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Cyclin A1 and P450 Aromatase Promote Metastatic Homing and Growth of Stem-like Prostate Cancer Cells in the Bone Marrow

Miftakhova, Regina; Hedblom, Andreas; Semenas, Julius; Robinson, Brian D.; Simoulis, Athanasios; Malm, Johan; Rizvanov, Albert; David Heery, David; Mongan, Nigel P.; Maitland, Norman J.; Allegrucci, Cinzia; Persson, Jenny L.

Authors

Regina Miftakhova

Andreas Hedblom

Julius Semenas

Brian D. Robinson

Athanasios Simoulis

Johan Malm

Albert Rizvanov

DAVID HEERY david.heery@nottingham.ac.uk
Professor of Eucaryoticgene Regulation

Norman J. Maitland

Jenny L. Persson



Abstract

Bone metastasis is a leading cause of morbidity and mortality in prostate cancer (PCa). While cancer stem-like cells have been implicated as a cell of origin for PCa metastases, the pathways which enable metastatic development at distal sites remain largely unknown. In this study, we illuminate pathways relevant to bone metastasis in this disease. We observed that cyclin A1 (CCNA1) protein expression was relatively higher in PCa metastatic lesions in lymph node, lung, and bone/bone marrow. In both primary and metastatic tissues, cyclin A1 expression was also correlated with aromatase (CYP19A1), a key enzyme that directly regulates the local balance of androgens to estrogens. Cyclin A1 overexpression in the stem-like ALDHhigh subpopulation of PC3M cells, one model of PCa, enabled bone marrow integration and metastatic growth. Further, cells obtained from bone marrow metastatic lesions displayed self-renewal capability in colony forming assays. In the bone marrow, Cyclin A1 and aromatase enhanced local bone marrow-releasing factors, including androgen receptor, estrogen and matrix metalloproteinase MMP9 and promoted hte metastatic growth of PCa cells. Moreover, ALDHhigh tumor cells expressing elevated levels of aromatase stimulated tumor/host estrogen production and acquired a growth advantage in the presence of host bone marrow cells. Overall, these findings suggest that local production of steroids and MMPs in the bone marrow may provide a suitable microenvironment for ALDHhigh PCa cells to establish metastatic growths, offering new approaches to therapeutically target bone metastases.

Citation

Miftakhova, R., Hedblom, A., Semenas, J., Robinson, B. D., Simoulis, A., Malm, J., …Persson, J. L. (2016). Cyclin A1 and P450 Aromatase Promote Metastatic Homing and Growth of Stem-like Prostate Cancer Cells in the Bone Marrow. Cancer Research, 76(8), 2453-2464. https://doi.org/10.1158/0008-5472.CAN-15-2340

Journal Article Type Article
Acceptance Date Jan 25, 2016
Online Publication Date Feb 26, 2016
Publication Date Apr 15, 2016
Deposit Date Mar 1, 2016
Publicly Available Date Mar 1, 2016
Journal Cancer Research
Print ISSN 0008-5472
Electronic ISSN 1538-7445
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
Volume 76
Issue 8
Pages 2453-2464
DOI https://doi.org/10.1158/0008-5472.CAN-15-2340
Public URL http://eprints.nottingham.ac.uk/id/eprint/32025
Publisher URL http://cancerres.aacrjournals.org/content/early/2016/02/26/0008-5472.CAN-15-2340
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf







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