ReviewCirculating tumour cells, their role in metastasis and their clinical utility in lung cancer
Introduction
Cancer is a leading cause of death worldwide and lung cancer specifically is the leading cause of cancer related death in the western world [1], [2]. Metastatic disease is responsible for the vast majority of cancer related deaths [3], [4], not least in the case of lung cancer, where the majority of patients are diagnosed with advanced disease and even those with early stage disease have high rates of relapse even after potentially curative treatment [5].
The metastatic process is a complex series of events in which malignant cells from the primary tumour must first invade through the basement membrane, and then migrate into the circulation, either directly via a blood vessel or indirectly via a lymphatic vessel, to finally spread to distant sites to form metastases [6], [7], [8]. It is clear therefore, that in many cancer patients, there exist Circulating Tumour Cells (CTCs), which disseminate from the primary tumour through the circulatory system and at least some of which are ultimately capable of forming distant metastases.
CTCs have attracted much recent interest in cancer research as a potential biomarker and as a means to study the process of metastasis. However the concept of circulating tumour cells is not a new one. It has long been understood that metastasis is a hallmark of malignancy [9], [10], and conceptual theories on the basis of metastasis from a very early stage foretold the existence of a tumour “seed” which is capable of establishing discrete tumours in the “soil” of distant organs. This “seed and soil” hypothesis, which predicted the existence of circulating tumour cells was first expounded by Paget in the late nineteenth century [11]. Similar hypotheses were also theorized by other prescient nineteenth century physicians, with some even identifying the existence of malignant cells in the circulation of cancer patients post mortem [12], [13].
It is clear that even in patients with advanced disease, CTCs exist in extreme rarity in blood, and there are significant technical challenges in their isolation. It is only in recent years that technology to reliably identify CTCs in peripheral blood has become available. Indeed it has now been shown that CTCs can be harvested from blood in numerous cancer subtypes, such as breast, colon, lung, prostate and urothelial cancers [14], [15], [16], [17], [18], [19], [20].
In the course of this review, we shall discuss the biology of CTCs and their role in metastagenesis, the most commonly used techniques for their detection and the evidence to date of their clinical utility, with particular reference to lung cancer.
Section snippets
Feasibility of CTC isolation and potential clinical utility
While many challenges still exist, the detection of CTCs in blood is becoming increasingly feasible, giving rise to some tantalizing questions about the use of CTCs as a potential biomarker. The detection of CTCs has been consistently demonstrated in epithelial malignancies, such as breast cancer, prostate cancer, colorectal cancer, urothelial cancer, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) [14], [16], [17], [19], [20], [21].
To date, the majority of studies have
The biology of CTCs and their role in the process of metastasis
The process of metastasis is extremely complex and is still imperfectly understood. An understanding of the metastatic process and how it relates to circulating tumour cells is of great importance in understanding the likely clinical significance of CTCs, in addition to providing important lessons in how the biology of metastasis impacts the various methods of CTC detection.
The process of metastasis requires a series of steps to occur, in order for a distant metastasis to be formed
Methods of CTC isolation and capture
It is known that even in patients with advanced cancers, CTCs exist in extreme rarity in patient blood, vastly outnumbered by normal blood cells, perhaps at a frequency of 1 CTC per 106–107 peripheral blood mononuclear cells, with even lower numbers seen in patients with early stage disease [86], [88], [89]. Therefore accurate, reliable and reproducible techniques to capture and purify CTCs from peripheral blood remain technically challenging. While more comprehensive reviews of CTC detection
Clinical utility of CTCs in lung cancer
Although many challenges remain, the detection, enumeration and molecular analysis of CTCs are now feasible in most cancers. In the case of lung cancer, there is perhaps not quite the same depth and breadth of data on CTCs as there is in some other cancer types, but nevertheless most of the commonly used techniques for CTC detection have been investigated in lung cancer models with some success.
Of particular importance in relation to CTCs and NSCLC, and a fine example of the demonstration of
Future directions
As previously discussed, the concept of tumour cells in the circulation is not new, having been first described by several far-sighted scientists and physicians in the nineteenth century. However the technology to reliably isolate and examine CTCs in meaningful and reproducible ways has really only been present in very recent times. Considerable challenges still exist however, and there is no one technique that is obviously superior. It is clear that every technique has some weaknesses and the
Conflict of interest statement
The authors have no conflict of interest to declare.
References (102)
- et al.
Hallmarks of cancer: the next generation
Cell
(2011) The distribution of secondary growths in cancer of the breast
Lancet
(1889)- et al.
Evaluation of circulating tumor cells and serological cell death biomarkers in small cell lung cancer patients undergoing chemotherapy
Am J Pathol
(2009) - et al.
The CTC-chip: an exciting new tool to detect circulating tumor cells in lung cancer patients
J Thorac Oncol
(2009) - et al.
Detection of circulating tumor cells in patients with urothelial cancer
Ann Oncol
(2009) - et al.
Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer
Ann Oncol
(2010) - et al.
Deadly allies: the fatal interplay between platelets and metastasizing cancer cells
Blood
(2010) - et al.
Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases
Am J Pathol
(1998) - et al.
ALDH1A1 and ALDH3A1 expression in lung cancers: correlation with histologic type and potential precursors
Lung Cancer
(2008) - et al.
Aldehyde dehydrogenase activity as a functional marker for lung cancer
Chem Biol Interact
(2009)
Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer
Cancer Lett
Epithelial–mesenchymal transitions in development and pathologies
Curr Opin Cell Biol
Circulating tumor cells as a window on metastasis biology in lung cancer
Am J Pathol
Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells
Blood
Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype
Cancer Cell
Inhibition of platelet GPIb alpha and promotion of melanoma metastasis
J Invest Dermatol
Frequent EpCam protein expression in human carcinomas
Hum Pathol
Methods for isolating circulating epithelial cells and criteria for their classification as carcinoma cells
Cytotherapy
Pitfalls in the detection of disseminated non-hematological tumor cells
Ann Oncol
Circulating tumour cell detection on its way to routine diagnostic implementation?
Eur J Cancer
Circulating tumor cells (CTC) detection: clinical impact and future directions
Cancer Lett
Circulating tumour cells in cancer patients: challenges and perspectives
Trends Mol Med
Circulating tumour cells in clinical practice: methods of detection and possible characterization
Methods
Isolation by size of epithelial tumor cells: a new method for the immunomorphological and molecular characterization of circulatingtumor cells
Am J Pathol
Isolation by size of epithelial tumor cells in peripheral blood of patients with breast cancer: correlation with real-time reverse transcriptase-polymerase chain reaction results and feasibility of molecular analysis by laser microdissection
Hum Pathol
Cancer statistics, 2008
CA Cancer J Clin
United States cancer statistics: 1999–2007 incidence and mortality web-based report
Cancer invasion and metastasis
Oncology
Metastasis of cancer: a conceptual history from antiquity to the 1990s
Cancer Metastasis Rev
The present status of postoperative adjuvant chemotherapy for completely resected non-small cell lung cancer
Ann Thorac Cardiovasc Surg
Dissemination and growth of cancer cells in metastatic sites
Nat Rev Cancer
Molecular basis of metastasis
N Engl J Med
Dissecting the metastatic cascade
Nat Rev Cancer
Cancer: principles and practice of oncology
A case of cancer in which cells similar to those in the tumours were seen in the blood after death
Aust Med J
Das Sarkom des Uvealtractus
Graefe's Archiv für Ophthalmologie
Circulating tumor cells, disease progression, and survival in metastatic breast cancer
N Engl J Med
Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer
J Clin Oncol
Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer
J Clin Oncol
Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer
Clin Cancer Res
Detection of mutations in EGFR in circulating lung-cancer cells
N Engl J Med
Circulating tumor cell as a diagnostic marker in primary lung cancer
Clin Cancer Res
Circulating tumor cells monitored over time in lung cancer patients
J Clin Oncol
Circulating tumor cells versus imaging--predicting overall survival in metastatic breast cancer
Clin Cancer Res
Use of circulating tumor cells (CTCs) in peripheral blood of breast cancer patients before and after adjuvant chemotherapy to predict risk for relapse: the SUCCESS trial
J Clin Oncol
Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse
J Clin Oncol
Preoperative circulating tumor cell detection using the isolation by size of epithelial tumor cell method for patients with lung cancer is a new prognostic biomarker
Clin Cancer Res
Increase in number of circulating disseminated epithelial cells after surgery for non-small cell lung cancer monitored by MAINTRAC(R) is a predictor for relapse: a preliminary report
World J Surg Oncol
Correlation of HER2 status between primary tumors and corresponding circulating tumor cells in advanced breast cancer patients
Breast Cancer Res Treat
Monitoring expression of HER-2 on circulating epithelial cells in patients with advanced breast cancer
Int J Oncol
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