization as a novel means to further individualize cancer treatment.
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Affiliation(s)
- Bianca Mostert
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Anieta M Sieuwerts
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Joan Bolt-de Vries
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jaco Kraan
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Zarina Lalmahomed
- Department of Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Anne van Galen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Petra van der Spoel
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Vanja de Weerd
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Raquel Ramírez-Moreno
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Marcel Smid
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Cornelis Verhoef
- Department of Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jan W Gratama
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Stefan Sleijfer
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - John A Foekens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands
| | - John W M Martens
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.
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