Dissociated Primary Human Prostate Cancer Cells Coinjected with the Immortalized Hs5 Bone Marrow Stromal Cells Generate Undifferentiated Tumors in NOD/SCID-γ Mice

297 Background: Interactions between epithelial and stroma cells are important in the development of prostate cancer (PCa). Cancer-associated fibroblasts (CAFs) have been to support tumor progression, metastasis, and differentiation. Androgen receptor (AR) and related pathways are known to support the growth and survival of prostate epithelial cancer cells, the roles of AR-dependent processes in cancerous stroma are less clear. We sought to investigate if AR-dependent pathways present in CAF cells influence the growth and tumorogencity of epithelial cancer cells in relation to androgen-deprivation therapy in prostate cancer. Methods: Murine CAFs were isolated from a well-described PTEN-dependent cancer mouse model (Liao, et al Cancer Res, 2010. 70(18):7294). A co-culture system was developed based on multiple lines of murine CAFs grown along with human prostate cancer epithelial cells, and a murine-specific anti-sense oligonucleotide (ASO) against murine AR was used to specifically suppress AR expression in murine CAFs in this system. RT-PCR was used to investigate changes in gene expression. Results: Using this co-culture system, we found that murine CAFs promoted cell proliferation and colony formation in several human prostate cancer cell lines. Further, these processes were decreased by suppression of AR-expression in CAFs. Expression of genes related to tumorigenicity in epithelial cells were investigated. Markers associated with epithelial-mesenchymal transition (EMT, N-Cad) and “stemness” (OCT4, Sox2, Nanog) were increased in human prostate cancer cells grown with low-AR CAFs. Conclusions: Our data indicates that suppression of AR in CAFs results in down-regulation in the growth and tumorigenicity of prostate cancer cells through pathways related to EMT and “cell reprograming”. As such, development of therapies which inhibit the tumor-promoting pathways present in stromal cells may be one approach to improve the treatment of prostate cancer.

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275: Bi-Directional Interactions of Bone Marrow Mesenchymal Stem Cells with Human Prostate Cancer Cells

The Journal of Urology ◽

10.1016/s0022-5347(18)30540-8 ◽

2007 ◽

Vol 177 (4S) ◽

pp. 92-92 ◽

Cited By ~ 3

Author(s):

Chunmeng Shi ◽

Ying Zhu ◽

Wen-Chin Huang ◽

Haiyen E. Zhau ◽

Ruoxiang Wang ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Cancer Cells ◽

Human Prostate ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Marrow Mesenchymal Stem Cells

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Neutrophil-Secreted Proteinase 3 Mediates Metastasis of Prostate Cancer Cells Expressing RAGE to the Bone Marrow

Blood ◽

10.1182/blood.v128.22.1025.1025 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1025-1025 ◽

Cited By ~ 1

Author(s):

Mikhail Kolonin ◽

Anna Sergeeva ◽

Daniela Staquicini ◽

Jeffrey J. Molldrem ◽

Renata Pasqualini ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Marrow ◽

Cancer Cells ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Human Prostate ◽

Proteinase 3 ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Cell Surfaces

Abstract Human prostate cancer non-randomly metastasizes to the bone marrow, but the biological basis for such site-specific tropism remains largely unresolved. Differential expression of molecules in the bone marrow microenvironment "niche" has recently been proposed to play a role. In previous work, combinatorial selection of random peptide libraries in end-of-life cancer patients has revealed an unexpected interaction between the receptor for advanced glycation end products (RAGE), a molecule expressed on malignant cell surfaces in advanced prostate cancer, and proteinase 3 (PR3), a serine protease abundantly present on neutrophils and promyelocytes within the bone marrow microenvironment. Because RAGE is selectively overexpressed in prostate cancer bone metastases, we hypothesize here that its specific binding to PR3 might mediate homing of prostate cancer cells to the bone marrow. We demonstrate that PR3 non-proteolytically binds to RAGE on prostate cancer cell surfaces and thereby promotes tumor cell activation and motility. We also show that the downstream signal transduction cascade triggered by RAGE/PR3 binding involves p44/42 (Erk1/2) and JNK1 phosphorylation. Finally, we use a mouse model of experimental metastasis to demonstrate that RAGE protein expression on human prostate cancer cells promotes their homing to bone marrow within a short time frame. These results validate a functional protein interaction between RAGE and PR3 and uncover a mechanism through which neutrophils mediate prostate cancer cell metastasis to the skeleton. Disclosures Sergeeva: Astellas: Patents & Royalties. Molldrem:Astellas Pharma: Patents & Royalties.

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