American Association for Cancer Research
Browse
00085472can152340-sup-154521_1_supp_3328001_71m7k5.docx (44.88 kB)

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

Download (44.88 kB)
journal contribution
posted on 2023-03-31, 00:04 authored by Regina Miftakhova, Andreas Hedblom, Julius Semenas, Brian Robinson, Athanasios Simoulis, Johan Malm, Albert Rizvanov, David M. Heery, Nigel P. Mongan, Norman J. Maitland, Cinzia Allegrucci, Jenny L. Persson

Supplemental Materials and Methods and figure text for supplemental figures

Funding

the Swedish Cancer Foundation, the National Research council, the Government Health Grant, the Malmö Cancer Foundation, the Skåne University Hospital Foundation

History

ARTICLE ABSTRACT

Bone metastasis is a leading cause of morbidity and mortality in prostate cancer. While cancer stem-like cells have been implicated as a cell of origin for prostate cancer metastasis, the pathways that 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 prostate cancer 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 prostate cancer, 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 the metastatic growth of prostate cancer 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 prostate cancer cells to establish metastatic growths, offering new approaches to therapeutically target bone metastases. Cancer Res; 76(8); 2453–64. ©2016 AACR.

Usage metrics

    Cancer Research

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC