Circulating tumour cells: their utility in cancer management and predicting outcomes

Recent advances in technology now permit robust and reproducible detection of circulating tumour cells (CTCs) from a simple blood test. Standardization in methodology has been instrumental in facilitating multicentre trials with the purpose of evaluating the clinical utility of CTCs. We review the current body of evidence supporting the prognostic value of CTC enumeration in breast, prostate and colorectal cancer, using standardized approaches, and studies evaluating the correlation of CTC number with radiological outcome. The exploitation of CTCs in cancer management, however, is now extending beyond prognostication. As technologies emerge to characterize CTCs at the molecular level, biological information can be obtained in real time, with the promise of serving as a 'surrogate tumour biopsy'. Current studies illuminate the potential of CTCs as pharmacodynamic and predictive biomarkers and potentially their use in revealing drug resistance in real time. Approaches for CTC characterization are summarized and the potential of CTCs in cancer patient management exemplified via the detection of epidermal growth factor receptor mutations from CTCs in patients with non-small cell lung cancer. The opportunity to learn more about the biology of metastasis through CTC analysis is now being realized with the horizon of CTC-guided development of novel anticancer therapies.     

Circulating tumour cells in breast cancer

By use of modern immunological and molecular analytical techniques, cells with the characteristics of tumour cells can be detected in the blood of many patients with breast cancer. The ability to detect and characterise such cells routinely could have a profound influence on the early diagnosis of breast cancer, risk stratification in the adjuvant setting, early detection of relapse, and the development of new targeted strategies. In this review we discuss current techniques to detect circulating breast-cancer cells and the limitations of these approaches. We also review the clinical studies in breast cancer and discuss the potential relevance of this research to the future management of the disorder.     

Circulating tumour cells in colorectal cancer

BackgroundThe detection of circulating tumour cells (CTC) in blood sample in patients with early or advanced colorectal cancer has a potential prognostic value.MethodsThe challenge of CTC detection is related to the requirement of high sensitivity combined with high specificity method. CTCs detection can be distinguished between indirect and direct methods. The former ones are based on the recognition of tissue-, organ- or tumour-specific markers by immuno-histochemistry (indirect immuno-mediated methods) or (real-time) RT-PCR (indirect molecular methods), whilst the latter are related to CTCs selection based on the physical properties of density and sizes. Ongoing and future isolation by size of epithelial tumour cells (ISET) developments concerning automated image analysis on the filter and transmission of high definition images through the web for ‘on line’ cytopathological consultations are aimed to speed up the work of cytopathologists on CTC/ circulating tumour microemboli (CTM) detection.ConclusionsCTC detection in colorectal cancer (CRC) correlates with pathological stage and clinical outcome in particular in those patients with advanced disease. CRC CTC level before and after CT are an independent prognostic factor for progression-free and overall survival. The positive prognostic value of complete clearance CTC after surgery may be useful to select patients for adjuvant chemotherapy.     

细胞黏附分子与肺癌侵袭转移的关系

细胞黏附分子（CAM）与肿瘤侵袭转移的关系密切,能够介导肿瘤细胞与细胞外基质、血管内皮细胞、实质器官组织细胞以及肿瘤细胞之间的相互作用。现就近年来细胞黏附分子在肺癌侵袭转移中的作用作一综述。     

细胞黏附分子与肺癌侵袭转移的关系

细胞黏附分子(CAM)与肿瘤侵袭转移的关系密切,能够介导肿瘤细胞与细胞外基质、血管内皮细胞、实质器官组织细胞以及肿瘤细胞之间的相互作用。现就近年来细胞黏附分子在肺癌侵袭转移中的作用作一综述。     

循环肿瘤细胞与肺癌

循环肿瘤细胞(CTC)与肿瘤转移有明显的相关性,CTC检测有助于指导肿瘤治疗,为判断预后、预测疗效提供可靠依据.CTC与非小细胞肺癌的分期及远处转移相关.CTC数量变化与非小细胞肺癌患者化放疗疗效及预后有关.小细胞肺癌中CTC检出率和数量均明显高于其他肿瘤,与其分期及化疗疗效有关.CTC有望用于指导肺癌个体化治疗.初步研究结果提示可用CTC来动态了解肺癌患者分子靶向药物治疗过程中耐药肿瘤细胞的出现.     

Circulating tumor cells in lung cancer:Detection methods and clinical impact

Circulating tumor cells（CTCs） are tumor cells that enter the blood circulation after detaching from the primary tumor and can migrate to reach distant organs, where they can give rise to aggressive metastasis. Clinical studies have revealed that the presence of CTCs in peripheral blood is correlated with disease progression in lung cancer. However, as CTCs are rare cancer cells released from tumors into the bloodstream, both enrichment and sensitive detection methods are technically challenging. In order to best understand how CTCs are currently being deployed, this review mainly focuses on the different detection methods for CTCs. Furthermore, we will describe the clinical impact of circulating tumor cells in lung cancer and discuss their potential use as biomarker to guide the prognosis.     

Circulating tumour cells in locally advanced breast cancer

Material and methods

A prospective study was conducted to determine the value of changes in circulating tumour cell (CTC) levels prior to and after the first cycle of neoadjuvant treatment in early prediction of pathologic response in locally advanced breast cancer (LABC). Two blood samples were obtained from 72 eligible LABC patients to isolate and enumerate CTCs before neoadjuvant chemotherapy started on day 1, and on day 21, immediately before second cycle administration.

Results

Sixty patients (83.3%) had <1 CTC in the first sample and response rates in this cohort were pathologic complete response (PCR) in 2 patients (5%), partial response (PR) in 35 (87.5%), stable disease (SD) in 2 (5%) and progressive disease (PD) in 1 (2.5%). Twelve patients (16.7%) had >2 CTCs in the first sample; these patients were more likely to have triple negative tumours. All 12 had fewer CTCs in the second sample. Response rates in this second cohort of 12 patients were PCR in 4 (34%), PR in 6 (50%), SD in 1 (8%) and PD in 1 (8%). PCR rate was markedly better in this second cohort (p<0.0042; OR 14.5, 95% CI 2.3–92).

Discussion

This study suggests that the presence of CTCs prior to neoadjuvant therapy might be a predictor of response to this therapy.     

A role for cancer stem cells in drug resistance and metastasis in non-small-cell lung cancer

The cancer stem cell (CSC) theory is currently a very important field in cancer research. This theory states that tumours are organised in a hierarchical manner with a subpopulation of limited number called CSCs with the ability to self-renew and undergo asymmetrical divisions, giving rise to a differentiated progeny that represents most of the tumour populations. CSCs are metastatic and chemoresistant, two features that very likely contribute to the poor response of locally advanced lung cancer. CSCs have been identified in non-small-cell lung cancer cell lines as well as those from patient primary samples. A correlation has been found in terms of chemoresistance and bad prognosis in patient-derived samples enriched with CSCs, indicating that these cells are an important target for future therapy combinations. Therefore, understanding the biology and exploring cell markers and signalling pathways specific for CSCs of lung cancer may help in achieving progress in the treatment of the disease.     

Circulating tumour cells as tumour biomarkers in melanoma: detection methods and clinical relevance

Circulating tumour cells (CTCs) are cells of solid tumour origin detectable in the peripheral blood. Their occurrence is considered a prerequisite step for establishing distant metastases. Metastatic melanoma was the first malignancy in which CTCs were detected and numerous studies have been published on CTC detection in melanoma at various stages of disease. In spite of this, there is no general consensus as to the clinical utility of CTCs in melanoma, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. In this review, we examine the possible clinical significance of CTCs in cutaneous, mucosal and ocular melanoma, focusing on detection methods and prognostic value of CTC detection.     

Circulating tumour cells in prostate cancer patients receiving salvage radiotherapy

Introduction

Within 10 years of radical prostatectomy (RP), up to 30% of prostate cancer (PCa) patients will have a rise in prostate-specific antigen (PSA), requiring radiation therapy (RT). However, with current technology, distinction between local and distant recurrent PCa is not possible. This lack of an accurate test constrains the decision whether to offer systemic or local treatment. We hypothesise tests for detecting circulating tumour cells (CTCs) within the blood may assist with clinical decision-making and in this pilot study we investigated whether CTCs could be detected in this patient population using the CellSearch® system.

Materials and methods

Blood samples were collected from PCa patients (n=26) prior to RT and 3 months following completion of RT. Samples were analysed for PSA level via immunoassay and CTC number using the CellSearch® system.

Results

CTCs could be detected in this patient population and following RT CTCs appeared to decrease. However, no association was observed between a higher PSA and an increased number of CTCs pre- or post-RT. Interestingly, patients who failed RT trended toward an increased/unchanged number of CTCs following RT vs. a decreased number in patients with RT response.

Conclusions

Our results demonstrate that CTCs can be detected in early-stage PCa and suggest the possibility that post-treatment reduction in CTC levels may be indicative of RT response. We are currently evaluating CTCs in a larger cohort of patients to validate our preliminary findings and further investigate the prognostic value of CTCs in this patient population.

     

Circulating tumour cells: the evolving concept and the inadequacy of their enrichment by EpCAM-based methodology for basic and clinical cancer research

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.     

可手术非小细胞肺癌淋巴结转移特点及其临床意义

目的：分析可手术非小细胞肺癌（non-small cell lung cancer ,NSCLC ）区域淋巴结的转移特点,探讨其在手术淋巴结清扫范围的选择以及术后放射治疗靶区勾画中的意义。方法：回顾性分析浙江省肿瘤医院2005年1 月至2010年12月810 例NSCLC 患者的临床资料,分析区域各组淋巴结转移频度以及肿瘤原发病灶与区域淋巴结转移部位的相关性。结果：NSCLC 区域淋巴结转移与患者年龄、肿瘤大小、组织学类型及肿瘤部位相关（P 值分别为0.013、0.000、0.009 和0.000）。 不同肿瘤原发部位有不同的淋巴结易转移区域。结论：左肺原发肿瘤中病灶大、组织学类型为腺癌的患者易发生区域淋巴结转移。非小细胞肺癌在纵隔淋巴结的转移中,右上肺癌主要转移至上纵隔2～4 区;右中肺和右下肺癌主要转移至上纵隔2～4 区、隆突下;左上肺癌主要转移至上纵隔2～4 区、主动脉弓下;左下肺癌主要转移至动脉弓下及隆突下。在手术选择淋巴结清扫范围及术后放射治疗靶区勾画时应特别注意这些淋巴结转移频度较高的区域。     

CIK细胞及其在肺癌治疗中的研究进展

肺癌作为恶性肿瘤导致死亡的首要原因,严重影响人类的健康。由于细胞因子诱导的杀伤细胞(cytokine-induced killer cells,CIK)强大的增殖活性和细胞毒活性、非主要组织相容性复合体(major histocompatibilityantigens,MHC)限制性以及低毒副作用等优点成为近年研究的热点。本文旨在介绍CIK细胞的基本特征及发挥作用的机制,综述CIK细胞用于肺癌治疗的研究进展,讨论CIK细胞大规模用于临床前需要解决的若干问题并作出展望。