Stem-like and highly invasive prostate cancer cells expressing CD44v8-10 marker originate from CD44-negative cells
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Chiara Di Stefano1, Paola Grazioli2, Rosaria Anna Fontanella1, Paola De Cesaris3, Antonella D’Amore1, Michele Regno1, Donatella Starace1, Fabrizio Padula1, Micol Elena Fiori4, Rita Canipari1, Antonella Stoppacciaro6, Margherita Pesce6, Antonio Filippini1, Antonio Francesco Campese5, Elio Ziparo1,* and Anna Riccioli1,*
1Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Section of Histology and Medical Embryology, Sapienza University, Rome, Italy
2Department of Experimental Medicine, Sapienza University, Rome, Italy
3Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
4Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
5Department of Molecular Medicine, Sapienza University, Rome, Italy
6Division of Pathology, Sant'Andrea University Hospital, Rome, Italy
*These authors have contributed equally to this work
Antonio Francesco Campese, email: [email protected]
Antonio Filippini, email: [email protected]
Keywords: CD44; invasiveness; alternative splicing; prostate stem cells
Received: April 16, 2018 Accepted: June 22, 2018 Published: July 20, 2018
In human prostate cancer (PCa), the neuroendocrine cells, expressing the prostate cancer stem cell (CSC) marker CD44, may be resistant to androgen ablation and promote tumor recurrence. During the study of heterogeneity of the highly aggressive neuroendocrine PCa cell lines PC3 and DU-145, we isolated and expanded in vitro a minor subpopulation of very small cells lacking CD44 (CD44neg). Unexpectedly, these sorted CD44neg cells rapidly and spontaneously converted to a stable CD44high phenotype specifically expressing the CD44v8-10 isoform which the sorted CD44high subpopulation failed to express. Surprisingly and potentially interesting, in these cells expression of CD44v8-10 was found to be induced in stem cell medium. CD44 variant isoforms are known to be more expressed in CSC and metastatic cells than CD44 standard isoform. In agreement, functional analysis of the two sorted and cultured subpopulations has shown that the CD44v8-10pos PC3 cells, resulting from the conversion of the CD44neg subpopulation, were more invasive in vitro and had a higher clonogenic potential than the sorted CD44high cells, in that they produced mainly holoclones, known to be enriched in stem-like cells. Of interest, the CD44v8-10 is more expressed in human PCa biopsies than in normal gland. The discovery of CD44v8-10pos cells with stem-like and invasive features, derived from a minoritarian CD44neg cell population in PCa, alerts on the high plasticity of stem-like markers and urges for prudency on the approaches to targeting the putative CSC.
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