Disseminated and circulating tumor cells in gastrointestinal oncology
Introduction
Onset of metastasis is a complex yet poorly understood process, which is responsible for most of cancer-related deaths. For several years, cellular dissemination from primary to secondary sites has been a “black-box” of clinical research. In non-metastatic (M0) patients, clinical studies have isolated strong prognostic factors associated with the risk of metastatic relapse, and these factors are being used to make decisions on adjuvant treatments. Adjuvant chemotherapy targets cancer cells that may have disseminated throughout the body, but is currently given blinded to the real dissemination status of each patient. With continuous technical improvements, detection methods have been recently set up and validated to isolate cancer cells in the blood (circulating tumor cells (CTCs)) and in the bone marrow (disseminated tumor cells (DTCs)). The opening of these two windows on the metastatic process in patients has raised three main critical issues: Are detection methods accurate? Is quantitative analysis (i.e., counts) of CTCs/DTCs of clinical relevance? Could qualitative analysis (i.e., molecular characterization) of CTCs/DTCs uncover new cancer features/targets? This review focuses on results obtained by different CTC/DTC detection methods in gastro-intestinal cancers.
Section snippets
CTC and DTC detection sites
Metastasis is a complex multistep process, which emerged as a biological and clinical research field more than a century ago. In one of the first studies to investigate the metastatic spread of breast cancer, James Paget made the well-known “seed and soil” hypothesis to explain the discrepancy between the blood supply of the different organs and the distribution of breast-cancer metastases [1]. Since this seminal report, several steps in the hematogeneous metastatic process have been described:
DTCs
Although bone and bone marrow are not preferential sites for macrometastasis of esophageal cancer, DTCs have been primarily found in 37% of 90 non-metastatic patients after an iliac-crest puncture using a cytological technique based on cytokeratin detection [15]. DTCs were associated, in this study, with poor survival in patients with completely excised tumors. Interestingly, bone-marrow DTCs were more frequently detected (79%) when extracted from a rib contiguous to the tumor than from the
DTCs
Bone marrow DTCs have been reported by several detection techniques in surgically resected gastric cancers: CK18 [33]; CK2-immunostaining [34]; anti-human epithelial antigen (Ber-EP4) [35]; CK20 RT-PCR [36], CK20/CK19/CEA RT-PCR [37], CK7/CK8 RT-PCR [38], CEA/CK20/TFF1/MUC2 RT-PCR [39]. About half of these studies reported a significant negative prognostic impact on metastases-free and/or overall survival. DTC detection has been associated with increased tumor-microvessel density [40], [41];
Pancreatic cancer
In the metastatic setting, the CTC detection rate, using the CellSearch® system, has been recently investigated in four small cohorts (n = 16 [10]; n = 23 [60]; n = 14 [61]; n = 40 [62]): CTCs were detected in ∼50% of patients (≥1 CTC/7.5 ml), but the mean count appears lower than in colorectal cancers. Although underpowered, three of these studies addressed the prognostic significance of CTC detection and reported contradictory results (two being rather positive, one rather negative). Using a
DTCs
The first large study to show an association between DTC detection and worse prognosis in non-metastatic colorectal cancer patients (n = 88) was reported almost 20 years ago [76]. Adjuvant trials that tested the anti-EpCAM monoclonal antibody, edrecolomab, were launched on the bases that most bone-marrow DTCs express EpCAM [77] and that tumor response or stabilization has been observed in metastatic patients in Phase-2 studies [78]. However, adjuvant Phase-3 trials with edrecolomab have shown no
DTCs
Bone-marrow DTC detection in the metastatic setting has been reported only in small studies [94], [95], and has no clear prognostic significance. This is consistent with similar findings for metastatic breast cancer [96].
CTCs
CTCs have been also detected by cytological or molecular techniques in this setting. Several small studies have been published on molecular techniques, using the same markers as already discussed, alone or in combination with CEA, CK 8/18/19/20, hTERT, MUC1/2… Interestingly,
Hepatocarcinoma (HCC)
Non-metastatic hepatocarcinomas are treated whenever possible by local treatments, which may include liver resection, liver allograft, chemoembolization, and alcoholization. Beyond the issue of a possible surgery-induced CTC release [108], any metastasis-associated biomarker could be clinically relevant, as most patients relapse after treatment of the primary tumor. Following initial studies, which have reported that AFP mRNA detection in blood was associated with disease stage [109], [110],
Conclusion
Globally, molecular tools used for CTC and DTC detection, based on their epithelial phenotype, are very heterogeneous, and it is hazardous to assess their importance based of them being a small series. Most of the reports in the literature had positive results (i.e., association with outcome), but publication bias may seriously distort any attempts, including those of the published meta-analyses, to estimate the effect of CTC/DTC detection. One may hypothesize that molecular techniques were
Funding source
Institut Curie incitative and collaborative programs fund (“PIC CTC”). The funding source had no role in the collection, analyses, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.
Conflict of interest statement
None.
Reviewer
Professor Hans-Joachim Schmoll, Martin-Luther-Universitat Halle-Wittenberg, Innere Med. IV, Ernst-Grube-Strasse 40, D-06120 Halle, Germany.
F.C. Bidard Dr. is 31 years old and is currently assistant-professor in the Department of Medical Oncology at the Institut Curie, Paris, France. His Ph.D. thesis was about cooperation between heterogeneous cancer cells during the metastatic process in mice models, and his MD thesis concerned circulating tumor cells in breast-cancer patients. He has published more than 20 articles, most of them about disseminated and circulating tumor cells.
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2016, European Journal of Surgical OncologyCitation Excerpt :Different methods for CTC detection have been developed since then.9 It could also be shown that the number of CTCs, which can be found in the patient's circulation largely depends on the tumor entity, stage and phenotype as well as on the time point, when the blood is drawn (e.g. pre-versus post-operative or pre-versus during chemotherapy).7,10,11 However, the exact mechanisms leading to the generation of CTCs are not completely understood.12
Nanoparticle-based sorting of circulating tumor cells by epithelial antigen expression during disease progression in an animal model
2015, Nanomedicine: Nanotechnology, Biology, and MedicineAssessing colorectal cancer heterogeneity: One step closer to tailored medicine
2013, Journal of Applied BiomedicineCitation Excerpt :Therefore, in recent years, much effort has been dedicated to developing new, non-invasive methods that would enable us to determine the tumour subtype, its mutations and other characteristics, to better predict response to treatment. Two promising options are the detection of circulating or disseminated tumour cells, which are released from the tumour into the blood stream or bone marrow (Bidard et al. 2012), and the detection and analysis of cell-free DNA from stool samples (Miller and Steele 2012). The fact that tumours release individual cells into bodily fluids was first observed by T. R. Ashworth almost 150 years ago (Sleijfer et al. 2007), and since this discovery, there have been attempts to use them for diagnostic as well as therapeutic purposes.
Circulating tumor cells in locally advanced pancreatic adenocarcinoma: The ancillary CirCe 07 study to the LAP 07 trial
2013, Annals of OncologyCitation Excerpt :Moreover, CTC detection may be a valuable tool to monitor the metastatic process in these patients with no radiologically detectable metastases and may finally guide the physician's choice toward a systemic (chemotherapy-based) or local (radiotherapy-based) treatment. CTCs have not been studied yet in this specific clinical setting [8]. We report here the results of the prospective CTC detection in a subgroup of patients included in the LAP 07 trial (CirCe 07 ancillary study).
F.C. Bidard Dr. is 31 years old and is currently assistant-professor in the Department of Medical Oncology at the Institut Curie, Paris, France. His Ph.D. thesis was about cooperation between heterogeneous cancer cells during the metastatic process in mice models, and his MD thesis concerned circulating tumor cells in breast-cancer patients. He has published more than 20 articles, most of them about disseminated and circulating tumor cells.