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Original Article | Open Access

CD44v8-10 is a marker for malignant traits and a potential driver of bone metastasis in a subpopulation of prostate cancer cells

Rosaria A. Fontanella1, Silvia Sideri1, Chiara Di Stefano1, Angiolina Catizone1, Silvia Di Agostino2, Daniela F. Angelini3, Gisella Guerrera3, Luca Battistini3, Giulia Battafarano4, Andrea Del Fattore4, Antonio Francesco Campese5, Fabrizio Padula1, Paola De Cesaris6 ( ), Antonio Filippini1 ( ), Anna Riccioli1
Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University, Rome 00161, Italy
Department of Health Sciences School of Medicine – “Magna Graecia” University of Catanzaro, Catanzaro 88100, Italy
IRCCS Fondazione Santa Lucia, Rome 00143, Italy
Bone Physiopathology Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome 00146, Italy
Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila 67100, Italy
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Abstract

Objective

Bone metastasis is a clinically important outcome of prostate carcinoma (PC). We focused on the phenotypic and functional characterization of a particularly aggressive phenotype within the androgen-independent bone metastasis-derived PC3 cell line. These cells, originated from the spontaneous conversion of a CD44-negative subpopulation, stably express the CD44v8-10 isoform (CD44v8-10pos) and display stem cell-like features and a marked invasive phenotype in vitro that is lost upon CD44v8-10 silencing.

Methods

Flow cytometry, enzyme-linked immunoassay, immunofluorescence, and Western blot were used for phenotypic and immunologic characterization. Real-time quantitative polymerase chain reaction and functional assays were used to assess osteomimicry.

Results

Analysis of epithelial–mesenchymal transition markers showed that CD44v8-10pos PC3 cells surprisingly display epithelial phenotype and can undergo osteomimicry, acquiring bone cell phenotypic and behavioral traits. Use of specific siRNA evidenced the ability of CD44v8-10 variant to confer osteomimetic features, hence the potential to form bone-specific metastasis. Moreover, the ability of tumors to activate immunosuppressive mechanisms which counteract effective immune responses is a sign of the aggressiveness of a tumor. Here we report that CD44v8-10pos cells express programmed death ligand 1, a negative regulator of anticancer immunity, and secrete exceptionally high amounts of interleukin-6, favoring osteoclastogenesis and immunosuppression in bone microenvironment. Notably, we identified a novel pathway activated by CD44v8-10, involving tafazzin (TAZ) and likely the Wnt/TAZ axis, known to play a role in upregulating osteomimetic genes.

Conclusions

CD44v8-10 could represent a marker of a more aggressive bone metastatic PC population exerting a driver role in osteomimicry in bone. A novel link between TAZ and CD44v8-10 is also shown.

Keywords

MetastasisEMTMETIL-6epithelial phenotypeTAZ

Electronic Supplementary Material

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Cancer Biology & Medicine
Volume 18 Issue 3,
August 2021
Pages 788-807
DOI: 10.20892/j.issn.2095-3941.2020.0495
Cite this article:
Fontanella RA, Sideri S, Di Stefano C, et al. CD44v8-10 is a marker for malignant traits and a potential driver of bone metastasis in a subpopulation of prostate cancer cells. Cancer Biology & Medicine, 2021, 18(3): 788-807. https://doi.org/10.20892/j.issn.2095-3941.2020.0495

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Received: 25 August 2020
Accepted: 08 March 2021
Published: 01 August 2021
©2021 Cancer Biology & Medicine.

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