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Eskandarion MR, Eskandarieh S, Tutunchi S, Shakoori Farahani A, Shirkoohi R. Investigating the role of circulating tumor cells in gastric cancer: a comprehensive systematic review and meta-analysis. Clin Exp Med 2024; 24:59. [PMID: 38554188 PMCID: PMC10981629 DOI: 10.1007/s10238-024-01310-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 02/19/2024] [Indexed: 04/01/2024]
Abstract
Investigating the role of circulating tumor cells (CTCs) and their characteristics is still controversial in patients with gastric cancer (GC). Therefore, in this study, to provide a comprehensive review and meta-analyses of the literature on association of CTCs with gastric cancer, Scopus, Web of Science, Embase, and Medline were searched for systematic reviews and meta-analyses conducted during February 2022 using the keywords. Risk of bias, hazard ratios (HRs), and risk differences (RD) were assessed. Forty-five studies containing 3,342 GC patients from nine countries were assessed. The overall prevalence of CTC in GC was 69.37% (60.27, 77.78). The pooled result showed that increased mortality in GC patients was significantly associated with positive CTCs, poor overall survival (HR = 2.73, 95%CI 2.34-3.24, p < 0.001), and progression-free survival rate (HR = 2.78, 95%CI 2.01-3.85, p < 0.001). Subgroup analyses regarding markers, detection methods, treatment type, presence of distance metastasis, presence of lymph node metastasis, and overall risk of bias showed significant associations between the groups in terms of the incidence rates of CTCs, OS, and PFS. In addition, the results of risk differences based on sampling time showed that the use of the cell search method (RD: - 0.19, 95%CI (- 0.28, - 0.10), p < 0.001), epithelial marker (RD: - 0.12, 95%CI (- 0.25, 0.00), p 0.05) and mesenchymal markers (RD: - 0.35, 95%CI (- 0.57, - 0.13), p 0.002) before the treatment might have a higher diagnostic power to identify CTCs and also chemotherapy treatment (RD: - 0.17, 95%CI (- 0.31, - 0.03), p 0.016) could significantly reduce the number of CTCs after the treatment. We also found that the risk differences between the clinical early and advanced stages were not statistically significant (RD: - 0.10, 95%CI (- 0.23, 0.02), P 0.105). Also, in the Lauren classification, the incidence of CTC in the diffuse type (RD: - 0.19, 95%CI (- 0.37, - 0.01), P0.045) was higher than that in the intestinal type. Meta-regression analysis showed that baseline characteristics were not associated with the detection of CTCs in GC patients. According to our systematic review and meta-analysis, CTCs identification may be suggested as a diagnostic technique for gastric cancer screening, and the outcomes of CTC detection may also be utilized in the future to create personalized medicine programs.
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Affiliation(s)
| | - Sharareh Eskandarieh
- Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Tutunchi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Shakoori Farahani
- Medical Genetics Ward, IKHC Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Shirkoohi
- Cancer Research Center, Cancer Institute, IKHC, Tehran University of Medical Sciences, Tehran, Iran.
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Wang Y, Pan J, Sun Z. LncRNA NCK1-AS1-mediated regulatory functions in human diseases. Clin Transl Oncol 2023; 25:323-332. [PMID: 36131072 DOI: 10.1007/s12094-022-02948-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 09/05/2022] [Indexed: 06/15/2023]
Abstract
Disease development requires the activation of complex multi-factor processes involving numerous long noncoding RNAs (lncRNAs), which describe non-protein-coding RNAs longer than 200 nucleotides. Emerging evidence indicates that lncRNAs act as essential regulators that perform pivotal roles in the pathogenesis and progression of human diseases. The mechanisms underlying lncRNA involvement in diverse diseases have been extensively explored, and lncRNAs are considered powerful biomarkers for clinical practice. The lncRNA noncatalytic region of tyrosine kinase adaptor protein 1 (NCK1) antisense 1 (NCK1-AS1), also known as NCK1 divergent transcript (NCK1-DT), is encoded on human chromosome 3q22.3 and produces a 27,274-base-long transcript. NCK1-AS1 has increasingly been characterized as a causative agent for multiple diseases. The abnormal expression and involvement of NCK1-AS1 in various biological processes have been associated with several diseases. Further exploration of the mechanisms through which NCK1-AS1 contributes to disease development and progression will provide a foundation for potential clinical applications of NCK1-AS1 in the diagnosis and treatment of various diseases. This review summarizes the current understanding of the various functions and mechanisms through which NCK1-AS1 contributes to various diseases and the clinical application prospects for NCK1-AS1.
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Affiliation(s)
- Yingfan Wang
- Department of Obstetrics and Gynaecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Jie Pan
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zongzong Sun
- Department of Obstetrics and Gynaecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Brown ZJ, Patwardhan S, Bean J, Pawlik TM. Molecular diagnostics and biomarkers in cholangiocarcinoma. Surg Oncol 2022; 44:101851. [PMID: 36126350 DOI: 10.1016/j.suronc.2022.101851] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/26/2022] [Accepted: 09/09/2022] [Indexed: 10/14/2022]
Abstract
Regardless of anatomic origin, cholangiocarcinoma is generally an aggressive malignancy with a relatively high case fatality. Surgical resection with curative intent remains the best opportunity to achieve meaningful long-term survival. Most patients present, however, with advanced disease and less than 20% of patients are candidates for surgical resection. Unfortunately, even patients who undergo resection have a 5-year survival that ranges from 20 to 40%. Biomarkers are indicators of normal, pathologic, or biologic responses to an intervention and can range from a characteristic (i.e., blood pressure reading which can detect hypertension) to specific genetic mutations or proteins (i.e., carcinoembryonic antigen level). Novel biomarkers and improved molecular diagnostics represent an attractive opportunity to improve detection as well as to identify novel therapeutic targets for patients with cholangiocarcinoma. We herein review the latest advances in molecular diagnostics and biomarkers related to the early detection and treatment of patients with cholangiocarcinoma.
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Affiliation(s)
- Zachary J Brown
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
| | - Satyajit Patwardhan
- Dept of HPB Surgery and Liver Transplantation, Global Hospital, Mumbai, India
| | - Joal Bean
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
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Liquid biopsy as a perioperative biomarker of digestive tract cancers: review of the literature. Surg Today 2020; 51:849-861. [PMID: 32979121 DOI: 10.1007/s00595-020-02148-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 08/10/2020] [Indexed: 10/23/2022]
Abstract
Tissue biopsies are the gold-standard for investigating the molecular characterization of tumors. However, a "solid" biopsy is an invasive procedure that cannot capture real-time tumor dynamics and may yield inaccurate information because of intratumoral heterogeneity. In this review, we summarize the current state of knowledge about surgical treatment-associated "liquid" biopsy for patients with digestive organ tumors. A liquid biopsy is a technique involving the sampling and testing of non-solid biological materials, including blood, urine, saliva, and ascites. Previous studies have reported the potential value of blood-based biomarkers, circulating tumor cells, and cell-free nucleic acids as facilitators of cancer treatment. The applications of a liquid biopsy in a cancer treatment setting include screening and early diagnosis, prognostication, and outcome and recurrence monitoring of cancer. This technique has also been suggested as a useful tool in personalized medicine. The transition to precision medicine is still in its early stages. Soon, however, liquid biopsy is likely to form the basis of patient selection for molecular targeted therapies, predictions regarding chemotherapy sensitivity, and real-time evaluations of therapeutic effects.
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Voronin DV, Kozlova AA, Verkhovskii RA, Ermakov AV, Makarkin MA, Inozemtseva OA, Bratashov DN. Detection of Rare Objects by Flow Cytometry: Imaging, Cell Sorting, and Deep Learning Approaches. Int J Mol Sci 2020; 21:E2323. [PMID: 32230871 PMCID: PMC7177904 DOI: 10.3390/ijms21072323] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/25/2020] [Accepted: 03/25/2020] [Indexed: 12/14/2022] Open
Abstract
Flow cytometry nowadays is among the main working instruments in modern biology paving the way for clinics to provide early, quick, and reliable diagnostics of many blood-related diseases. The major problem for clinical applications is the detection of rare pathogenic objects in patient blood. These objects can be circulating tumor cells, very rare during the early stages of cancer development, various microorganisms and parasites in the blood during acute blood infections. All of these rare diagnostic objects can be detected and identified very rapidly to save a patient's life. This review outlines the main techniques of visualization of rare objects in the blood flow, methods for extraction of such objects from the blood flow for further investigations and new approaches to identify the objects automatically with the modern deep learning methods.
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Affiliation(s)
- Denis V. Voronin
- Laboratory of Biomedical Photoacoustics, Saratov State University, 410012 Saratov, Russia
- Department of Physical and Colloid Chemistry, National University of Oil and Gas (Gubkin University), 119991 Moscow, Russia
| | - Anastasiia A. Kozlova
- Laboratory of Biomedical Photoacoustics, Saratov State University, 410012 Saratov, Russia
| | - Roman A. Verkhovskii
- Laboratory of Biomedical Photoacoustics, Saratov State University, 410012 Saratov, Russia
- School of Urbanistics, Civil Engineering and Architecture, Yuri Gagarin State Technical University of Saratov, 410054 Saratov, Russia
| | - Alexey V. Ermakov
- Laboratory of Biomedical Photoacoustics, Saratov State University, 410012 Saratov, Russia
- Department of Biomedical Engineering, I. M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Mikhail A. Makarkin
- Laboratory of Biomedical Photoacoustics, Saratov State University, 410012 Saratov, Russia
| | - Olga A. Inozemtseva
- Laboratory of Biomedical Photoacoustics, Saratov State University, 410012 Saratov, Russia
| | - Daniil N. Bratashov
- Laboratory of Biomedical Photoacoustics, Saratov State University, 410012 Saratov, Russia
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Woestemeier A, Harms-Effenberger K, Karstens KF, Konczalla L, Ghadban T, Uzunoglu FG, Izbicki JR, Bockhorn M, Pantel K, Reeh M. Clinical Relevance of Circulating Tumor Cells in Esophageal Cancer Detected by a Combined MACS Enrichment Method. Cancers (Basel) 2020; 12:E718. [PMID: 32197486 PMCID: PMC7140099 DOI: 10.3390/cancers12030718] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/11/2020] [Accepted: 03/12/2020] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Current modalities to predict tumor recurrence and survival in esophageal cancer are insufficient. Even in lymph node-negative patients, a locoregional and distant relapse is common. Hence, more precise staging methods are needed. So far, only the CellSearch system was used to detect circulating tumor cells (CTC) with clinical relevance in esophageal cancer patients. Studies analyzing different CTC detection assays using advanced enrichment techniques to potentially increase the sensitivity are missing. METHODS In this single-center, prospective study, peripheral blood samples from 90 esophageal cancer patients were obtained preoperatively and analyzed for the presence of CTCs by Magnetic Cell Separation (MACS) enrichment (combined anti-cytokeratin and anti-epithelial cell adhesion molecules (EpCAM)), with subsequent immunocytochemical staining. Data were correlated with clinicopathological parameters and patient outcomes. RESULTS CTCs were detected in 25.6% (23/90) of the patients by combined cytokeratin/EpCAM enrichment (0-150 CTCs/7.5 mL). No significant correlation between histopathological parameters and CTC detection was found. Survival analysis revealed that the presence of more than two CTCs correlated with significantly shorter overall survival (OS) and progression-free survival (PFS). CONCLUSION With the use of cytokeratin as an additional enrichment target, the CTC detection rate in esophageal cancer patients can be elevated and displays the heterogeneity of cytokeratin (CK) and EpCAM expression. The presence of >2CTCs correlated with a shorter relapse-free and overall survival in a univariate analysis, but not in a multivariate setting. Moreover, our results suggest that the CK7/8+/EpCAM+ or CK7/8+/EpCAM- CTC subtype does not lead to an advanced tumor staging tool in non-metastatic esophageal cancer (EC) patients.
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Affiliation(s)
- Anna Woestemeier
- Department of General, Visceral and Thoracic Surgery, University Medical Centre, Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (A.W.); (K.-F.K.); (L.K.); (T.G.); (F.G.U.); (J.R.I.); (M.B.)
| | - Katharina Harms-Effenberger
- Department of Tumor Biology, University Medical Centre, Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (K.H.-E.); (K.P.)
| | - Karl-F. Karstens
- Department of General, Visceral and Thoracic Surgery, University Medical Centre, Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (A.W.); (K.-F.K.); (L.K.); (T.G.); (F.G.U.); (J.R.I.); (M.B.)
| | - Leonie Konczalla
- Department of General, Visceral and Thoracic Surgery, University Medical Centre, Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (A.W.); (K.-F.K.); (L.K.); (T.G.); (F.G.U.); (J.R.I.); (M.B.)
| | - Tarik Ghadban
- Department of General, Visceral and Thoracic Surgery, University Medical Centre, Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (A.W.); (K.-F.K.); (L.K.); (T.G.); (F.G.U.); (J.R.I.); (M.B.)
| | - Faik G. Uzunoglu
- Department of General, Visceral and Thoracic Surgery, University Medical Centre, Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (A.W.); (K.-F.K.); (L.K.); (T.G.); (F.G.U.); (J.R.I.); (M.B.)
| | - Jakob R. Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Centre, Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (A.W.); (K.-F.K.); (L.K.); (T.G.); (F.G.U.); (J.R.I.); (M.B.)
| | - Maximilian Bockhorn
- Department of General, Visceral and Thoracic Surgery, University Medical Centre, Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (A.W.); (K.-F.K.); (L.K.); (T.G.); (F.G.U.); (J.R.I.); (M.B.)
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Centre, Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (K.H.-E.); (K.P.)
| | - Matthias Reeh
- Department of General, Visceral and Thoracic Surgery, University Medical Centre, Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (A.W.); (K.-F.K.); (L.K.); (T.G.); (F.G.U.); (J.R.I.); (M.B.)
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Agatsuma N, Nishikawa Y, Horimatsu T, Nakatani Y, Juri N, Akamatsu T, Seta T, Minamiguchi S, Yamashita Y. Bone metastasis as a recurrence of early papillary adenocarcinoma of the stomach. Clin J Gastroenterol 2019; 13:349-353. [PMID: 31606847 DOI: 10.1007/s12328-019-01050-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/24/2019] [Indexed: 12/28/2022]
Abstract
Papillary adenocarcinomas of the stomach are rare and associated with a high rate of lymphovascular invasion and distant metastasis. However, the association between papillary adenocarcinoma and bone metastasis in gastric cancer remains largely unexplored. We report a rare case of bone metastasis as a recurrence of early papillary adenocarcinoma of the stomach after curative surgery. A 75-year-old man with a pedunculated polyp at the pylorus of the stomach was diagnosed with papillary adenocarcinoma after biopsy of the lesion, and the polyp was surgically resected. Pathohistological examination revealed intramucosal cancer without lymphovascular invasion or lymph node metastasis. Eight months after surgery, imaging studies showed osteolysis in the right sacrum, and the lesion was diagnosed as a bone metastasis after biopsy. The patient received palliative chemotherapy and radiotherapy for the bone metastasis, which resulted in relief of his leg pain. Subsequently, he was provided supportive care when his condition deteriorated, and he died 8 months after the diagnosis of bone metastasis. Our case shows that bone metastasis should not be overlooked, even though it is rare in gastric cancer patients. Papillary adenocarcinoma of the stomach should be carefully followed up through imaging examinations, even after curative resection.
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Affiliation(s)
- Nobukazu Agatsuma
- Department of Gastroenterology and Hepatology, Japanese Red Cross Wakayama Medical Center, 20 Banchi 4 Chome Komatsubara-Dori, Wakayama, 640-8558, Wakayama, Japan.
| | - Yoshitaka Nishikawa
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Horimatsu
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yasuki Nakatani
- Department of Gastroenterology and Hepatology, Japanese Red Cross Wakayama Medical Center, 20 Banchi 4 Chome Komatsubara-Dori, Wakayama, 640-8558, Wakayama, Japan
| | - Noriko Juri
- Department of Gastroenterology and Hepatology, Japanese Red Cross Wakayama Medical Center, 20 Banchi 4 Chome Komatsubara-Dori, Wakayama, 640-8558, Wakayama, Japan
| | - Takuji Akamatsu
- Department of Gastroenterology and Hepatology, Japanese Red Cross Wakayama Medical Center, 20 Banchi 4 Chome Komatsubara-Dori, Wakayama, 640-8558, Wakayama, Japan
| | - Takeshi Seta
- Department of Gastroenterology and Hepatology, Japanese Red Cross Wakayama Medical Center, 20 Banchi 4 Chome Komatsubara-Dori, Wakayama, 640-8558, Wakayama, Japan
| | | | - Yukitaka Yamashita
- Department of Gastroenterology and Hepatology, Japanese Red Cross Wakayama Medical Center, 20 Banchi 4 Chome Komatsubara-Dori, Wakayama, 640-8558, Wakayama, Japan
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Zhang J, Quadri S, Wolfgang CL, Zheng L. New Development of Biomarkers for Gastrointestinal Cancers: From Neoplastic Cells to Tumor Microenvironment. Biomedicines 2018; 6:biomedicines6030087. [PMID: 30104497 PMCID: PMC6163728 DOI: 10.3390/biomedicines6030087] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 07/30/2018] [Accepted: 08/10/2018] [Indexed: 02/07/2023] Open
Abstract
Biomarkers refer to a plethora of biological characteristics that can be quantified to facilitate cancer diagnosis, forecast the prognosis of disease, and predict a response to treatment. The identification of objective biomarkers is among the most crucial steps in the realization of individualized cancer care. Several tumor biomarkers for gastrointestinal malignancies have been applied in the clinical setting to help differentiate between cancer and other conditions, facilitate patient selection for targeted therapies, and to monitor treatment response and recurrence. With the coming of the immunotherapy age, the need for a new development of biomarkers that are indicative of the immune response to tumors are unprecedentedly urgent. Biomarkers from the tumor microenvironment, tumor genome, and signatures from liquid biopsies have been explored, but the majority have shown a limited prognostic or predictive value as single biomarkers. Nevertheless, use of multiplex biomarkers has the potential to provide a significantly increased diagnostic accuracy compared to traditional single biomarker. A comprehensive analysis of immune-biomarkers is needed to reveal the dynamic and multifaceted anti-tumor immunity and thus imply for the rational design of assays and combinational strategies.
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Affiliation(s)
- Jiajia Zhang
- Departments of Oncology and Surgery, the Sidney Kimmel Comprehensive Cancer Center, the Bloomberg-Kimmel Institute for Cancer Immunotherapy, the Pancreatic Cancer Precision Medicine Center of Excellence Program, the Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
| | - Shafat Quadri
- Merck Research Laboratory, Merck & Co., Kenilworth, NJ 07033, USA.
| | - Christopher L Wolfgang
- Departments of Oncology and Surgery, the Sidney Kimmel Comprehensive Cancer Center, the Bloomberg-Kimmel Institute for Cancer Immunotherapy, the Pancreatic Cancer Precision Medicine Center of Excellence Program, the Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
| | - Lei Zheng
- Departments of Oncology and Surgery, the Sidney Kimmel Comprehensive Cancer Center, the Bloomberg-Kimmel Institute for Cancer Immunotherapy, the Pancreatic Cancer Precision Medicine Center of Excellence Program, the Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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Chitty JL, Filipe EC, Lucas MC, Herrmann D, Cox TR, Timpson P. Recent advances in understanding the complexities of metastasis. F1000Res 2018; 7. [PMID: 30135716 DOI: 10.12688/f1000research.15064.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/24/2018] [Indexed: 12/14/2022] Open
Abstract
Tumour metastasis is a dynamic and systemic process. It is no longer seen as a tumour cell-autonomous program but as a multifaceted and complex series of events, which is influenced by the intrinsic cellular mutational burden of cancer cells and the numerous bidirectional interactions between malignant and non-malignant cells and fine-tuned by the various extrinsic cues of the extracellular matrix. In cancer biology, metastasis as a process is one of the most technically challenging aspects of cancer biology to study. As a result, new platforms and technologies are continually being developed to better understand this process. In this review, we discuss some of the recent advances in metastasis and how the information gleaned is re-shaping our understanding of metastatic dissemination.
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Affiliation(s)
- Jessica L Chitty
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia
| | - Elysse C Filipe
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia
| | - Morghan C Lucas
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia
| | - David Herrmann
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW , 2010, Australia
| | - Thomas R Cox
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW , 2010, Australia
| | - Paul Timpson
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW , 2010, Australia
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10
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Chitty JL, Filipe EC, Lucas MC, Herrmann D, Cox TR, Timpson P. Recent advances in understanding the complexities of metastasis. F1000Res 2018; 7. [PMID: 30135716 PMCID: PMC6073095 DOI: 10.12688/f1000research.15064.2] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2018] [Indexed: 12/14/2022] Open
Abstract
Tumour metastasis is a dynamic and systemic process. It is no longer seen as a tumour cell-autonomous program but as a multifaceted and complex series of events, which is influenced by the intrinsic cellular mutational burden of cancer cells and the numerous bidirectional interactions between malignant and non-malignant cells and fine-tuned by the various extrinsic cues of the extracellular matrix. In cancer biology, metastasis as a process is one of the most technically challenging aspects of cancer biology to study. As a result, new platforms and technologies are continually being developed to better understand this process. In this review, we discuss some of the recent advances in metastasis and how the information gleaned is re-shaping our understanding of metastatic dissemination.
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Affiliation(s)
- Jessica L Chitty
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia
| | - Elysse C Filipe
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia
| | - Morghan C Lucas
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia
| | - David Herrmann
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW , 2010, Australia
| | - Thomas R Cox
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW , 2010, Australia
| | - Paul Timpson
- Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, NSW, 2010, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW , 2010, Australia
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11
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Agnes A, Biondi A, Ricci R, Gallotta V, D'Ugo D, Persiani R. Krukenberg tumors: Seed, route and soil. Surg Oncol 2017; 26:438-445. [PMID: 29113663 DOI: 10.1016/j.suronc.2017.09.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Revised: 08/28/2017] [Accepted: 09/09/2017] [Indexed: 01/10/2023]
Abstract
The aim of this narrative review was to summarize the current evidence on Krukenberg tumors (KTs), addressing what is known on their natural history and their impact on the clinical prognosis and which are the most appropriate management strategies to treat this condition. A literature search was conducted on Pubmed up to December 2016, selecting the most relevant studies on the basis of the scope of the review. KTs are ovarian metastases from primary signet-ring cell carcinomas., characterized by the presence of a sarcoma-like stroma. They have three possible routes of diffusion (lymphatic, peritoneal and hematogenous), but the preferential one is still unclear. Prognosis is dismal. When KTs are encountered in the clinical practice, it is reasonable to offer surgical resection to young, fit patients with limited disease. Palliative surgery should be considered for all patients with symptomatic disease. Further studies should clarify the clinicopathologic characteristics of KTs, their main routes of diffusion, and the possible role of prophylactic oophorectomy, lymphadenectomy and intraperitoneal chemotherapy. Molecular and transitional research should parallel the clinical one to help understanding the natural history of signet-ring cell carcinomas.
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Affiliation(s)
- Annamaria Agnes
- Polo Scienze Gastroenterologiche ed Endocrino-Metaboliche, Università Cattolica del Sacro Cuore Fondazione Policlinico Universitario Agostino Gemelli Largo F. Vito, 1 00168 Rome, Italy
| | - Alberto Biondi
- Polo Scienze Gastroenterologiche ed Endocrino-Metaboliche, Università Cattolica del Sacro Cuore Fondazione Policlinico Universitario Agostino Gemelli Largo F. Vito, 1 00168 Rome, Italy.
| | - Riccardo Ricci
- Polo Scienze Oncologiche ed Ematologiche, Università Cattolica del Sacro Cuore Fondazione Policlinico Universitario Agostino Gemelli Largo F. Vito, 1 00168 Rome, Italy
| | - Valerio Gallotta
- Polo Scienze Della Salute Della Donna E Del Bambino, Università Cattolica del Sacro Cuore Fondazione Policlinico Universitario Agostino Gemelli Largo F. Vito, 1 00168 Rome, Italy
| | - Domenico D'Ugo
- Polo Scienze Gastroenterologiche ed Endocrino-Metaboliche, Università Cattolica del Sacro Cuore Fondazione Policlinico Universitario Agostino Gemelli Largo F. Vito, 1 00168 Rome, Italy
| | - Roberto Persiani
- Polo Scienze Gastroenterologiche ed Endocrino-Metaboliche, Università Cattolica del Sacro Cuore Fondazione Policlinico Universitario Agostino Gemelli Largo F. Vito, 1 00168 Rome, Italy
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Du YY, Zhang QJ, Sun GP. Expression and Clinical Significance of Cytokeratin-19 and Thymidine Kinase-1 in Advanced Gastrointestinal Cancer. Chin Med J (Engl) 2017; 129:2168-72. [PMID: 27625087 PMCID: PMC5022336 DOI: 10.4103/0366-6999.189919] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background: As the clinical value of cytokeratin-19 (CK19) and thymidine kinase-1 (TK1) in advanced gastrointestinal cancer remains controversial, we investigated their expression and clinical significance in this disease. Methods: A total of 171 advanced gastrointestinal cancer patients were prospectively enrolled in this study. The mRNA level of CK19 was detected using quantitative real-time reverse transcription-polymerase chain reaction (PCR) in all patients, along with a control group of fifty healthy individuals. Furthermore, detection of TK1 protein was carried out in 96 patients using a chemiluminescence dot blot assay. The primary endpoint was overall survival (OS) time. Results: Positive CK19 mRNA expression was detected in 74 (43.3%) of the 171 patients and positive TK1 expression was detected in 66 (68.8%) of the 96 patients. Furthermore, of the 96 patients, 36 (37.5%) were positive for both TK1 protein and CK19 mRNA, 30 (31.3%) were negative for TK1 protein, and 15 (15.6%) were negative for TK1 protein and positive for CK19 mRNA. The results indicated that patients who were positive for CK19 mRNA expression had significantly shorter OS times than those who were negative for it (median OS 7.7 vs. 9.7 months, respectively; P = 0.02). Moreover, patients who were positive for CK19 mRNA and TK1 protein expression had shorter OS times (median OS 6.1 months) than those who were positive for CK19 mRNA and negative for TK1 protein expression (median OS 9.1 months; P = 0.028). Positive CK19 mRNA expression was significantly associated with shorter OS in the univariate analysis (P = 0.027). Based on a multivariate Cox regression analysis, CK19 mRNA together with TK1 protein expression (P = 0.024) was an independent predictor for OS in gastrointestinal cancer patients. Conclusions: Our results suggest that positive expression of CK19 mRNA and TK1 protein is closely correlated with poor prognosis in advanced gastrointestinal cancer. Furthermore, both CK19 and TK1 are possible gastrointestinal cancer biomarkers.
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Affiliation(s)
- Ying-Ying Du
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Qiu-Jun Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Guo-Ping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
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Arigami T, Uenosono Y, Yanagita S, Okubo K, Kijima T, Matsushita D, Amatatsu M, Kurahara H, Maemura K, Natsugoe S. Clinical significance of circulating tumor cells in blood from patients with gastric cancer. Ann Gastroenterol Surg 2017; 1:60-68. [PMID: 29863113 PMCID: PMC5881297 DOI: 10.1002/ags3.12005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 02/27/2017] [Indexed: 12/19/2022] Open
Abstract
Circulating tumor cells (CTC) have been focused on as a target for detecting occult tumors, predicting therapeutic responses and prognoses, and monitoring postoperative recurrence in the clinical management of patients with various malignancies, including gastric cancer. Recent advances in molecular diagnostic tools have contributed to high sensitivity and specificity for the detection of CTC. A conspicuous disparity exists in the incidence of CTC among studies. However, a close relationship has been reported between positivity for CTC and well-known prognostic clinicopathological factors including depth of tumor invasion, lymph node metastasis, stage, and lymphatic and venous invasion in patients with gastric cancer. According to most studies published on the clinical impact of CTC, the presence of CTC negatively affects the prognosis of patients with gastric cancer. Moreover, the study of CTC based on a meta-analysis demonstrated their importance as a poor prognostic indicator. In clinical management, pre- and post-therapeutic monitoring of CTC using liquid biopsy may be useful for early detection of subclinical patients or disease recurrence, prediction of tumor progression, and administrative control of adjuvant chemotherapy. Although their functional properties remain unclear, molecular profiling of CTC may contribute to the development of personalized treatment that effectively inhibits tumor progression in patients with advanced gastric cancer. We herein review the clinical significance of CTC as a promising blood marker and therapeutic target in patients with gastric cancer.
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Affiliation(s)
- Takaaki Arigami
- Department of Digestive SurgeryBreast and Thyroid SurgeryField of OncologyKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
- Molecular Frontier SurgeryCourse of Advanced TherapeuticsKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
| | - Yoshikazu Uenosono
- Molecular Frontier SurgeryCourse of Advanced TherapeuticsKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
| | - Shigehiro Yanagita
- Department of Digestive SurgeryBreast and Thyroid SurgeryField of OncologyKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
| | - Keishi Okubo
- Department of Digestive SurgeryBreast and Thyroid SurgeryField of OncologyKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
| | - Takashi Kijima
- Department of Digestive SurgeryBreast and Thyroid SurgeryField of OncologyKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
| | - Daisuke Matsushita
- Department of Digestive SurgeryBreast and Thyroid SurgeryField of OncologyKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
| | - Masahiko Amatatsu
- Department of Digestive SurgeryBreast and Thyroid SurgeryField of OncologyKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
| | - Hiroshi Kurahara
- Department of Digestive SurgeryBreast and Thyroid SurgeryField of OncologyKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
| | - Kosei Maemura
- Department of Digestive SurgeryBreast and Thyroid SurgeryField of OncologyKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
| | - Shoji Natsugoe
- Department of Digestive SurgeryBreast and Thyroid SurgeryField of OncologyKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
- Molecular Frontier SurgeryCourse of Advanced TherapeuticsKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
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Zhong J, Chen Y, Wang LJ. Emerging molecular basis of hematogenous metastasis in gastric cancer. World J Gastroenterol 2016; 22:2434-2440. [PMID: 26937132 PMCID: PMC4768190 DOI: 10.3748/wjg.v22.i8.2434] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/29/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
Lymphatic metastasis is commonly observed in gastric cancer (GC), but hematogenous metastasis is more likely responsible for the cancer-related mortality. Since Stephen Paget first introduced the “seed and soil hypothesis” a century ago, growing evidence recognizes that numerous essential secreted factors and signaling pathway effectors participate in the pre-metastatic niche formation and distant organ metastasis. The cross-talk between GC cells and surrounding microenvironment may consist of a series of interrelated steps, including epithelial mesenchymal transition, intravasation into blood vessels, circulating tumor cell translocation, and secondary organ metastasis. Secreted factors including vascular endothelial growth factor (VEGF), matrix metalloproteinases and cancer-derived extracellular vesicles, especially exosomes, are essential in formation of premetastatic niche. Circulating tumor cells and microRNAs represent as ‘‘metastatic intermediates’’ between primary tumors and sites of dissemination. Many biomarkers have been identified as novel metastatic markers and prognostic effectors. In addition, molecular therapy has been designed to target biomarkers such as growth factors (human epidermal growth factor receptor 2, VEGF) and chemokines, although they have not clearly proven to be effective in inhibiting GC metastasis in clinical trials. In this review, we will systematically discuss the emerging molecules and their microenvironment in hematogenous metastasis of GC, which may help us to find new therapeutic strategies in the future.
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Circulating tumour cells predict survival in gastric cancer patients: a meta-analysis. Contemp Oncol (Pozn) 2016; 19:451-7. [PMID: 26843841 PMCID: PMC4731451 DOI: 10.5114/wo.2015.56651] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 05/29/2014] [Indexed: 12/11/2022] Open
Abstract
AIM OF THE STUDY The prognostic value of the detection of circulating tumour cells (CTCs) in gastric cancer has been studied intensely in recent years. However, the application of different technologies led to inconsistent results between the studies. Here, we performed a meta-analysis of published studies to summarise the evidence. MATERIAL AND METHODS Medline and ISI Web of Knowledge were searched up to March 2013 using "circulating tumor cells" and "gastric cancer" as search terms. Hazard ratio (HR) with 95% confidence intervals (CIs) for prognostic outcomes and clinical characteristics were extracted from each study. Pooled hazard ratios (HR) and odds ratios (OR) were calculated using random or fixed-effects models. RESULTS Twelve studies enrolling 774 patients were included. The combined HR estimate for overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) were 1.41 (95% CI: 1.28-1.62), 2.99 (95% CI: 2.01-4.45) and 1.64 (95% CI: 1.02-2.62), respectively. Subgroup analysis concerning detection methods and sampling time showed that results of RT-PCR for the OS group and RT-PCR for the DFS group suggest a prognostic significance of CTC detection (pooled HR [95% CI]: 1.45 [1.28-1.65], I(2) = 38%, p = 0.13; 2.99 [2.01-4.45], I(2) = 0%, p = 0.32). In addition, results of the baseline CTC detection group also indicated a significant prognostic value to predict OS and DFS (pooled HR [95% CI]: 1.47 [1.19-1.82], I(2) = 38%, p = 0.14; 2.99 [2.01-4.45], I(2) = 0%, p = 0.32). We simultaneously found that the detection of CTCs correlated with pathological stage (pooled OR [95% CI]: 2.95 [1.65-5.28], I(2) = 56%, p = 0.03), lymph node status (pooled OR [95% CI]: 2.26 [1.50-3.41], I(2) = 37%, p = 0.09), the depth of invasion (pooled OR [95% CI]: 3.21 [1.38-7.43], I(2) = 72%, p = 0.002), and distant metastasis (pooled OR [95% CI]: 2.68 [1.25-5.73], I(2) = 43%, p = 0.15). CONCLUSIONS Detection of CTCs is associated with poorer prognosis in gastric cancer patients.
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16
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Kubisch I, de Albuquerque A, Schuppan D, Kaul S, Schaich M, Stölzel U. Prognostic Role of a Multimarker Analysis of Circulating Tumor Cells in Advanced Gastric and Gastroesophageal Adenocarcinomas. Oncology 2015; 89:294-303. [PMID: 26315108 DOI: 10.1159/000437373] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 07/02/2015] [Indexed: 01/14/2023]
Abstract
OBJECTIVE We aimed to assess the prognostic value of circulating tumor cells (CTC) in patients with advanced gastric and gastroesophageal adenocarcinomas. METHODS The presence of CTC was evaluated in 62 patients with advanced gastric and gastroesophageal adenocarcinomas before systemic therapy and at follow-up through immunomagnetic enrichment for mucin 1- and epithelial cell adhesion molecule (EpCAM)-positive cells, followed by real-time RT-PCR of the tumor-associated genes KRT19, MUC1, EPCAM, CEACAM5 and BIRC5. RESULTS The patients were stratified into groups according to CTC detection (CTC negative: with all marker genes negative; CTC positive: with at least 1 of the marker genes positive). Patients who were CTC positive at baseline had a significantly shorter median progression-free survival (PFS; 3.5 months, 95% CI: 2.9-4.2) and overall survival (OS; 5.8 months, 95% CI: 4.5-7.0) than patients lacking CTC (PFS 10.7 months, 95% CI: 6.9-14.4, p<0.001; OS 13.3 months, 95% CI: 8.0-18.6, p=0.003). Alterations in the marker profile during the course of chemotherapy were not predictive of clinical outcome or response to therapy. Yet, a favorable clinical response depended significantly on CTC negativity (p=0.03). CONCLUSION Our data suggest that the presence of CTC is a major predictor of outcome in patients with gastric and gastroesophageal malignancies.
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Affiliation(s)
- Ilja Kubisch
- Department of Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, Metabolic Disorders, Oncology, Klinikum Chemnitz gGmbH, Chemnitz, Germany
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Grover PK, Cummins AG, Price TJ, Roberts-Thomson IC, Hardingham JE. Circulating tumour cells: the evolving concept and the inadequacy of their enrichment by EpCAM-based methodology for basic and clinical cancer research. Ann Oncol 2014; 25:1506-16. [PMID: 24651410 DOI: 10.1093/annonc/mdu018] [Citation(s) in RCA: 166] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence suggests that circulating tumour cells (CTCs) are responsible for metastatic relapse and this has fuelled interest in their detection and quantification. Although numerous methods have been developed for the enrichment and detection of CTCs, none has yet reached the 'gold' standard. Since epithelial cell adhesion molecule (EpCAM)-based enrichment of CTCs offers several advantages, it is one of the most commonly used and has been adapted for high-throughput technology. However, emerging evidence suggests that CTCs are highly heterogeneous: they consist of epithelial tumour cells, epithelial-to-mesenchymal transition (EMT) cells, hybrid (epithelial/EMT(+)) tumour cells, irreversible EMT(+) tumour cells, and circulating tumour stem cells (CTSCs). The EpCAM-based approach does not detect CTCs expressing low levels of EpCAM and non-epithelial phenotypes such as CTSCs and those that have undergone EMT and no longer express EpCAM. Thus, the approach may lead to underestimation of the significance of CTCs, in general, and CTSCs and EMT(+) tumour cells, in particular, in cancer dissemination. Here, we provide a critical review of research literature on the evolving concept of CTCs and the inadequacy of their enrichment by EpCAM-based technology for basic and clinical cancer research. The review also outlines future perspectives in the field.
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Affiliation(s)
| | | | - T J Price
- Haematology-Oncology, The Queen Elizabeth Hospital, Woodville South, Australia
| | | | - J E Hardingham
- Haematology-Oncology, The Queen Elizabeth Hospital, Woodville South, Australia
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18
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Bustin SA, Murphy J. RNA biomarkers in colorectal cancer. Methods 2013; 59:116-25. [DOI: 10.1016/j.ymeth.2012.10.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Revised: 09/28/2012] [Accepted: 10/04/2012] [Indexed: 02/08/2023] Open
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Clinical Implications of Circulating Tumor Cells in Advanced Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2012. [DOI: 10.1007/s11888-012-0138-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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20
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Takeuchi H, Kitagawa Y. Detection of circulating tumor cells in gastrointestinal cancer: Has its time come? J Gastrointest Oncol 2012; 3:84-5. [PMID: 22811873 DOI: 10.3978/j.issn.2078-6891.2012.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Accepted: 03/14/2012] [Indexed: 11/14/2022] Open
Affiliation(s)
- Hiroya Takeuchi
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
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21
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Faltas B. Cornering metastases: therapeutic targeting of circulating tumor cells and stem cells. Front Oncol 2012; 2:68. [PMID: 22783544 PMCID: PMC3388423 DOI: 10.3389/fonc.2012.00068] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Accepted: 06/12/2012] [Indexed: 12/21/2022] Open
Abstract
The last decade has witnessed an evolution of our understanding of the biology of the metastatic cascade. Recent insights into the metastatic process show that it is complex, dynamic, and multi-directional. This process starts at a very early stage in the natural history of solid tumor growth leading to early development of metastases that grow in parallel with the primary tumor. The role of stem cells in perpetuating cancer metastases is increasingly becoming more evident. At the same time, there is a growing recognition of the crucial role circulating tumor cells (CTCs) play in the development of metastases. These insights have laid the biological foundations for therapeutic targeting of CTCs, a promising area of research that aims to reduce cancer morbidity and mortality by preventing the development of metastases at a very early stage. The hematogenous transport phase of the metastatic cascade provides critical access to CTCs for therapeutic targeting aiming to interrupt the metastatic process. Recent advances in the fields of nanotechnology and microfluidics have led to the development of several devices for in vivo targeting of CTC during transit in the circulation. Selectin-coated tubes that target cell adhesion molecules, immuno-magnetic separators, and in vivo photo-acoustic flow cytometers are currently being developed for this purpose. On the pharmacological front, several pharmacological and immunological agents targeting cancer stem cells are currently being developed. Such agents may ultimately prove to be effective against circulating tumor stem cells (CTSCs). Although still in its infancy, therapeutic targeting of CTCs and CTSCs offers an unprecedented opportunity to prevent the development of metastasis and potentially alter the natural history of cancer. By rendering cancer a "local" disease, these approaches could lead to major reductions in metastasis-related morbidity and mortality.
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Affiliation(s)
- Bishoy Faltas
- Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY, USA
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22
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Yu QM, Wang XB, Luo J, Wang S, Fang XH, Yu JL, Ling ZQ. CDH1 methylation in preoperative peritoneal washes is an independent prognostic factor for gastric cancer. J Surg Oncol 2012; 106:765-71. [PMID: 22514028 PMCID: PMC3495294 DOI: 10.1002/jso.23116] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 03/15/2012] [Indexed: 02/06/2023]
Abstract
Background and Objectives To investigate the clinical value of CDH1 methylation in preoperative peritoneal washes (PPW) from gastric cancer patients. Methods CDH1 methylation was detected by real-time methylation specific-PCR in tumor tissues and corresponding PPW from 92 gastric cancer patients, gastric mucosa from 40 chronic gastritis patients and 48 normal persons. Results CDH1 methylation was found in 75 of 92 (81.5%) gastric cancer tissues, which significantly correlated with size, growth pattern, differentiation, lymphatic invasion, venous invasion, invasion depth, lymph node metastasis, distant metastasis, and TNM stage of tumor (all P < 0.05), but its relationship to age, gender, tumor site, and H. pylori infection was not found (all P > 0.05). The percentage of CDH1 methylation in PPW was 48.9%, of which the Aζ value of ROC curve was 0.8 compared to that in gastric cancer tissues. Kaplan–Meier analysis showed that there was a significant difference in disease-free survival (DFS) between the patients with or without methylated CDH1 in their PPW (χ2 = 109.64, P < 0.000). Cox regression analysis revealed CDH1 methylation in PPW was an independent risk factor for gastric cancer patients, with a remarkable decrease in DFS after postoperative 30 months. Conclusions Methylated CDH1 in PPW predicts poor prognosis for gastric cancer patients. J. Surg. Oncol. 2012; 106:765–771. © 2012 Wiley Periodicals, Inc.
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Affiliation(s)
- Qi-Ming Yu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Banshanqiao District, Hangzhou, China
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de Albuquerque A, Kubisch I, Breier G, Stamminger G, Fersis N, Eichler A, Kaul S, Stölzel U. Multimarker gene analysis of circulating tumor cells in pancreatic cancer patients: a feasibility study. Oncology 2012; 82:3-10. [PMID: 22270149 DOI: 10.1159/000335479] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2011] [Accepted: 11/15/2011] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The aim of this study was to develop an immunomagnetic/real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay and assess its clinical value for the molecular detection of circulating tumor cells (CTCs) in peripheral blood of pancreatic cancer patients. METHODS The presence of CTCs was evaluated in 34 pancreatic cancer patients before systemic therapy and in 40 healthy controls, through immunomagnetic enrichment, using the antibodies BM7 and VU1D9 [targeting mucin 1 and epithelial cell adhesion molecule (EpCAM), respectively], followed by real-time RT-PCR analysis of the genes KRT19, MUC1, EPCAM, CEACAM5 and BIRC5. RESULTS The developed assay showed high specificity, as none of the healthy controls were found to be positive for the multimarker gene panel. CTCs were detected in 47.1% of the pancreatic cancer patients before the beginning of systemic treatment. Shorter median progression-free survival (PFS) was observed for patients who had at least one detectable tumor-associated transcript, compared with patients who were CTC negative. Median PFS time was 66.0 days [95% confidence interval (CI) 44.8-87.2] for patients with baseline CTC positivity and 138.0 days (95% CI 124.1-151.9) for CTC-negative patients (p = 0.01, log-rank test). CONCLUSION Our results suggest that in addition to the current prognostic methods, CTC analysis represents a potential complementary tool for prediction of outcome in pancreatic cancer patients.
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Detection of circulating tumor cells in peripheral blood from patients with gastric cancer using piRNAs as markers. Clin Biochem 2011; 44:1050-1057. [PMID: 21704610 DOI: 10.1016/j.clinbiochem.2011.06.004] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2011] [Revised: 06/07/2011] [Accepted: 06/09/2011] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate the feasibility of detecting circulating cancer cells in peripheral blood from gastric cancer patients using Piwi-interacting RNAs (piRNAs) as markers. DESIGN AND METHODS Real-time quantitative reverse transcription-polymerase chain reaction was used to analyze piR-651 and piR-823 levels in the peripheral blood of 93 patients with gastric cancer and 32 healthy volunteers. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic values. RESULTS The peripheral blood levels of piR-651 and piR-823 in the patients with gastric cancer were significantly lower than those from controls (P<0.001). The piR-651 level in gastric adenocarcinoma was higher than that in gastric signet ring cell carcinoma (P = 0.003). The piR-823 level was positively associated with tumor-node-metastasis stage (P = 0.027) and distant metastasis (P = 0.026). The areas under the ROC curve were 0.841, 0.812 and 0.860 for piR-651, piR-823 and the combination, respectively. CONCLUSIONS piRNAs may be valuable biomarkers for detecting circulating gastric cancer cells.
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25
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Ren C, Han C, Wang D, Zhao X, Jin G, Shen H. Detection of circulating tumor cells: Clinical relevance of a novel metastatic tumor marker. Exp Ther Med 2011; 2:385-391. [PMID: 22977514 DOI: 10.3892/etm.2011.234] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Accepted: 02/08/2011] [Indexed: 12/18/2022] Open
Abstract
Most cancer-related deaths are caused by the hematogenous spread of cancer cells to distant organs and their subsequent metastasis. During the early stages of the metastatic cascade, cancer cells disseminate from the primary site via the lymphatic vessels and/or by hematogenous routes. Circulating tumor cells (CTCs), cancer cells that have disseminated into the systemic circulation, may be a predictor of poor prognosis in several carcinomas. An understanding of the molecular mechanisms involved in the blood-borne dissemination of cancer cells may help to clarify the process of metastasis and provide a powerful and non-invasive approach for anticancer treatments that are tailored to individual patients.
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Affiliation(s)
- Chuanli Ren
- Clinical Laboratory, Medical College of Yangzhou University, Yangzhou
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26
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Dardaei L, Shahsavani R, Ghavamzadeh A, Behmanesh M, Aslankoohi E, Alimoghaddam K, Ghaffari SH. The detection of disseminated tumor cells in bone marrow and peripheral blood of gastric cancer patients by multimarker (CEA, CK20, TFF1 and MUC2) quantitative real-time PCR. Clin Biochem 2010; 44:325-30. [PMID: 21130081 DOI: 10.1016/j.clinbiochem.2010.11.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2010] [Revised: 11/01/2010] [Accepted: 11/20/2010] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To investigate the suitability of multimarker detection of DTCs in PB and BM of GC patients. DESIGN AND METHOD A qRT-PCR assay was developed to estimate the number of CEA, CK20, TFF1 and MUC2 transcripts in PB and BM samples of 35 GC patients prior to the initiation of therapy. PB samples from healthy volunteers and BM from patients with hematological malignancies were used as negative controls. RESULTS In PB analysis; 22.9%, 37.1%, 31.4%, and 22.9% of GC patients and in BM analysis; 20%, 28.6%, 45.7%, and 22.9% of GC patients were positive for CEA, CK20, TFF1 and MUC2 mRNAs, respectively. Samples from the control group were negative for the expression of all the markers tested in this study. A higher positive ratio was obtained with the multimarker detection in comparison to the single marker detection. There was a significant correlation between the PB and BM samples for DTC detection. CONCLUSION Multimarker detection assay is a reliable and powerful tool for the early detection of DTCs in GC patients.
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Affiliation(s)
- L Dardaei
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
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