Stat3-positive tumor cells contribute to vessels neoformation in primary central nervous system lymphoma.

Simona Ruggieri,Nicoletta Coccaro,Giorgina Specchia,Rebecca Senetta,Nicoletta Resta,Domenico Ribatti,Tiziana Annese,Francesco Albano,Beatrice Nico,Mariella Errede,Roberto Tamma,Paola Cassoni,Daria Loconte

doi:10.18632/oncotarget.16115

Simona Ruggieri, Nicoletta Coccaro + Show 11 more

Open Access

https://doi.org/10.18632/oncotarget.16115

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Journal: Oncotarget	Publication Date: Mar 10, 2017
Citations: 15	License type: cc-by

Affiliation: University of Bari Aldo Moro, University of Turin

Abstract

With the aim of elucidating the relationship between Stat3 expression and tumor vessels abnormalities in the PCNLs, in this study we evaluated Stat3 and pStat3 expression by Real-time PCR and by immunohistochemistry in biopsy sections from PCNSL patients. Correlations of the expression levels with the presence of aberrant vessels were analyzed by confocal laser microscopy analysis, using FVIII as endothelial cell marker, CD133 and nestin as cancer stem cell (CSC) marker, CD20 as tumor cell marker, and Stat3. In addition, we investigated Stat3 mutations in lymphoma cells to clarify the role of the constitutive expression of Stat3 and of its phosphorylated forms. Results showed that in PCNSL, putative endothelial cells lining the vessels are heterogeneous, expressing FVIII/ pStat3/CD133 (presumably originally they are vascular progenitor cells), as well as FVIII/CD20/CD133 (presumably originally they are tumor cells). Finally, we detected a fraction of the FVIII+ endothelial cell that co-expressed Stat3 bearing a tetraploid karyotype, while no amplification signal for the Stat3 gene was detected.

Highlights

Primary Central Nervous System Lymphoma (PCNSL) has an aggressive course and poor prognosis, with a median survival of less than 20–24 months [1, 2]
signal transducer and activator of transcription 3 (Stat3) showed an intense staining in tumor tissues (Figure 1A) compared to normal brain lacking Stat3 labeling (Figure 1C).Tumor vessels were lined by Stat3+ cells and tumor cells were identified near to the vessel wall (Figure 1B)
Stat3 displayed a higher expression (Figure 2A) compared to phosphorylated Stat3 (pStat3), which strongly labeled the nuclei of the endothelial cells and clusters of tumor perivascular cells in the same area (Figure 2B). pStat3 was not detected in the control brain tissue (Figure 2C)

Summary

Introduction

Primary Central Nervous System Lymphoma (PCNSL) has an aggressive course and poor prognosis, with a median survival of less than 20–24 months [1, 2]. The majority of PCNSL are diffuse large B-cell Lymphomas [4] and lymphomatous cells are typically localized in the perivascular areas [3]. Expression of vascular endothelial growth factor (VEGF) in PCNSL cells is correlated with microvascular density, with longer survival and blood-brain barrier alterations [6]. We have previously demonstrated that different type of cells are involved in the formation of vascular wall in PCNSL [7]. Cancerlike stem cells (CSCs) may be involved in formation of tumor vessels, including brain tumors, through a cross-talk between endothelial cells and CSCs [8,9,10]

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