Prostate cancers (PCa) have an astonishing ability to disseminate, invade and survive in the bone marrow. Once there, disseminated tumor cells (DTCs) may lie dormant for years. How dormancy of DTCs is established, how it is maintained, and how DTCs escape from dormancy remains unknown. Hematopoietic stem cells (HSCs), like DTCs, are largely quiescent In the marrow. HSC quiescence is regulated by a region in marrow termed the 'niche', that is comprised of osteoblasts, endothelial cells and other elements. Recent work demonstrates that when HSCs bind to proteins expressed by niche osteoblasts (annexin 2 or AX2), they increase their expression of the tyrosine kinase receptor AXL (from the Greek word 'anexelekto,' or uncontrolled). Sequentially, AXL binds to growth arrest-specific 6 (GAS6), which is secreted in the marrow niche by osteoblasts. In many systems GAS6 inhibits cellular proliferation, promotes survival and increases resistance to chemotherapy. We have recentiy show that; (i) PCa DTCs target the HSC niche during metastasis (submitted) (ii) when PCa cells bind to niche osteoblasts or components of the niche (AX2), they increase expression of AXL, (iii) GAS6 inhibits PCa cell growth, (iv) GAS6 protects PCa cells from apoptosis, (v) GAS6 confers resistance of PCa cells to chemotherapy. These data suggest that once DTCs enter the niche, interactions between GAS6 and its receptors regulates dormancy of DTCs and resistance to chemotherapies that target proliferating cells. Our central hypothesis is that GAS6 regulates dormancy of PCa bone metastases The proposed aims will demonstrate the extent to which GAS6 signaling determines whether DTCs remain quiescent or proliferate in bone Aim 1: Determine the extent to which GAS6 induces quiescence of PCa cells in the HSC 'niche'. Sub hypothesis: Niche produced GAS6 is essential for establishing dormancy.
Aim 2 : Define the role that autocrine production of GAS6 regulates dormancy of PCa in the niche Sub hypothesis: PCa themselves express GAS6 which limits growth in an autocrine fashion. We hypothesize that dormancy is established by cells that maintain this activity - but that it is eventually lost by cells that undergo metastatic growth.
Aim 3 : Define the role that GAS6 signaling plays in regulating resistance of PCa to chemotherapy in the HSC 'niche'. Sub hypothesis: Dormant PCa cells are resistant to chemotherapy.
These investigations focus on fundamental mechanisms related to tumor cell dormancy of PCa bone metastasis. We are confident that our observations are relevant to a more complete understanding prostate cancer skeletal disease. That new insights derived from these studies will lead to the development of innovative strategies to minimize the morbidity and mortality associated with bone metastatic prostate cancer.
|Hill, Elliott E; Kim, Jin Koo; Jung, Younghun et al. (2018) Integrin alpha V beta 3 targeted dendrimer-rapamycin conjugate reduces fibroblast-mediated prostate tumor progression and metastasis. J Cell Biochem 119:8074-8083|
|de Groot, Amber E; Pienta, Kenneth J (2018) Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages. Oncotarget 9:20908-20927|
|Wu, Amy; Liao, David; Kirilin, Vlamimir et al. (2018) Cancer dormancy and criticality from a game theory perspective. Cancer Converg 2:1|
|Park, Sun H; Keller, Evan T; Shiozawa, Yusuke (2018) Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis. Calcif Tissue Int 102:152-162|
|Lee, Eunsohl; Wang, Jingcheng; Jung, Younghun et al. (2018) Reduction of two histone marks, H3k9me3 and H3k27me3 by epidrug induces neuroendocrine differentiation in prostate cancer. J Cell Biochem 119:3697-3705|
|van der Toom, Emma E; Axelrod, Haley D; de la Rosette, Jean J et al. (2018) Prostate-specific markers to identify rare prostate cancer cells in liquid biopsies. Nat Rev Urol :|
|Valkenburg, Kenneth C; de Groot, Amber E; Pienta, Kenneth J (2018) Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol 15:366-381|
|Chalfin, Heather J; Glavaris, Stephanie A; Malihi, Paymaneh D et al. (2018) Prostate Cancer Disseminated Tumor Cells are Rarely Detected in the Bone Marrow of Patients with Localized Disease Undergoing Radical Prostatectomy across Multiple Rare Cell Detection Platforms. J Urol 199:1494-1501|
|Decker, A M; Taichman, L S; D'Silva, N J et al. (2018) Periodontal Treatment in Cancer Patients: An Interdisciplinary Approach. Curr Oral Health Rep 5:7-12|
|Maley, Carlo C; Aktipis, Athena; Graham, Trevor A et al. (2017) Classifying the evolutionary and ecological features of neoplasms. Nat Rev Cancer 17:605-619|
Showing the most recent 10 out of 79 publications