Review article
Potential use of circulating endothelial cells as a biomarker of renal cell carcinoma

https://doi.org/10.1016/j.urolonc.2009.07.001Get rights and content

Abstract

Each year, renal cell carcinoma (RCC) accounts for significant mortality in the population. Whilst the disease is now being diagnosed earlier, determining patient prognosis remains a challenge. Current prognostic indicators, such as TNM stage, Fuhrman grade, and RCC subtype, are inadequate. Unlike several other malignancies, RCC lacks a biomarker that can stratify patients into high, intermediate, or low risk for developing metastases. Additionally, antiangiogenic therapy is currently offered to patients with metastatic disease, however, a biomarker to monitor treatment efficacy is lacking. Recent attention has focused on surrogate markers of tumor vascularization as a source of prognostic biomarkers, as tumor growth is ultimately dependent on neovascularization. Two cell populations of interest, circulating endothelial cells (CECs) and circulating endothelial progenitors (CEPs), have been demonstrated across several studies to contribute to tumor vascularization. Given these findings, studies have examined their utility as biomarkers of prognosis by correlating their levels with progression-free survival and prognostic determinants such as tumor volume and weight. However, their role in predicting prognosis in RCC, as well as their potential to act as markers of treatment efficacy in metastatic RCC, remains to be established. Previous studies on CECs and CEPs in the context of cancer will be outlined in this review.

Introduction

Renal cell carcinoma (RCC) represents approximately 3% of all cancers worldwide [1]. In 2008, an estimated 46,232 diagnoses were made in the United States alone, of which approximately 11,059 resulted in death [2]. The majority are now detected through abdominal ultrasounds or CT scans, often incidentally while evaluating nonspecific symptoms [1]. Consequently, many renal tumors are now detected earlier in the course of disease, presenting smaller and at a lower stage and grade. Nevertheless, up to 30% of patients with RCC have metastatic disease at presentation, and recurrence develops in 40% of patients treated for localized disease [3], thus requiring some form of systemic therapy.

Section snippets

The challenge: Prognosis, not diagnosis

With the advent of superior imaging techniques for diagnosis, the need for more accurate prognostication has intensified. The clinical management of RCC involves a series of critical decisions that are strongly influenced by the patient's prognosis, which ultimately dictates the treatment options. For patients with metastatic disease, in addition to prognostication, there is a need to accurately determine the optimal biologic dose of anti-angiogenic agents, as well as a method to monitor

Tumor vascularization

Given that a biomarker for RCC does not exist, the question that follows is: From where and how should this biomarker be derived? Quite possibly, the answer may lie with tumor neovascularization. In terms of cancer etiology, vascularization is considered one of the six established hallmarks of solid, malignant tumors [12]. Small tumors can acquire sufficient nutrients and oxygen through simple diffusion, but this becomes inefficient once cells are located further than 100 to 200 μm from a blood

Tumor vascularization in RCC: Molecular mechanism

The rationale for a surrogate marker of angiogenesis as a biomarker of RCC progression is straightforward—renal cell carcinoma is inherently a highly vascular tumor [21], [22], [23], [24], with the relationship clearly that the larger the tumor, the greater the network of blood vessels required.

The link between angiogenesis and RCC is further highlighted by the genetics of RCC tumorigenesis [25], [26], [27]. In the autosomal dominant von Hippel-Lindau (VHL) syndrome, patients develop hundreds

Tumor vascularization in RCC: Clinical evidence from antiangiogenic therapy

The introduction of antiangiogenic treatment as systemic therapy for metastatic RCC further underlines the crucial role of vascularization in RCC progression. In more aggressive cases, traditional cytotoxic chemotherapy has yielded poor results, with response rates typically less than 15% [28], [29], [30], [31], [32]. Subsequently interferon-α and interleukin-2 therapy have yielded relatively low response rates and toxic side effects, encouraging the continual search for alternative agents for

Tumor vascularization: Predictor of patient outcomes in RCC

Given the body of evidence demonstrating the integral role of vascularization in RCC progression, it is logical to consider this as a possible marker of disease outcome. Previous studies have compared microvessel density (MVD), a common measure of tumor vascularity, with patient survival in RCC. Determined by staining for surface antigens typically expressed on endothelial cells, MVD is now widely accepted as an indicator of disease severity across a range of cancers, including melanomas,

Endothelial cells: Potential biomarkers for RCC

While the true prognostic value of MVD and VEGF remains to be determined, recent attention has now focused on two populations of cells, CECs and CEPs, and their role as surrogate markers of tumor neovascularization. Whilst their utility in predicting RCC progression specifically is unclear, previous studies have already correlated their levels with tumor progression and progression-free survival across a range of malignancies. This review will now focus on these studies, building a rationale

Circulating endothelial cells

Circulating endothelial cells (CECs), a subpopulation of endothelial cells thought to originate from blood vessel walls, shed into the circulation following detachment from the basement membrane [49]. This sequence of events is integral to the angiogenic process that occurs in the body physiologically and in some pathologic contexts, such as in tumor growth. CECs express the phenotype of mature, terminally differentiated endothelial cells [49].

Bone marrow derived circulating endothelial progenitors (CEPs)

Circulating endothelial progenitors (CEPs) comprise a separate population of cells that originate from the bone marrow, expressing a pattern of surface antigens typically observed in stem cells [50]. CEPs are thought to play a role in the formation of new blood vessels through vasculogenesis [50].

Detection and identification of CECs and CEPs

CECs are traditionally considered to be CD31+CD45. For greater specificity, CD146+ staining can be utilized as it is most typically expressed on endothelial cells. CEPs, on the other hand, are considered to be CD31+CD45intermediateCD133+. In reality however, CEPs are a collection of phenotypically heterogenous stem cells that are still highly influenced by their surrounding environment [51].

CECs as biomarkers of tumor progression

An elevation in CECs has been observed in various diseased states ranging from vasculitis, kidney transplant rejection to myocardial infarction [52]. This observation extended to cancer patients, where Mancuso et al. measured higher levels of CECs in patients across a range of malignancies compared to healthy controls [53]. Interestingly, CEC levels were found to decrease in response to treatment, observed in patients post-chemotherapy for lymphoma, and post-mastectomy for breast cancer.

Some of

CEP contribution to tumor vascularization

The correlation between CEP levels and tumor progression has also been investigated across several malignancies, although this remains to be examined in the RCC context. Results have indicated that CEPs contribute to tumor vasculature in Lewis lung carcinoma [56], neuroblastomas [19], mammary adenocarcinomas [57], and lymphomas [58]. These results were supported by Peters et al., who utilized fluorescent in situ hybridization (FISH) techniques to demonstrate that up to 12.1% of tumor

Conclusions

The literature presented thus far highlights the ongoing need for improved disease-specific markers for RCC to better characterize patient prognosis and monitor disease recurrence. As surrogate markers of neovascularization, CECs and CEPs, show potential to reflect the progression of tumor growth. This relationship has been examined through animal models and clinical studies, although CECs and CEPs have not yet been examined specifically in an RCC setting. Nevertheless, the intrinsically high

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      A wide variety of molecular markers, including mediators of cellular proliferation, the hypoxia-inducible pathway, cell cycle regulators, and adhesion molecules, have been demonstrated to be the powerful marker for the diagnosis or prognosis of RCC [17–19]. Many studies also indicate that progenitor cells play a role of cancer progression: initiation of metastasis and disease progression [20–22]. Recently, vascular endothelial growth factor receptor 1 (VEGFR1)–positive hematopoietic progenitor cells have also been linked to the regulation of metastasis [23].

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