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Wu S, Li R, Jiang Y, Yu J, Zheng J, Li Z, Li M, Xin K, Wang Y, Xu Z, Li S, Chen X. Liquid biopsy in urothelial carcinoma: Detection techniques and clinical applications. Biomed Pharmacother 2023; 165:115027. [PMID: 37354812 DOI: 10.1016/j.biopha.2023.115027] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/26/2023] Open
Abstract
The types of urothelial carcinoma (UC) include urothelial bladder cancer and upper tract urothelial carcinoma. Current diagnostic techniques cannot meet the needs of patients. Liquid biopsy is an accurate method of determining the molecular profile of UC and is a cutting-edge and popular technique that is expected to complement existing detection techniques and benefit patients with UC. Circulating tumor cells, cell-free DNA, cell-free RNA, extracellular vesicles, proteins, and metabolites can be found in the blood, urine, or other bodily fluids and are examined during liquid biopsies. This article focuses on the components of liquid biopsies and their clinical applications in UC. Liquid biopsies have tremendous potential in multiple aspects of precision oncology, from early diagnosis and treatment monitoring to predicting prognoses. They may therefore play an important role in the management of UC and precision medicine.
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Affiliation(s)
- Siyu Wu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Rong Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Yuanhong Jiang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Jiazheng Yu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Jianyi Zheng
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Zeyu Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Mingyang Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Kerong Xin
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Yang Wang
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China.
| | - Zhenqun Xu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
| | - Shijie Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
| | - Xiaonan Chen
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
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Crocetto F, Cimmino A, Ferro M, Terracciano D. Circulating tumor cells in bladder cancer: a new horizon of liquid biopsy for precision medicine. J Basic Clin Physiol Pharmacol 2021; 33:525-527. [PMID: 34563104 DOI: 10.1515/jbcpp-2021-0233] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Felice Crocetto
- Department of Neurosciences, Sciences of Reproduction and Odontostomatology, University of Naples Federico II, Naples, Italy
| | - Amelia Cimmino
- Institute of Genetics and Biophysics, National Research Council, Naples, Italy
| | - Matteo Ferro
- Department of Urology of European Institute of Oncology (IEO), IRCCS, Milan, Italy
| | - Daniela Terracciano
- Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy
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Heck MM, Koll FJ, Retz M, Autenrieth M, Magg K, Lunger L, Gschwend JE, Nawroth R. Molecular lymph node staging for bladder cancer patients undergoing radical cystectomy with pelvic lymph node dissection. Urol Oncol 2020; 38:639.e11-639.e19. [PMID: 32146127 DOI: 10.1016/j.urolonc.2020.01.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 01/27/2020] [Accepted: 01/29/2020] [Indexed: 10/24/2022]
Abstract
OBJECTIVE Presence of lymph node (LN) metastasis in bladder cancer (BCa) is a main risk factor for tumor recurrence after radical cystectomy (RC). Molecular analysis facilitates detection of small-volume LN metastases with higher sensitivity than standard histopathology. The aim of the present study was to establish molecular LN analysis in BCa patients undergoing RC with lymph node dissection (LND) and to determine its ability to predict tumor recurrence. PATIENTS AND METHODS Five transcripts with overexpression in BCa (FXYD3, KRT17, KRT20, SPINK1, UPKII) were evaluated for molecular LN analysis. We included 76 BCa patients from the prospective, randomized surgical phase-III trial (LEA AUO AB 25/02, NCT01215071) investigating extended vs. limited LND at RC. The primary endpoint was recurrence-free survival (RFS). As control, 136 LNs from 45 patients without BCa were analyzed to determine a threshold for pathologic gene expression. RESULTS About 1,319 LNs were investigated with molecular and histopathologic examination. Histopathology detected 39 LN metastases in 17 (22%) patients. Of the tested genes FXYD3 performed best and classified all pN+-patients correctly as node-positive (pN+/molN+). In addition, FXYD3 reclassified 43 histopathologic negative LNs and 7 (9%) pN0-patients as molecular node-positive (pN0/molN+). Molecular and histopathologic LN status (pN0/molN0 vs. pN0/molN+ vs. pN+/molN+) was significantly associated with locally advanced disease (P = 0.006) and poor RFS (P < 0.001). Median RFS was not reached in LN-negative patients (pN0/molN0), 45 months (95%CI 8-83) in exclusively molecular positive patients (pN0/molN+) and 9 months (95%CI 5-13) in patients with histopathologic and molecular positive LNs (pN+/molN+). CONCLUSIONS Molecular LN analysis with FXYD3 identified additional LN metastases in histopathologic negative LNs and identified patients with elevated risk of tumor recurrence after RC. Thus, molecular LN analysis improves LN staging and might serve as a tool to guide adjuvant treatment.
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Affiliation(s)
- Matthias M Heck
- Technical University of Munich, School of Medicine, Rechts der Isar Medical Center, Department of Urology, Munich, Germany.
| | - Florestan J Koll
- Technical University of Munich, School of Medicine, Rechts der Isar Medical Center, Department of Urology, Munich, Germany
| | - Margitta Retz
- Technical University of Munich, School of Medicine, Rechts der Isar Medical Center, Department of Urology, Munich, Germany
| | - Michael Autenrieth
- Technical University of Munich, School of Medicine, Rechts der Isar Medical Center, Department of Urology, Munich, Germany
| | - Kathrin Magg
- Technical University of Munich, School of Medicine, Rechts der Isar Medical Center, Department of Urology, Munich, Germany
| | - Lukas Lunger
- Technical University of Munich, School of Medicine, Rechts der Isar Medical Center, Department of Urology, Munich, Germany
| | - Jürgen E Gschwend
- Technical University of Munich, School of Medicine, Rechts der Isar Medical Center, Department of Urology, Munich, Germany
| | - Roman Nawroth
- Technical University of Munich, School of Medicine, Rechts der Isar Medical Center, Department of Urology, Munich, Germany
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Zhang Z, Fan W, Deng Q, Tang S, Wang P, Xu P, Wang J, Yu M. The prognostic and diagnostic value of circulating tumor cells in bladder cancer and upper tract urothelial carcinoma: a meta-analysis of 30 published studies. Oncotarget 2017; 8:59527-59538. [PMID: 28938656 PMCID: PMC5601752 DOI: 10.18632/oncotarget.18521] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 06/02/2017] [Indexed: 01/01/2023] Open
Abstract
There are inconsistent conclusions in the association between circulating tumor cells (CTCs) and urothelial cancer (UC). We performed a meta-analysis to assess the prognostic and diagnostic value of CTCs in UC. We search Medline, Embase and Web of science for relevant studies. The study was set up according to the inclusion/exclusion criteria. 30 published studies with a total of 2161 urothelial cancer patients were included. Meta-analysis showed that CTC-positive was significantly associated with tumor stage (≤ II vs III, IV) (OR = 4.60, 95% CI: 2.34-9.03), histological grade (I, II vs III) (OR = 2.91, 95% CI: 1.92-4.40), metastasis (OR = 5.12, 95% CI: 3.47-7.55) and regional lymph node metastasis (OR = 2.47, 95% CI: 1.75-3.49). It was also significantly associated with poor overall survival (OS) (HR = 3.98, 95% CI: 2.20-7.21), progression/disease-free survival (PFS/DFS) (HR = 2.22, 95% CI: 1.80-2.73) and cancer-specific survival (CSS) (HR = 5.18, 95% CI: 2.21-12.13). Overall sensitivity and specificity of CTC detection assays were 0.35 (95% CI: 0.28-0.43) and 0.97 (95% CI: 0.92-0.99) respectively. In summary, our meta-analysis suggests that the presence of CTCs in the peripheral blood is an independent predictive indicator of poor outcomes for urothelial cancer patients. It can also be used as a noninvasive method for the confirmation of cancer diagnosis. More studies are required to further explore the role of this marker in clinical practice.
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Affiliation(s)
- Zheng Zhang
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Wei Fan
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.,Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Qiaoling Deng
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Shihui Tang
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Ping Wang
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Peipei Xu
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - June Wang
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
| | - Mingxia Yu
- Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
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Detection of Circulating Tumour Cells in Urothelial Cancers and Clinical Correlations: Comparison of Two Methods. DISEASE MARKERS 2017; 2017:3414910. [PMID: 28321147 PMCID: PMC5340956 DOI: 10.1155/2017/3414910] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 01/15/2017] [Indexed: 12/21/2022]
Abstract
Circulating tumour cells (CTC) are identified exploiting their protein/gene expression patterns or distinct size compared to blood cells. Data on CTC in bladder cancer (BC) are still scarce. We comparatively analyzed CTC enrichment by AdnaTest ProstateCancerSelect (AT) and ScreenCell®Cyto (SC) kits, combined with identification by EPCAM, MUC1, and ERBB2 expression and by cytological criteria, respectively, in 19 nonmetastatic (M0) and 47 metastatic (M+) BC patients, at baseline (T0) and during treatment (T1). At T0, CTC positivity rates by AT were higher in M+ compared to M0 cases (57.4% versus 25%, p = 0.041). EPCAM was detected in 75% of CTC-positive samples by AT, showing increasing expression levels from T0 to T1 (median (interquartile range, IQR): 0.18 (0.07-0.42) versus 0.84 (0.33-1.84), p = 0.005) in M+ cases. Overall, CTC positivity by SC was around 80% regardless of clinical setting and time point of analysis, except for a lower occurrence at T1 in M0 cases. At T0, circulating tumour microemboli were more frequently (25% versus 8%) detected and more numerous in M+ compared to M0 patients. The approach used for CTC detection impacts the outcome of CTC studies. Further investigations are required to clarify the clinical validity of AT and SC in specific BC clinical contexts.
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In stage pT1 non-muscle-invasive bladder cancer (NMIBC), high KRT20 and low KRT5 mRNA expression identify the luminal subtype and predict recurrence and survival. Virchows Arch 2017; 470:267-274. [DOI: 10.1007/s00428-017-2064-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 12/12/2016] [Accepted: 01/03/2017] [Indexed: 12/17/2022]
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Abbosh PH, Rosenberg JE, Plimack ER. Circulating biomarkers to guide systemic therapy for urothelial carcinoma. Urol Oncol 2016; 34:502-509. [PMID: 27751785 DOI: 10.1016/j.urolonc.2016.08.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 08/18/2016] [Accepted: 08/30/2016] [Indexed: 12/26/2022]
Abstract
There are very few biomarkers used to diagnose bladder cancer and no clinically approved biomarkers for prediction or prognostication of this disease. All currently available biomarkers are based on urine tests, and thus, they may not be applicable to patients with extravesical tumors. Biopsy of metastatic sites requires an invasive procedure, whereas serum-based markers, which can be easily obtained and serially measured, thus have obvious merit. These deficiencies may be overcome with advances in genome sequencing, identification of circulating tumor cells, and RNA-, protein-, and DNA-based biomarkers. Here, progress in circulating biomarkers in both superficial and invasive bladder cancer is described.
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Affiliation(s)
- Philip H Abbosh
- Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA; Department of Urology, Albert Einstein Medical Center, Philadelphia, PA
| | - Jonathan E Rosenberg
- Department of Urology, Albert Einstein Medical Center, Philadelphia, PA; Department of Medical Oncology, New York, NY
| | - Elizabeth R Plimack
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA.
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Soave A, Riethdorf S, Pantel K, Fisch M, Rink M. Do circulating tumor cells have a role in deciding on adjuvant chemotherapy after radical cystectomy? Curr Urol Rep 2016; 16:46. [PMID: 26025496 DOI: 10.1007/s11934-015-0520-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Radical cystectomy (RC) with bilateral pelvic lymphadenectomy with or without perioperative chemotherapy is the golden standard treatment in muscle invasive and recurrent high-grade non-muscle invasive urothelial carcinoma of the bladder (UCB). Despite treatment with curative intent, up to 50% of patients develop metastasis and die from UCB due to micro-metastatic disease undetectable for current staging techniques prior to definitive therapy. Tumor cell dissemination is a crucial step in the natural history of the metastatic cascade. Circulating tumor cells (CTC) are malignant epithelial cells detectable in the peripheral blood of patients with various malignancies. In UCB, CTC are detectable in a significant number of patients prior to RC and associated with inferior outcomes. In this review, we summarize the current literature regarding CTC in UCB, discussing their potential on clinical decision-making regarding multimodal treatment and implications on the application of novel targeted therapies in the future. There is reliable evidence that presence of CTC in clinically non-metastatic UCB patients treated with RC are a powerful predictor for unfavorable outcomes and may be useful for adjuvant chemotherapy decision-making and monitoring. However, currently, the evidence is limited, and thus, integration of CTC in future UCB clinical trials is strongly recommended to shed more light on the potential of this promising biomarker.
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Affiliation(s)
- Armin Soave
- Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246, Hamburg, Germany
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Pirozzi G, Tirino V, Camerlingo R, La Rocca A, Martucci N, Scognamiglio G, Franco R, Cantile M, Normanno N, Rocco G. Prognostic value of cancer stem cells, epithelial-mesenchymal transition and circulating tumor cells in lung cancer. Oncol Rep 2013; 29:1763-8. [PMID: 23426441 DOI: 10.3892/or.2013.2294] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Accepted: 10/23/2012] [Indexed: 12/25/2022] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a program involved in embryonic development that is often activated during cancer invasion and metastasis. CD133 is the main marker identifying cancer stem cells (CSCs) in lung cancer. Circulating tumor cells (CTCs) are demonstrated to be useful as a biomarker for the diagnosis and treatment of cancer. The aim of this study was to correlate EMT, CSCs and CTCs with patient prognosis to verify whether they can contribute to better stratification of lung cancer patients at risk for recurrent and metastatic disease. Pulmonary venous blood was drawn after major pulmonary surgery in 45 patients with resectable non-small cell lung cancer (NSCLC) in order to identify CTCs. For the same patients, we also constructed prognostic lung tissue microarrays (TMA) for CD133 and c-kit and evaluated CSC and EMT markers using flow cytometry. Cytokeratin-positive cells were detectable in 11 (23.9%) cases. c-kit expression was heterogeneous in prognostic TMAs while CD133 expression was low or absent which was also confirmed by flow cytometry and RT-PCR. Flow cytometric analysis showed that the mean percentage of cells with CD133 expression was 1.6%. CD90 and CD326 markers were co-expressed with a mean percentage of 10.41%. When CD133 and CD90/CD326 expression was correlated with follow-up, CD133 showed a higher correlation with deceased patients when compared with CD90/CD326 co-expression (32.5 vs. 9.5%). CD133 expression demonstrated a strong significant association with patients exhibiting progressive disease when compared to CD90/CD326 expression (15 vs. 7.1%). CD133 may be significantly associated with invasion and metastatic spread of NSCLC. The co-expression of CD90, CD326 and CD133 has definite prognostic value in patients with NSCLC.
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Affiliation(s)
- G Pirozzi
- Department of Experimental Oncology, National Cancer Institute, Pascale Foundation, I-80131 Naples, Italy.
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Utility of urothelial mRNA markers in blood for staging and monitoring bladder cancer. Urology 2011; 79:240.e9-15. [PMID: 22055693 DOI: 10.1016/j.urology.2011.09.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Revised: 09/07/2011] [Accepted: 09/07/2011] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To test the efficiency of 6 mRNA bladder markers in staging urothelial cell carcinoma (UCC) and monitoring UCC dissemination from blood samples. METHODS From 2002 to 2009, 347 blood samples were collected from 150 patients with UCC and 29 healthy controls. Sequential blood sampling was performed in patients undergoing cystectomy at surgery and 6, 12, 18, and 24 months postoperatively. The median follow-up was 33 months. The presence of KRT20, FXYD3, C10orf116, UPK2, AGR2, and KRT19 markers in blood was evaluated in all patients and controls by measuring the gene expression using preamplified cDNA and reverse transcriptase quantitative polymerase chain reaction. Gene expression data were correlated with the tumor risk, follow-up, and outcomes data. RESULTS Expression of C10orf116 and KRT19 genes differed between patients and controls (P<.001). KRT20, C10orf116, and AGR2 differentiated between low- and high-risk nonmuscle-invasive bladder cancer (P=.001, P=.011, and P=.001, respectively). FXYD3 differentiated between patients with high-risk nonmuscle-invasive bladder cancer and those with muscle-invasive bladder cancer (P=.009). In contrast, the 6 markers showed no differences in gene expression between metastatic and patients without metastases who had not undergone cystectomy (P=NS). None of the markers were significantly increased in the metastatic patients at 6, 12, 18, or 24 months after surgery. CONCLUSION The gene expression of bladder-specific mRNA markers in blood was different among the various tumor risk groups of patients with UCC. However, this gene expression analysis is not suitable for predicting metastases or monitoring UCC hematogenous dissemination in patients who have undergone cystectomy.
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Msaouel P, Koutsilieris M. Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and meta-analysis. BMC Cancer 2011; 11:336. [PMID: 21816094 PMCID: PMC3161042 DOI: 10.1186/1471-2407-11-336] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Accepted: 08/04/2011] [Indexed: 12/16/2022] Open
Abstract
Background The diagnostic value and prognostic significance of circulating tumor cell (CTC) detection in patients with bladder cancer is controversial. We performed a meta-analysis to consolidate current evidence regarding the use of CTC detection assays to diagnose bladder and other urothelial cancers and the association of CTC positivity with advanced, remote disease. Methods Studies that investigated the presence of CTCs in the peripheral blood of patients with bladder cancer and/or urothelial cancer were identified and reviewed. Sensitivities, specificities, and positive (LR+) and negative likelihood ratios (LR-) of CTC detection in individual studies were calculated and meta-analyzed by random effects model. Overall odds ratio of CTC positivity in patients with advanced disease versus those with organ-confined cancer was also calculated. Results Overall sensitivity of CTC detection assays was 35.1% (95%CI, 32.4-38%); specificity, LR+, and LR- was 89.4% (95%CI, 87.2-91.3%), 3.77 (95%CI, 1.95-7.30) and 0.72 (95%CI, 0.64-0.81). CTC-positive patients were significantly more likely to have advanced (stage III-IV) disease compared with CTC-negative patients (OR, 5.05; 95%CI, 2.49-10.26). Conclusions CTC evaluation can confirm tumor diagnosis and identify patients with advanced bladder cancer. However, due to the low overall sensitivity, CTC detection assays should not be used as initial screening tests.
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Affiliation(s)
- Pavlos Msaouel
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, 75 Micras Asias str., Goudi-Athens 115 27, Greece.
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Flaig TW, Wilson S, van Bokhoven A, Varella-Garcia M, Wolfe P, Maroni P, Genova EE, Morales D, Lucia MS. Detection of circulating tumor cells in metastatic and clinically localized urothelial carcinoma. Urology 2011; 78:863-7. [PMID: 21813167 DOI: 10.1016/j.urology.2011.05.045] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Revised: 05/26/2011] [Accepted: 05/26/2011] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To examine the incidence and prognostic value of circulating tumor cells (CTCs) in urothelial cancer (UC). The detection of CTCs is prognostic in several cancer types. METHODS A total of 44 subjects with UC were assessed for CTCs using CellSearch Technology and 7.5 mL of peripheral blood, sorted by magnetic separation (epithelial cell adhesion molecule positive) and immunofluorescent staining (positive for cytokeratin 8, 18, or 19, negative for CD45, positive for 4',6-diamidino-2-phenylindole) to identify the CTCs. RESULTS Five (17%) of 30 subjects with clinically localized and 7 (50%) of 14 subjects with metastatic UC had ≥1 detectable CTC (range 1-177). Six subjects had ≥5 CTCs. Fluorescence in situ hybridization analysis was performed in 20 samples from 18 unique subjects using the UroVysion probe set. Copy number gains consistent with neoplasm were observed in those with measurable CTCs but not in any of the CTC-negative samples tested. With a median follow-up of 337 days, all 7 patients with metastasis and detectable CTCs had died compared with 3 (43%) of the 7 with metastasis but without detectable CTCs. CONCLUSION CTCs are commonly observed in metastatic UC. CTCs were observed in 50% of the patients with metastatic UC tested. Fluorescence in situ hybridization analysis confirmed the aneusomic chromosomal content in the CTCs. These findings suggest that measurable CTCs might be prognostic for shortened survival in patients with metastatic UC, although the optimal threshold for a "positive" finding is unknown. CTCs were also detected in a subset of patients with clinically localized disease, identifying a potential high-risk, preoperative group for future study.
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Affiliation(s)
- Thomas W Flaig
- Department of Medicine, University of Colorado, School of Medicine, Aurora, CO, USA.
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Siddiqui MM, Feldman AS. Advances in the evaluation and management of lymph node involvement in urothelial carcinoma of the bladder. Expert Rev Anticancer Ther 2010; 10:1855-9. [PMID: 21110750 DOI: 10.1586/era.10.151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Nezos A, Pissimisis N, Lembessis P, Sourla A, Dimopoulos P, Dimopoulos T, Tzelepis K, Koutsilieris M. Detection of circulating tumor cells in bladder cancer patients. Cancer Treat Rev 2008; 35:272-9. [PMID: 19103472 DOI: 10.1016/j.ctrv.2008.11.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2008] [Revised: 11/06/2008] [Accepted: 11/10/2008] [Indexed: 12/31/2022]
Abstract
The methods employed for the detection of circulating bladder cancer cells (CBCs) and their use as a molecular staging tool in clinical settings are thoroughly reviewed. CBC isolation and enrichment methods are discussed according to their advantages and pitfalls along with the clinical data of PCR-based techniques used for CBC detection. In addition, we review the specificity of molecular markers that have been proposed so far for CBC identification, and we comment on the controversial clinical data, proposing laboratory approaches which may improve the clinical significance of CBC detection in bladder cancer.
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Affiliation(s)
- Adrianos Nezos
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, Goudi 115 27, Athens, Greece
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Marín-Aguilera M, Mengual L, Burset M, Oliver A, Ars E, Ribal MJ, Colomer D, Mellado B, Villavicencio H, Algaba F, Alcaraz A. Molecular Lymph Node Staging in Bladder Urothelial Carcinoma: Impact on Survival. Eur Urol 2008; 54:1363-72. [DOI: 10.1016/j.eururo.2008.04.059] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2007] [Accepted: 04/23/2008] [Indexed: 01/27/2023]
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Zhang L, Wang CY, Yang R, Shi J, Fu R, Chen L, Klocker H, Zhang J. Real-time quantitative RT-PCR assay of prostate-specific antigen and prostate-specific membrane antigen in peripheral blood for detection of prostate cancer micrometastasis. Urol Oncol 2008; 26:634-40. [PMID: 18367130 DOI: 10.1016/j.urolonc.2007.07.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2007] [Revised: 07/24/2007] [Accepted: 07/25/2007] [Indexed: 01/30/2023]
Abstract
OBJECTIVE Reverse transcription-polymerase chain reaction (RT-PCR) was widely used to detect disseminated tumor cells. However, high percentages of false-positive cases have been reported. Herein, we developed a method to detect prostate cancer (PCa) micrometastasis by real-time quantitative RT-PCR. METHODS Blood samples were obtained from 118 males, including 13 healthy volunteers, 17 patients with metastatic PCa, 20 patients with localized PCa, and 68 patients with BPH. RNA was isolated from blood samples of different patients. Real-time RT-PCR was used to quantify the copy number of PSA and PSMA. The primers and probe of PSMA were designed to specifically discriminate between PSMA and PSM', an alternatively spliced variant, mRNA. RESULTS There was significant difference in the PSA and PSMA mRNA levels among BPH, locally confined PCa, and metastatic PCa blood specimens. The real-time quantitative RT-PCR is sensitive, accurate, and has a high reproducibility within a wide dynamic range (10(3)-10(8)), which permits simultaneous quantitative analysis of samples with varying input concentrations. CONCLUSIONS This method improves accuracy and liability of assessment of disseminated prostate cancer cells in peripheral blood and is promising for clinical diagnosis purpose.
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Affiliation(s)
- Liguo Zhang
- Bioactive Materials Key Laboratory of the Ministry of Education, Institute for Molecular Biology, Nankai University, Tianjin, People's Republic of China
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17
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Scheunemann P, Stoecklein NH, Rehders A, Bidde M, Metz S, Peiper M, Eisenberger CF, Schulte Am Esch J, Knoefel WT, Hosch SB. Occult tumor cells in lymph nodes as a predictor for tumor relapse in pancreatic adenocarcinoma. Langenbecks Arch Surg 2007; 393:359-65. [PMID: 17704938 DOI: 10.1007/s00423-007-0215-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2007] [Accepted: 07/16/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Occurrence of tumor relapse is frequent in patients with pancreatic cancer despite the absence of residual tumor detectable at primary surgery and in histopathological examination. Therefore, it has to be assumed that current tumor staging procedures fail to identify minimal amounts of disseminated tumor cells, which might be precursors of subsequent metastatic relapse. The aim of this study was to assess the prognostic impact of minimal tumor cell spread detected in lymph nodes classified as "tumor-free" in routine histopathologic evaluation. MATERIALS AND METHODS A total of 154 "tumor-free" lymph nodes from 59 patients with pancreatic cancer who underwent intentionally curative tumor resection were examined by immunohistochemistry for disseminated tumor cells. RESULTS Fifty (32.5%) of the "tumor-free" lymph nodes obtained from 36 (61%) patients displayed disseminated tumor cells. Multivariate survival analysis revealed that the presence of disseminated tumor cells in "tumor-free" lymph nodes is an independent prognostic factor for both a significantly reduced relapse-free survival (p = 0.03) and overall survival (p = 0.02). CONCLUSIONS The frequent occurrence and prognostic impact of immunohistochemically identifiable disseminated tumor cells in lymph nodes of patients with operable pancreatic cancer supports the need for a refined staging system of excised lymph nodes, which should include immunohistochemical examination.
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Affiliation(s)
- Peter Scheunemann
- Department of General Surgery, Heinrich-Heine University, University Hospital Düsseldorf, Düsseldorf, Germany.
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18
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Feng Q, Yu M, Kiviat NB. Molecular biomarkers for cancer detection in blood and bodily fluids. Crit Rev Clin Lab Sci 2007; 43:497-560. [PMID: 17050080 DOI: 10.1080/10408360600922632] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Cancer is a major and increasing public health problem worldwide. Traditionally, the diagnosis and staging of cancer, as well as the evaluation of response to therapy have been primarily based on morphology, with relatively few cancer biomarkers currently in use. Conventional biomarker studies have been focused on single genes or discrete pathways, but this approach has had limited success because of the complex and heterogeneous nature of many cancers. The completion of the human genome project and the development of new technologies have greatly facilitated the identification of biomarkers for assessment of cancer risk, early detection of primary cancers, monitoring cancer treatment, and detection of recurrence. This article reviews the various approaches used for development of such markers and describes markers of potential clinical interest in major types of cancer. Finally, we discuss the reasons why so few cancer biomarkers are currently available for clinical use.
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Affiliation(s)
- Qinghua Feng
- Department of Pathology, School of Medicine, University of Washington, Seattle, Washington 98109, USA.
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19
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20
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Janni W, Rack B, Lindemann K, Harbeck N. Detection of Micrometastatic Disease in Bone Marrow: Is It Ready for Prime Time? Oncologist 2005; 10:480-92. [PMID: 16079315 DOI: 10.1634/theoncologist.10-7-480] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Minimal residual disease (MRD), or isolated tumor cells (ITCs) in bone marrow, may be the source of potentially fatal overt distant metastases in solid tumors even years after primary treatment. MRD can be detected by immunohistochemical methods using antibodies directed against cytokeratins or cell-surface markers or molecular, polymerase chain reaction-based techniques. Among solid tumors, the clinical relevance of MRD has been most extensively studied in breast cancer patients. Recently, the highest level of evidence for the prognostic impact of MRD in primary breast cancer was reached by a pooled analysis comprising more than 4,000 patients, showing poor outcome in patients with MRD at primary therapy. Yet the clinical application of MRD detection is hampered by the lack of a standardized detection assay. Moreover, clinical trial results demonstrating the benefit of a therapeutic intervention determined by bone marrow status are still absent. Recent results suggest that, in addition to its prognostic impact, MRD can be used for therapy monitoring or as a potential therapeutic target after phenotyping of the tumor cells. Persistent MRD after primary treatment may lead to an indication for extended adjuvant therapy. However, until clinically relevant data regarding successful therapy of MRD are available, treatment interventions on the basis of MRD should only be performed within clinical trials.
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Affiliation(s)
- Wolfgang Janni
- Department of Obstetrics and Gynecology,Ludwig-Maximilians University, Munich, Germany
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21
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Koch M, Kienle P, Hinz U, Antolovic D, Schmidt J, Herfarth C, von Knebel Doeberitz M, Weitz J. Detection of hematogenous tumor cell dissemination predicts tumor relapse in patients undergoing surgical resection of colorectal liver metastases. Ann Surg 2005; 241:199-205. [PMID: 15650626 PMCID: PMC1356902 DOI: 10.1097/01.sla.0000151795.15068.27] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE To examine the prognostic significance of disseminated tumor cells in blood and bone marrow of patients undergoing surgical resection of colorectal liver metastases. SUMMARY BACKGROUND DATA Despite curative hepatic resection of colorectal liver metastases, a high percentage of patients develop tumor recurrence. These recurrences probably originate from disseminated tumor cells released into the circulation before or during surgery. METHODS Thirty-seven patients with potentially curative (R0) resection of colorectal liver metastases were prospectively enrolled into the study. Preoperative bone marrow samples and preoperative, intraoperative, and postoperative blood samples were examined for disseminated tumor cells by CK20 RT-PCR. RESULTS Tumor cells were detected in preoperative blood samples in 11 of 37 (30%) patients, in intraoperative blood samples in 17 of 37 (46%) patients, and in postoperative blood samples in 8 of 37 (22%) patients. Four of 25 (16%) patients tested positive for disseminated tumor cells in bone marrow samples. Median follow-up time for all patients was 38 months (range, 10-63 months). Multivariate analysis confirmed tumor cell detection in intraoperative blood (P = 0.009) and in bone marrow samples (P = 0.013) to be independent prognostic factors of tumor relapse. CONCLUSIONS This is the first study demonstrating that detection of hematogenous tumor cell dissemination during hepatic resection of colorectal cancer metastases predicts tumor relapse. Detection of disseminated tumor cells may help to individualize adjuvant therapy for patients with colorectal liver metastases and to develop surgical strategies to prevent intraoperative hematogenous tumor cell shedding.
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Affiliation(s)
- Moritz Koch
- Department of Surgery, University of Heidelberg, Heidelberg, Germany
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22
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Okegawa T, Kinjo M, Nutahara K, Higashihara E. VALUE OF REVERSE TRANSCRIPTION POLYMERASE CHAIN ASSAY IN PERIPHERAL BLOOD OF PATIENTS WITH UROTHELIAL CANCER. J Urol 2004; 171:1461-6. [PMID: 15017198 DOI: 10.1097/01.ju.0000118648.29024.b7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE The nested reverse transcription polymerase chain reaction (RT-PCR) method was used to determine expression of uroplakin II (UP II) or cytokeratin 20 (CK-20) in cells separated from the peripheral blood of patients with urothelial cancer. We examine whether UP II or CK-20 expression can be used as a urothelial cancer marker for urothelial cancer in cells isolated from peripheral blood. MATERIALS AND METHODS Peripheral blood was taken from 20 healthy volunteers without a history of urothelial cancer, from 10 patients with a negative bladder biopsy for urothelial cancer and from 108 patients with urothelial cancer. Results of a nested RT-PCR assay were compared with pathological stage and recurrence. RESULTS None of the peripheral blood samples from the control subjects revealed a positive polymerase chain reaction result. Among 108 patients with transitional cell carcinoma of the bladder nested RT-PCR for UP II was positive in 25 (23%) versus 31 (29%) for CK-20 (p >0.05). Nested RT-PCR for UP II was positive in 5 (8%) patients with superficial stage disease (pTa and pT1) versus 8 (11%) positive for CK-20. Nested RT-PCR for UP II was positive in 15 (58%) patients with a stage of pT2 or advanced stages versus 17 (65%) positive for CK-20. Nested RT-PCR for UP II was positive in 13 (20%) and 10 (56%) patients with grades 2 and 3, respectively, versus 17 (27%) and 12 (67%) nested RT-PCR positive for CK-20. A significant difference in the Kaplan-Meier recurrence-free actuarial curve was noted among patients with superficial stage who were positive and negative on nested RT-PCR for UP II and CK-20 in peripheral blood, respectively, but not in the invasive stage. On multivariate analysis nested RT-PCR for UP II and CK-20 in peripheral blood were independent prognostic factors in patients with superficial stage disease but not with invasive stage disease. Lung and/or liver metastasis developed in 5 (80%) of 6 patients whose results after chemotherapy (consisting of cisplatin, doxorubicin hydrochloride, vinblastine sulfate and methotrexate) for nested RT-PCR for UP II and CK-20 remained positive. CONCLUSIONS These results seem to indicate that UP II and CK-20 mRNA in the blood may be useful tumor markers for predicting patient survival and the extent of urothelial cancer.
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Affiliation(s)
- Takatsuga Okegawa
- Department of Urology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
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23
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Kienle P, Koch M, Autschbach F, Benner A, Treiber M, Wannenmacher M, von Knebel Doeberitz M, Büchler M, Herfarth C, Weitz J. Decreased detection rate of disseminated tumor cells of rectal cancer patients after preoperative chemoradiation: a first step towards a molecular surrogate marker for neoadjuvant treatment in colorectal cancer. Ann Surg 2003; 238:324-30; discussion 330-1. [PMID: 14501498 PMCID: PMC1422712 DOI: 10.1097/01.sla.0000086547.27615.e6] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To compare the detection rates for rectal cancer cells in blood and bone marrow in patients with or without preoperative chemoradiation. SUMMARY BACKGROUND DATA Previous reports have postulated a resistance of disseminated tumor cells to antiproliferative agents because of tumor cell dormancy. METHODS Blood samples from 142 patients (pre, intra-, and postoperative samples) and bone marrow samples from 127 patients undergoing resection of rectal adenocarcinoma were analyzed for tumor cells using a cytokeratin (CK) 20-reverse transcription polymerase chain reaction. The results were stratified according to preoperative therapy. RESULTS In patients without preoperative chemoradiation, tumor cell detection in blood and bone marrow correlated to tumor stage (Cochran Armitage trend test, P < 0.05). Tumor cells were detected in 34 of 103 (33%) bone marrow and 65 of 117 (55.6%) blood samples of patients without neoadjuvant treatment versus in 4 of 24 (16.7%) bone marrow and in 10 of 25 (40%) blood samples of patients with neoadjuvant treatment. The tumor cell detection rate was significantly lower in the group having undergone chemoradiation (binary logistic regression analysis, P < 0.05). The overall and disease-free survival were significantly worse in patients with tumor cell detection in the bone marrow after neoadjuvant therapy. CONCLUSIONS Preoperative chemoradiation is associated with a decreased detection rate of rectal cancer cells in blood and bone marrow. These findings may explain the observed clinical benefit of patients with rectal cancer receiving chemoradiation. This is the first study suggesting that detection of disseminated rectal cancer cells may be useful for assessing the efficacy of neoadjuvant therapy.
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Affiliation(s)
- Peter Kienle
- Division for Molecular Diagnostics and Therapy and Division for Surgical Oncology of the Department of Surgery, University of Heidelberg, Germany
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24
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El-Salahy EM. Evaluation of cytokeratin-19 & cytokeratin-20 and interleukin-6 in Egyptian bladder cancer patients. Clin Biochem 2002; 35:607-13. [PMID: 12498994 DOI: 10.1016/s0009-9120(02)00382-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES This study was designed to detect the expression of CK-19 and CK-20 in tissue specimens and IL-6 in the sera (as a noninvasive maneuver) of bladder cancer patients. Results were correlated with the clinico-pathologic parameters, Bilharziasis and the occurrence of relapse of the carcinoma among Egyptian bladder cancer patients. METHODS Subjects of this study were 50 cases of bladder carcinoma (19 cases were positive for Bilharziasis) as well as 20 cystitis cases as control (7 cases were positive for Bilharziasis). Messenger ribonucleic acid extracted from fresh frozen tissue specimens with bladder tumor and the control group were collected and subjected to RT-PCR to detect expression of the amplification bands of CK-19 and CK-20 (214 and 370 base pairs). In the mean time, Interleukin-6 was quantified in the sera of the patients using ELISA kit. RESULTS CK-19 and CK-20 RNAs were expressed in bladder cancer cases, but not expressed in the control group. They were significantly correlated to advanced tumor stage and grade, while CK-19 positivity, was also, correlated to tumor recurrence and tumor pathology being more in SCC than TCC. Moreover, IL-6 positivity was correlated to the occurrence of malignancy, advanced grade and pathology being more in SCC than TCC. ROC curve was utilized to choose the best cut-off for serum IL-6 (49.2 pg/mL). At the determined cut-off, the sensitivity was 66% and the specificity was 95%. Bilharziasis was found to be related to advanced stages and grades of bladder cancer. CONCLUSION CK-19, CK-20 and IL-6 were strongly associated with malignant phenotype of Egyptian bladder tissues, so they may be used as additional markers for assessment of bladder cancer patients.
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Affiliation(s)
- P Scheuemann
- Chirurgische Klinik und Poliklinik, Universitätsklinikum Eppendorf, Hamburg, Germany
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26
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THE MOLECULAR DETECTION OF CIRCULATING TUMOR CELLS IN BLADDER CANCER USING TELOMERASE ACTIVITY. J Urol 2002. [DOI: 10.1097/00005392-200201000-00100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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SORIA JEANCHARLES, MORAT LUC, DURDUX CATHERINE, HOUSSET MARTIN, CORTEZ ANNIE, BLAISE RENAUD, SABATIER LAURE. THE MOLECULAR DETECTION OF CIRCULATING TUMOR CELLS IN BLADDER CANCER USING TELOMERASE ACTIVITY. J Urol 2002. [DOI: 10.1016/s0022-5347(05)65467-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- JEAN-CHARLES SORIA
- From the Laboratoire de Radiobiologie et Oncologie, DRR/DSV, CEA, Fontenay-aux-Roses, Oncology-Radiotherapy Department, HEGP Hospital and Pathology Department, Tenon Hospital, AP-HP, Paris, France
| | - LUC MORAT
- From the Laboratoire de Radiobiologie et Oncologie, DRR/DSV, CEA, Fontenay-aux-Roses, Oncology-Radiotherapy Department, HEGP Hospital and Pathology Department, Tenon Hospital, AP-HP, Paris, France
| | - CATHERINE DURDUX
- From the Laboratoire de Radiobiologie et Oncologie, DRR/DSV, CEA, Fontenay-aux-Roses, Oncology-Radiotherapy Department, HEGP Hospital and Pathology Department, Tenon Hospital, AP-HP, Paris, France
| | - MARTIN HOUSSET
- From the Laboratoire de Radiobiologie et Oncologie, DRR/DSV, CEA, Fontenay-aux-Roses, Oncology-Radiotherapy Department, HEGP Hospital and Pathology Department, Tenon Hospital, AP-HP, Paris, France
| | - ANNIE CORTEZ
- From the Laboratoire de Radiobiologie et Oncologie, DRR/DSV, CEA, Fontenay-aux-Roses, Oncology-Radiotherapy Department, HEGP Hospital and Pathology Department, Tenon Hospital, AP-HP, Paris, France
| | - RENAUD BLAISE
- From the Laboratoire de Radiobiologie et Oncologie, DRR/DSV, CEA, Fontenay-aux-Roses, Oncology-Radiotherapy Department, HEGP Hospital and Pathology Department, Tenon Hospital, AP-HP, Paris, France
| | - LAURE SABATIER
- From the Laboratoire de Radiobiologie et Oncologie, DRR/DSV, CEA, Fontenay-aux-Roses, Oncology-Radiotherapy Department, HEGP Hospital and Pathology Department, Tenon Hospital, AP-HP, Paris, France
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Cui JH, Krueger U, Henne-Bruns D, Kremer B, Kalthoff H. Orthotopic transplantation model of human gastrointestinal cancer and detection of micrometastases. World J Gastroenterol 2001; 7:381-6. [PMID: 11819794 PMCID: PMC4688726 DOI: 10.3748/wjg.v7.i3.381] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish a relevant animal model of human gastrointestinal cancer, which can be used for repetitive investigations, so as to improve our understanding and management of carcinogenesis and cancer metastasis.
METHODS: Intact tissues of human colorectal and pancreatic cancers were transplanted in nude mice. The biological characteristics of the original and the corresponding transplanted tumors were investigated by HE staining, PAS staining and immunostaining. The metastases in the livers and lungs of nude mice were investigated by immunostaining with biotinylated mab KL-1 and by RT-PCR using CK20 specific primers.
RESULTS: There were totally 9 of 16 surgical specimens growing in nude mice subcutaneously and/or orthotopically (4 of 6 colorectal and 5 of 10 pancreatic cancer). Tumor cell content of the specimens and freezing of tissue specimens are important factors influencing the growth of transplanted tumor. In the group of fresh tumor tissues with greater than 50% tumor cell content, the success rate of the transplantation was 100% (3 cases of pancreatic cancer and 3 cases of colorectal cancer). The orthotopically transplanted tumors resemble the original tumor morphologically and biologically, including TAA expression such as CEA by immunohistochemistry, and CEA level in the serum of mice. Ki-67 labeling index and the expression of TAA especially K-ras, 17-1A and RA-96, are associated with the potential of tumor growth in nude mice. Micrometastases in the lungs and livers of tumor bearing mice can be detected by immunostaining with biotinylated mab KL-1 and CK20-specific RT-PCR.
CONCLUSION: An orthotopic transplantation model for human colon and pancreatic cancer in nude mice has been set up. We have also established sensitive detection methods with CK-immunohistochemistry and CK20-RT-PCR to study xenotransplanted human cancer and its metastatic cancer cells in the liver and lung of nude mice. This study may be helpful in understanding the mechanism of cancer metastasis and in developing new diagnostic methods and therapeutic strategies for metastases including micrometastases.
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Affiliation(s)
- J H Cui
- Department of General Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang Province,China.
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Lacroix J, Doeberitz MK. Technical aspects of minimal residual disease detection in carcinoma patients. SEMINARS IN SURGICAL ONCOLOGY 2001; 20:252-64. [PMID: 11747266 DOI: 10.1002/ssu.1042] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The burden of occult malignant cells which remains after a course of treatment that has resulted in clinical remission is referred to as minimal residual disease (MRD). MRD is increasingly considered as a determinant of local or systemic recurrence in cancer patients. During the last 20 years, methods for the detection of rare cancer cells have evolved from mere cytomorphological investigations to a variety of immunological and molecular assays. Since surgical therapy remains the best treatment option for cancer patients with resectable tumors, the first question to address is whether the removal of the tumor was complete or some cancer cells remained from the tumor at the primary site. Several tumor-associated DNA alterations have been identified to solve this diagnostic problem. Assays detecting tumor-associated DNA alterations have been applied to resection margins and body fluids such as bronchoalveolar lavage, sputum, urine, pancreatic juice, colonic lavage, and stool. Due to the higher sensitivity of immunocytochemical and reverse-transcriptase polymerase chain reaction (RT-PCR)-based assays, the second question to be addressed is whether systemic hematogenous or lymphatic spread of cancer cells occurred. Disseminated cancer cells have been detected in bone marrow aspirates, peripheral blood, and lymph node biopsies, and cancer cell dissemination is regarded as a relevant and independent prognostic factor. Thus, sensitive techniques for the detection of MRD are likely to guide indications for surgical or adjuvant therapy protocols in clinical oncology. However, since many of the assays for the detection of MRD are complex, and results are influenced by a variety of technical aspects, the majority of diagnostic applications have not yet been sufficiently standardized. Consequently, quality control and reproducibility of minimal disease detection assays remain unsolved problems. Therefore, well controlled collaborative studies are urgently required to evaluate indications and diagnostic standards for these assays. This review summarizes technical aspects and their implications for the clinical application of presently available assays for MRD detection in carcinoma patients.
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Affiliation(s)
- J Lacroix
- Division of Molecular Diagnostics and Therapy, Department of Surgery, University of Heidelberg, Germany.
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30
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Hosch SB, Scheunemann P, Izbicki JR. Minimal residual disease in non-small-cell lung cancer. SEMINARS IN SURGICAL ONCOLOGY 2001; 20:278-81. [PMID: 11747269 DOI: 10.1002/ssu.1045] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Early metastatic relapse after complete resection (R0) of apparently localized primary tumors is frequent in patients with non-small-cell lung cancer (NSCLC). This observation indicates an occult tumor cell dissemination already present at the time of primary surgery but undetectable by current tumor staging methods. During the past 10 years ultrasensitive immunohisto-/-cytochemical and molecular assays have been developed that are able to detect single tumor cells and small tumor cell clusters present in lymph nodes classified as tumor-free by conventional histopathologic analysis, bone marrow, or peripheral blood. Here we present an overview of the incidence and prognostic impact of such early disseminated tumor cells in patients with NSCLC.
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Affiliation(s)
- S B Hosch
- Department of Surgery, University Hospital Eppendorf, Hamburg, Germany
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