Non-Metastatic Esophageal Adenocarcinoma: Circulating Tumor Cells in the Course of Multimodal Tumor Treatment

Kuvendjiska, Jasmina; Bronsert, Peter; Martini, Verena; Lang, Sven A.; Pitman, Martha B.; Hoeppner, Jens; Kulemann, Birte

doi:10.3390/cancers11030397

Cited by 20 publications

(22 citation statements)

References 30 publications

(40 reference statements)

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“…In our samples we observed a very low proportion of white cells. As expected CTCs not showed the expression of CD45 receptor as compared to leucocytes (Figure S9B) [29,30].…”

Section: Resultssupporting

confidence: 67%

ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma: Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin

Ruggiero

Malpicci

Fattore

et al. 2019

Cancers

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In recent years the introduction of target therapies with BRAF and MEK inhibitors (MAPKi) and of immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies have dramatically improved survival of metastatic melanoma patients. Despite these changes drug resistance remains a major hurdle. Several mechanisms are at the basis of drug resistance. Particular attention has been devoted over the last years to unravel mechanisms at the basis of adaptive/non genetic resistance occurring in BRAF mutated melanomas upon treatment with to MAPKi. In this paper we focus on the involvement of activation of ErbB3 receptor following early exposure of melanoma cells to BRAF or MEK inhibitors, and the following induction of PI3K/AKT pathway. Although different mechanisms have been invoked in the past at the basis of this activation we show here with a combination of approaches that autocrine production of neuregulin by melanoma cells is a major factor responsible for ErbB3 phosphorylation and downstream AKT activation. Interestingly the kinetic of neuregulin production and of the ensuing ErbB3 phosphorylation is different in different melanoma cell lines which underscores the high degree of tumor heterogeneity. Moreover, heterogeneity is further highlighted by the evidence that in different cell lines neuregulin upregulation can occur at the transcriptional or at the post-transcritpional level. Finally we complement our study by showing with a liquid biopsy assay that circulating tumor cells (CTCs) from melanoma patients undergo upregulation of ErbB3 phosphorylation in vivo shortly after initiation of therapy.

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“…In our samples we observed a very low proportion of white cells. As expected CTCs not showed the expression of CD45 receptor as compared to leucocytes (Figure S9B) [29,30].…”

Section: Resultssupporting

confidence: 67%

ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma: Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin

Ruggiero

Malpicci

Fattore

et al. 2019

Cancers

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“…CTC heterogeneity has been shown and described in other tumor entities (21)(22)(23)(24). We also found a diverse population of CTC in a pilot study of 20 EAC patients undergoing multimodal treatment (14). The exact relevance of the CTC-subpopulations for the prognosis estimation is yet to be discovered.…”

mentioning

confidence: 63%

“…The processing of the blood samples was performed in the laboratory of the University Hospital Freiburg within 96 hours after blood draw from the patient. The CTC enrichment was performed by cell size-based filtration using the ScreenCell ® Cyto kit (ScreenCell, Sarcelles, France) as we have reported previously (14). This represents a surface marker independent CTC enrichment method.…”

Section: Methodsmentioning

confidence: 99%

Cytopathological Heterogeneity of Circulating Tumor Cells in Non-metastatic Esophageal Adenocarcinoma

et al. 2020

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Background/Aim: The presence of circulating tumor cells (CTC) has been reported to have an impact on prognosis in different tumor entities. Little is known about CTC morphology and heterogeneity. Patients and Methods: In a multicenter setting, pre-therapeutic peripheral blood specimens were drawn from patients with non-metastatic esophageal adenocarcinoma (EAC). CTCs were captured by size-based filtration (ScreenCell ®), subsequently Giemsa-stained and evaluated by two trained readers. The isolated cells were categorized in groups based on morphologic criteria. Results: Small and large single CTCs, as well as CTC-clusters, were observed in 69.2% (n=81) of the 117 specimens; small CTCs were observed most frequently (59%; n=69), followed by large CTCs (40%; n=47) and circulating cancer-associated macrophage-like cells (CAMLs; 34.2%, n=40). Clusters were rather rare (12%; n=14). CTC/CAML were heterogeneous in the cohort, but also within one specimen. Neither the presence of the CTC subtypes/CAMLs nor the exact cell count were associated with the primary clinical TNM stage. Conclusion: Morphologically heterogenic CTCs and CAMLs are present in patients with non-metastatic, non-pretreated EAC. Over the past decades the incidence of esophageal squamous cell carcinoma has decreased significantly in the U.S. and Europe. At the same time, the incidence of adenocarcinoma (EAC) has increased rapidly, especially among men (1). Although overall survival has improved over the years thanks to new treatment strategies, the prognosis is still limited (2). We still lack tools for better pre-therapeutic risk-stratification for cancer recurrence, which would enable us to design patientadapted treatment strategies. Currently, treatment decisions are being made based on CT-scans, endoscopic findings, endoscopic ultrasound and tumor biopsy. This momentary pretherapeutic "tumor-image" of the patient does not adequately reflect the actual tumor biology and aggressiveness. More than 50% of the patients initially considered curable will eventually relapse or develop metastasis after complete resection of the tumor (3). This relapse could be due to clinically invisible distant micro-metastases and tumor dissemination at an early time point, or due to lack of treatment response. A promising tool to evaluate these occult metastases for risk stratification and treatment surveillance is the use of liquid biopsy (4). Liquid biopsy summarizes the analysis of tumor cells and tumor-derived products in body fluids, like circulating tumor cells (CTC) (5-7), circulating tumor DNA (ctDNA) (8, 9) and extracellular vesicles (EVs) (10-12). In the case of EAC, there are very limited studies available regarding CTC presence and their significance in general (5, 13-16). CTC have been found in about 20% of patients using epithelial surface antigen (EpCAM)-dependent isolation devices in EAC. These patients 5679 This article is freely accessible online.

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“…The development of semiautomatic technologies, such as the CellSearch system, has allowed evaluation of the prognostic role of CTC status in patients with other types of cancer, such as lung and breast cancer, with promising results (37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49). A recent study from Chudasama et al (38) evaluated the efficacy of the ScreenCell filtration system, to capture, isolate and propagate CTCs from patients with primary lung cancer.…”

Section: Discussionmentioning

confidence: 99%

Detection of circulating tumor cells in patients with laryngeal cancer using ScreenCell: Comparative pre- and post-operative analysis and association with prognosis

et al. 2020

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The presence of circulating tumor cells (CTCs) in the blood of patients with metastatic breast, colorectal and prostate cancer have been widely investigated; however, few studies have examined CTCs in patients with laryngeal cancer. The present pilot study aimed to detect pre-and postoperative CTCs in the blood of patients with laryngeal cancer and evaluate the association with prognosis. Eight patients with laryngeal squamous cell carcinoma (LSCC) at stage III were included in the present study and underwent total or subtotal laryngectomy and radical bilateral neck lymph node dissection. Blood samples were collected from all patients before and after surgery at different time-points. The following processing steps were followed; preoperative blood sampling, surgery, postoperative blood sampling at 3, 6 and 12 month follow-ups, and prognostic association analysis. CTCs were retained on ScreenCell filters for cytological characterization. The presence of CTCs was associated with a less favorable prognosis, whereas a decrease of CTCs in the postoperative sampling was observed in patients who exhibited an improved therapeutic response. The results of the present pilot study revealed a possible association between the presence of CTCs and a less favorable prognosis in patients with LSCC; therefore, these preliminary findings may encourage further research into the incorporation of a liquid biopsy in the management of LSCC, as this may help identify patients with occult metastatic disease earlier and in a non-invasive manner. In addition, this approach may represent novel independent prognostic factor for use in the clinical evaluation of patients with LSCC.

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Non-Metastatic Esophageal Adenocarcinoma: Circulating Tumor Cells in the Course of Multimodal Tumor Treatment

Cited by 20 publications

References 30 publications

ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma: Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin

ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma: Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin

Cytopathological Heterogeneity of Circulating Tumor Cells in Non-metastatic Esophageal Adenocarcinoma

Detection of circulating tumor cells in patients with laryngeal cancer using ScreenCell: Comparative pre- and post-operative analysis and association with prognosis

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