Abstract
BackgroundCancer is a mosaic of tumor cell subpopulations, where only a minority is responsible for disease recurrence and cancer invasiveness. We focused on one of the most aggressive circulating tumor cells (CTCs) which, from the primitive tumor, spreads to the central nervous system (CNS), evaluating the expression of prognostic and putative cancer stem cell markers in breast cancer (BC) leptomeningeal metastasis (LM).MethodsFlow cytometry immunophenotypic analysis of cerebrospinal fluid (CSF) samples (4.5 ml) was performed in 13 consecutive cases of BCLM. Syndecan-1 (CD138), MUC-1 (CD227) CD45, CD34, and the putative cancer stem cell markers CD15, CD24, CD44, and CD133 surface expression were evaluated on CSF floating tumor cells. The tumor-associated leukocyte population was also characterized.ResultsDespite a low absolute cell number (8 cell/μl, range 1–86), the flow cytometry characterization was successfully conducted in all the samples. Syndecan-1 and MUC-1 overexpression was documented on BC cells in all the samples analyzed; CD44, CD24, CD15, and CD133 in 77%, 75%, 70%, and 45% of cases, respectively. A strong syndecan-1 and MUC-1 expression was also documented by immunohistochemistry on primary breast cancer tissues, performed in four patients. The CSF tumor population was flanked by T lymphocytes, with a different immunophenotype between the CSF and peripheral blood samples (P ≤ 0.02).ConclusionsFlow cytometry can be successfully employed for solid tumor LM characterization even in CSF samples with low cell count. This in vivo study documents that CSF floating BC cells overexpress prognostic and putative cancer stem cell biomarkers related to tumor invasiveness, potentially representing a molecular target for circulating tumor cell detection and LM treatment monitoring, as well as a primary target for innovative treatment strategies. The T lymphocyte infiltration, documented in all CSF samples, suggests a possible involvement of the CNS lymphatic system in both lymphoid and cancer cell migration into and out of the meninges, supporting the extension of a new form of cellular immunotherapy to LM. Due to the small number of cases, validation on large cohorts of patients are warranted to confirm these findings and to evaluate the impact and value of these results for diagnosis and management of LM.
Highlights
Cancer is a mosaic of tumor cell subpopulations, where only a minority is responsible for disease recurrence and cancer invasiveness
breast cancer (BC) was diagnosed in other centers and detailed histological data were not available; these three outpatients were referred to the Regina Elena National Cancer Institute Neuro-Oncology Division for diagnosis and treatment of leptomeningeal metastasis (LM) clinical symptoms
Thereafter, hypothesizing that a BC cell could take advantage from a cancer stem cell phenotype for cerebrospinal fluid (CSF) infiltration, we investigated the expression of a number of putative cancer stem cell markers on BC floating cells, documenting a stem cell-like phenotype, CD15, CD44, CD24, and CD133 positive, in a proportion of cases
Summary
Cancer is a mosaic of tumor cell subpopulations, where only a minority is responsible for disease recurrence and cancer invasiveness. New approaches are dramatically needed to facilitate diagnosis and treatment response monitoring, as well as the identification of new prognostic biomarkers, able to stratify patients according to risk of metastasis and cerebrospinal fluid (CSF) cancer dissemination. According to the tumor stem cell hypothesis, a subset of cells, defined as cancer-initiating cells, has a primary relevance in tumor metastases and cancer recurrence after chemotherapy [4,5,6]. This subpopulation, residing in a heterogeneous primary tumor, exhibits enhanced invasive properties as well as the ability to grow in anchorage-independent conditions [7, 8]. Isolated from solid biopsies and tumor cell lines, cancer stem cells are currently identified by surface antigen expression using a number of putative stem cell markers including CD15, CD24, CD44, and CD133 [9,10,11,12,13]
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