Elsevier

Human Pathology

Volume 39, Issue 7, July 2008, Pages 1096-1102
Human Pathology

Original contribution
The clinicopathologic and prognostic significance of CD44+/CD24−/low and CD44/CD24+ tumor cells in invasive breast carcinomas

https://doi.org/10.1016/j.humpath.2007.12.003Get rights and content

Summary

Cells with distinct phenotypes and stem cell–like properties have been reported to exist in breast cancer. The aim of the present study was to investigate the clinicopathologic and prognostic significance of the CD44+/CD24−/low and CD44/CD24+ tumor phenotypes' prevalence. Double immunohistochemistry was applied on a series of 155 paraffin-embedded breast tissue specimens to detect CD44 and CD24. Evaluation of the phenotypes was performed by image analysis. The prevalence of CD44+/CD24−/low and CD44/CD24+ tumor cells was 58.7% and 82.6%, respectively. The dominance of the CD44+/CD24−/low tumor cells was inversely associated with lymph node metastasis (P = .019) and tended to inversely associate with the stage of the disease (P = .068). Moreover, the prevalence of CD44+/CD24−/low was found to exert no significant impact on patients' prognosis although it displayed a tendency toward an increase in disease-free survival (P = .074). On the other hand, the prevalence of CD44/CD24+ tumor cells was found to have no clinicopathologic significance. However, it was found to exert an unfavorable impact on both relapse-free (P = .009) and overall survival (P = .046) of the patients with breast carcinomas of intermediate differentiation (grade 2). In breast tissue, CD44+/CD24−/low tumor cells seem to be associated with lack of lymph node metastasis and a tendency toward an increase of the relapse-free survival of the patients. On the contrary, tumor cells with the phenotype CD44/CD24+ seem to identify patients with worse disease-free and overall survival within the group of intermediate-grade differentiation patients whose prognosis is difficult to assess.

Introduction

Currently, a growing body of evidence has been reported supporting the notion that tumors are organized in a hierarchy of heterogeneous cell populations with different biological properties and that the capability to sustain tumor formation and growth exclusively resides in a small proportion of tumor cells termed cancer stem cells. The latter are believed to share the feature of self-renewal with stem cells as well as the differentiation into diverse cell types [1], [2]. More specifically, there is substantial evidence in favor of the stem cell theory of breast carcinogenesis based on the observation of phenotypes common to breast stem cells and tumor cells and on the demonstration that breast epithelial cells with stem cell features were more susceptible to neoplastic transformation [3]. Cancer stem cells were reported to have been identified in breast cancer as CD44+/CD24−/low cells, capable of driving tumor formation when injected into the mammary fat pad of NOD/SCID mice [4]. However, much concern has been expressed with regard to whether the cells that have been separated from solid tumors are truly cancer stem cells [5]. Moreover, CD44+/CD24−/low cells have not been cultured as adherent cells yet and their clinicopathologic or prognostic significance was never proved or remains controversial, respectively [6], [7].

In addition, molecular profiling studies have classified breast cancers and breast cancer lines into 5 types with distinct prognostic significance [8], [9]. Of these, luminal and basal are the most important types corresponding with the 2 types of normal breast epithelial cells (luminal and basal/myoepithelial) [10]. Interestingly, in vitro studies have shown that all cell lines that contained CD44+/CD24−/low population belonged to the basal group, whereas luminal cell types contained higher levels of CD44/CD24+, suggesting that the latter population may contain cancer stem cells, thus corresponding to the luminal type of tumors, which represent the majority of breast cancers [3], [11].

Given the aforementioned data, we identified CD44+/CD24−/low and CD44/CD24+ tumor cells in paraffin-embedded tissue sections of patients with breast cancer, by a double-staining immunohistochemical technique and searched for their potential pathologic and prognostic significance.

Section snippets

Patients and samples studied

One hundred and sixty paraffin blocks with tumor samples were available from patients with resectable breast cancer who had undergone surgery. We only selected women with histologically proven, clearly invasive breast carcinomas, regardless of their initial stage, in whom axillary lymph node dissection had been performed and who had all their resected materials studied histologically. The patients were aged from 25 to 86 years (mean age, 56.74 years). None of them had received radiation or

Results

CD44+/CD24−/low and CD44/CD24+ phenotypes were detected in the tumor cells (Fig. 1, [2], Fig. 2) as well as in the normal epithelium and in in situ carcinomas, when the latter were observable in the examined specimens. Moreover, CD44 protein was immunodetected in the tumor stroma, whereas CD24 was also localized in the cytoplasm of the malignant cells.

In breast cancer tissues, CD44+/CD24−/low tumor cells ranged between 0% and 70% (median value, 2). Of the 155 evaluable specimens, 91 (58.7%)

Discussion

The potential existence of a stem-like cell in tumors is an old concept [15]. The recent study of Al-Hajj et al [4] in breast cancer is believed to have provided evidence supporting the existence of stem cells in a solid tumor. However, much concern has been expressed about both theoretical and technical issues. Specifically, the likelihood of variations of stemness with time as well as whether these cells sorted from tumors are truly cancer stem cells [5], [16]. Moreover, data from in vitro

Acknowledgment

We are grateful to S Koulyras for editing the manuscript.

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