Elsevier

Lung Cancer

Volume 76, Issue 1, April 2012, Pages 19-25
Lung Cancer

Review
Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer

https://doi.org/10.1016/j.lungcan.2011.10.018Get rights and content

Abstract

Circulating tumour cells (CTCs) have attracted much recent interest in cancer research as a potential biomarker and as a means of studying the process of metastasis. It has long been understood that metastasis is a hallmark of malignancy, and conceptual theories on the basis of metastasis from the nineteenth century foretold the existence of a tumour “seed” which is capable of establishing discrete tumours in the “soil” of distant organs. This prescient “seed and soil” hypothesis accurately predicted the existence of CTCs; microscopic tumour fragments in the blood, at least some of which are capable of forming metastases. However, it is only in recent years that reliable, reproducible methods of CTC detection and analysis have been developed. To date, the majority of studies have employed the CellSearch™ system (Veridex LLC), which is an immunomagnetic purification method. Other promising techniques include microfluidic filters, isolation of tumour cells by size using microporous polycarbonate filters and flow cytometry-based approaches. 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. CTC enumeration has been used to guide prognosis in patients with metastatic disease, and to act as a surrogate marker for disease response during therapy. Other possible uses for CTC detection include prognostication in early stage patients, identifying patients requiring adjuvant therapy, or in surveillance, for the detection of relapsing disease. Another exciting possible use for CTC detection assays is the molecular and genetic characterization of CTCs to act as a “liquid biopsy” representative of the primary tumour. Indeed it has already been demonstrated that it is possible to detect HER2, KRAS and EGFR mutation status in breast, colon and lung cancer CTCs respectively. 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.

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.

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