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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 LU ; Hedblom, Andreas LU ; Semenas, Julius LU ; Robinson, Brian D; Simoulis, Athanasios; Malm, Johan LU ; Rizvanov, Albert; Heery, David; Mongan, Nigel P and Maitland, Norman J, et al. (2016) In Cancer Research 76(8). p.2453-2464
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... (More)
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. (Less)
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type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
76
issue
8
pages
2453 - 2464
publisher
American Association for Cancer Research
external identifiers
  • PMID:26921336
  • WOS:000374170700039
  • Scopus:84970990663
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-15-2340
language
English
LU publication?
yes
id
4c33f42e-3ef1-4489-b519-ed041d9973f2 (old id 8821447)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26921336?dopt=Abstract
date added to LUP
2016-03-04 09:02:12
date last changed
2016-10-30 04:36:19
@misc{4c33f42e-3ef1-4489-b519-ed041d9973f2,
  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.},
  author       = {Miftakhova, Regina and Hedblom, Andreas and Semenas, Julius and Robinson, Brian D and Simoulis, Athanasios and Malm, Johan and Rizvanov, Albert and Heery, David and Mongan, Nigel P and Maitland, Norman J and Allegrucci, Cinzia and Persson, Jenny L},
  issn         = {1538-7445},
  language     = {eng},
  month        = {02},
  number       = {8},
  pages        = {2453--2464},
  publisher    = {ARRAY(0xbc019b8)},
  series       = {Cancer Research},
  title        = {Cyclin A1 and P450 aromatase promote metastatic homing and growth of stem-like prostate cancer cells in the bone marrow.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-15-2340},
  volume       = {76},
  year         = {2016},
}