Clinical Significance of Micrometastatic Cells Detected by E48 (Ly-6D) Reverse Transcription-Polymerase Chain Reaction in Bone Marrow of Head and Neck Cancer Patients

Colnot, David R.; Nieuwenhuis, Eline J. C.; Kuik, Dirk J.; Leemans, C. René; Dijkstra, Janny; Snow, Gordon B.; Dongen, Guus A.M.S. van; Brakenhoff, Ruud H.

doi:10.1158/1078-0432.ccr-04-1090

Cited by 46 publications

(23 citation statements)

References 21 publications

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“…But we found no further association between the number of CTCs/DTCs and the time to relapse or death, possibly due to the small sample size of 10 and 18 patients, respectively, detected positive for CTCs or DTCs. These findings are consistent even if patients with metastatic disease at the time of diagnosis were excluded from the analysis and compatible to other studies (14,34,35) examining, however, a more heterogeneous group of patients with HNSCC. Our present study is, therefore, the first report on the prognostic value of CTCs and DTCs in a homogeneous group of patients with OSCC, which is of high clinical relevance.…”

Section: Discussionsupporting

confidence: 90%

Prognostic Relevance of Circulating Tumor Cells in Blood and Disseminated Tumor Cells in Bone Marrow of Patients with Squamous Cell Carcinoma of the Oral Cavity

Gröbe

Blessmann

Hanken

et al. 2014

Clinical Cancer Research

119

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Purpose: Current staging methods for squamous cell carcinomas (SCC) of the oral cavity (OSCC) need to be improved to predict the risk of individual patients. Because hematogenous tumor cell dissemination is a key event in tumor progression, we assessed the prognostic significance of disseminated tumor cells (DTC) in bone marrow and circulating tumor cells (CTC) in peripheral blood from patients with OSCC.Experimental Design: From 110 patients with OSCC, tumors were surgically resected (R0) without neoadjuvant therapy. The CellSearch system was used to enumerate CTCs. Bone marrow was aspirated from the iliac crest, and mononuclear cells (MNC) were enriched by Ficoll density gradient centrifugation. To detect DTCs, MNCs were immunostained with the pan-keratin antibody A45-B/B3. Results were correlated with clinicopathologic parameters and clinical outcome such as recurrence and death during follow-up time (mean 916 days).Results: Ten of 80 patients (12.5%) harbored CTCs in peripheral blood, whereas in 18 of 90 patients (20.0%) DTCs in bone marrow could be detected. Surprisingly, in only 2 patients (1.8%) CTCs and DTCs were detected simultaneously. Significant correlations could be found for CTCs and tumor size (P ¼ 0.04), nodal status and DTCs (P ¼ 0.02), and distant metastasis with CTCs (P ¼ 0.004) and DTCs (P ¼ 0.005). Univariate and multivariate analyses revealed that CTCs and DTCs were significant and independent predictors of recurrence-free survival (P < 0.001).Conclusions: Both DTCs and CTCs are independent prognostic markers in patients with OSCC, predicting relapse with higher sensitivity at various disease stages than routine staging procedures. Bone marrow might be an interesting target organ for future therapeutic interventions. Clin Cancer Res; 20(2); 425-33. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 90%

Prognostic Relevance of Circulating Tumor Cells in Blood and Disseminated Tumor Cells in Bone Marrow of Patients with Squamous Cell Carcinoma of the Oral Cavity

Gröbe

Blessmann

Hanken

et al. 2014

Clinical Cancer Research

119

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“…Distant haematogenous metastases were less frequently observed compared to locoregional relapses. Consistent with other studies examining more heterogeneous groups of HNSCC patients [29,79,80] , the subsequent development of recurrent disease was observed more frequently when patients were positive for CTCs/DTCs [35,81] . However, there are several incongruous and moderately significant results demonstrating that the higher the disease stage, the higher the yield of detected CTCs.…”

Section: A Discussion Of the Results From Studies On Head And Neck Casupporting

confidence: 89%

Squamous cell carcinoma of the oral cavity and circulating tumour cells

Wikner

Gröbe

Pantel

2014

WJCO

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Due to a lack of substantial improvement in the outcome of patients suffering from oral squamous cell carcinoma (OSCC) during the past decades, current staging methods need to be revised. This disease is associated with poor survival rates despite considerable advances in diagnosis and treatment. The early detection of metastases is an important indicator of survival, prognosis and relapse. Therefore, a better understanding of the mechanisms underlying metastasis is crucial. Exploring alternative measures apart from common procedures is needed to identify new prognostic markers. Similar to previous findings predominantly for other solid tumours, recently published studies demonstrate that circulating tumour cells (CTCs) and disseminated tumour cells (DTCs) might serve as prognostic markers and could supplement routine staging in OSCC. Thus, the detection of CTCs/DTCs is a promising tool to determine the individual need for therapeutic intervention. Encouraging results and new approaches point to the future use of targeted therapies for OSCC, an exceedingly heterogeneous subgroup of head and neck cancer. This review focuses on summarising technologies currently used to detect CTCs/DTCs. The translational relevance for OSCC is highlighted. The inherent challenges in detecting CTCs/DTCs will be emphasised. Core tip: Oral squamous cell carcinoma (OSCC), among head and neck cancer, is related to poor survival rates despite considerable advances in diagnosis and treatment. Therefore, detecting tumour cell dissemination early and understanding the underlying mechanisms are crucial for predicting prognosis, relapse and survival. According to previous findings, circulating tumour cells (CTCs) and disseminated tumour cells (DTCs) might serve as prognostic markers to supplement routine staging and support determining individual therapeutic interventions. This review focuses on summarising the current knowledge about the detection of CTCs/DTCs with special emphasis on patients suffering from OSCC. The translational relevance of CTCs/DTCs and challenges for clinical application are highlighted.Wikner J, Gröbe A, Pantel K, Riethdorf S. Squamous cell carcinoma of the oral cavity and circulating tumour cells.

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“…The E48 antigen is highly expressed in locally invasive squamous cell carcinomas of the head and neck and constitutes a marker of disseminated tumor cells both in lymph nodes and bone marrow (32). Recently, the presence of micrometastatic cells in bone marrow of patients with squamous cell carcinomas of the head and neck with two or more lymph node metastases has been correlated with a poor metastasis-free survival (33). It has been hypothesized that E48 is a signal transduction protein that plays a role in cell-cell communication, and recent reports suggest involvement in mediating selectin-dependent binding of premetastatic tumor cells to the endothelium (28).…”

Section: Invasiveness and Tumor Cell Dissemination Requires Regulatiomentioning

confidence: 99%

Genetic reprogramming of tumor cells by zinc finger transcription factors

Blancafort

Chen

González

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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Cancer arises by the accumulation of genetic alterations in DNA leading to aberrant gene transcription. Expression-profiling studies have correlated genomewide expression signatures with malignancy. However, functional analysis elucidating the contribution and synergy of genes in specific cancer cell phenotypes remains a formidable obstacle. Herein, we describe an alternative genetic approach for identification of genes involved in tumor progression by using a library of zinc finger artificial transcription factors (ATFs) and functional screening of tumor cells as a source of genetic plasticity and clonal selection. We isolated a six-zinc finger transcriptional activator (TF 20-VP, TF 20 containing the VP64 activator domain) that acts to reprogram a drug-sensitive, poorly invasive, and nonmetastatic cell line into a cell line with a drugresistant, highly invasive, and metastatic phenotype. Differential expression profiles of cells expressing TF 20-VP followed by functional studies, both in vitro and in animal models, revealed that invasion and metastasis requires coregulation of multiple target genes. Significantly, the E48 antigen, associated with poor metastasis-free survival in head and neck cancer, was identified as one specific target of TF 20-VP. We have shown phenotypic modulation of tumor cell behavior by E48 expression, including enhanced cell migration in vitro and tumor cell dissemination in vivo. This study demonstrates the use of ATFs to identify the group of genes that cooperate during tumor progression. By coregulating multiple targets, ATFs can be used as master genetic switches to reprogram and modulate complex neoplastic phenotypes. drug resistance ͉ metastasis ͉ invasion ͉ transcriptional regulation ͉ RNA inteference

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Clinical Significance of Micrometastatic Cells Detected by E48 (Ly-6D) Reverse Transcription-Polymerase Chain Reaction in Bone Marrow of Head and Neck Cancer Patients

Cited by 46 publications

References 21 publications

Prognostic Relevance of Circulating Tumor Cells in Blood and Disseminated Tumor Cells in Bone Marrow of Patients with Squamous Cell Carcinoma of the Oral Cavity

Prognostic Relevance of Circulating Tumor Cells in Blood and Disseminated Tumor Cells in Bone Marrow of Patients with Squamous Cell Carcinoma of the Oral Cavity

Squamous cell carcinoma of the oral cavity and circulating tumour cells

Genetic reprogramming of tumor cells by zinc finger transcription factors

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