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

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 ALDH high 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 colonyforming 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, ALDH high 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 ALDH high prostate cancer cells to establish metastatic growths, offering new approaches to therapeutically target bone metastases. Cancer Res; 76(8); 2453-64. Ó2016 AACR.

MTA1 drives malignant progression and bone metastasis in prostate cancer

“…Therefore, to delineate the role of MTA1 in bone metastasis, we utilized the experimental bone metastasis model with injections of cells into the left cardiac ventricle of athymic mice (Chong Seow Khoon, 2015; Holzapfel et al ., 2014; Miftakhova et al ., 2016; Rosol et al ., 2004). Metastases were monitored by weekly bioluminescence imaging until day 34, when mice were sacrificed.…”

Insight into the Mechanism of SDS Irritation on Human Skin Keratinocytes by Examination of Changes in Gene Expression

“…Metastatic growth was found in the lymph node, lung, and liver in subcutaneous and orthotropic xenograft mouse models after the induction of CCNA1 over-expression in PC3 cells. Regina reported that CCNA1 interacts with Erαto promote breast cancer progression in xenograft mouse models [22]. SDS stimulation for 1.5 h caused a high level of CCNA1 expression, which is closely related with the development of cancers.…”

Estradiol for the mitigation of adverse effects of androgen deprivation therapy

“…E 2 acts on local stromal and epithelial cells and there is paracrine regulation of its production, but this is lost in PCa. Increased aromatase expression in metastatic PCa lesions has been demonstrated (Miftakhova et al 2016). Estrogens along with other non-androgen ligands may be able to activate mutated ARs as one mechanism of 24:8 castrate resistance (Leach et al 2016).…”