Suppression of Prostate Cancer Cell Rolling and Adhesion to Endothelium by 1 ␣ ,25-Dihydroxyvitamin D

Department of Urology and Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.
American Journal Of Pathology (Impact Factor: 4.59). 02/2011; 178(2):872-80. DOI: 10.1016/j.ajpath.2010.10.036
Source: PubMed


Adhesion of circulating prostate cancer (PCa) cells to the microvascular endothelium is a critical step during cancer metastasis. To study PCa cell rolling and adhesion behavior, we developed a dynamic flow-based microtube system to mimic the microvascular environment. We found that PCa cell rolling capacity is mediated by E-selectin and can be enhanced by stromal cell-derived factor-1 under different wall shear stresses. Using this device, we tested if the chemopreventive agent, vitamin D, could interfere with PCa cell adhesion. We found that 1α,25-dihydroxyvitamin D(3) (1,25-VD), the bioactive form of vitamin D, reduced PCa cell rolling numbers and increased rolling velocities resulting in a significant decreased number of PCa cells adhering to the microtube. The inhibitory effects of 1,25-VD on PCa cell heterotypic adhesion were further confirmed using microvascular endothelial cells in a static condition. Furthermore, we demonstrated that 1,25-VD can increase E-cadherin expression in PCa cells and promote the homotypic cell-cell aggregation, which can then hinder PCa cell adhesion to the endothelium. Blocking E-cadherin with a neutralizing antibody can reverse 1,25-VD-mediated suppression of PCa cell adhesion to the endothelium. Taken together, our data revealed that 1,25-VD promoted PCa cell aggregation by increasing E-cadherin expression, thus interfering with circulating PCa cell adhesion to microvascular endothelial cells and potentially reducing their metastatic potential.

Download full-text


Available from: Michael R King, Oct 05, 2015
38 Reads
  • Source
    • "Chemotherapyorchemoradiotherapyisfrequentlyofferedinthe lattertwogroupsandasadjuvanttherapyintheformer. Theauthor(SGB)hasshownthatcalcitriolanaloguesaresafe inpatientsundergoingcurativeresection[58].Therationaleforusing calcitriolanaloguesinthisgroupofpatientsistheriskoftumour disseminationatthetimeofsurgery,eveninpatientswithappar- entlynon-metastaticdisease[60].Calcitriolanaloguesaffecttumour celldissemination[61]andinvasionandmetastasis[51]andthus mayhelppreventcellsfromseedingindistantlocationsduring surgery.Tothisend,furtherinvestigationsareneededtodeter- mineifcalcitriolanaloguesexertsuchaneffectinpancreaticcancer. Further,aclarificationoftheoptimaldosewouldthenberequired. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is currently the fourth leading cause of cancer-related death, and it is projected that within the next two decades it will become the second most common cause of death due to cancer. Few patients are diagnosed when surgical resection is feasible and the efficacy of existing chemotherapeutic agents for advanced/metastatic cancer is limited. Thus, there is a need to identify agents that can prevent pancreatic cancer or improve survival in those affected. Vitamin D and its analogues, with their ability to regulate cell growth, differentiation, apoptosis and angiogenesis, may be promising agents. This review explores the published literature about the potential role of vitamin D and its analogues in preventing or treating pancreatic cancer. The vitamin D system is altered in pancreatic cancer. Pancreatic cancer tissue expresses vitamin D receptors, but the calcitriol analogues may affect pancreatic cancer tissue by mechanisms that do not involve interaction with its receptors. Experimental evidence postulates multiple potential mechanisms by which calcitriol analogues may exert their anti-cancer effect, the most common being by action on cyclin-dependent kinases p21 and p27. Use of calcitriol analogues in pancreatic cancer remains largely underexplored and warrants further clinical trials. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer letters 08/2015; 368(1). DOI:10.1016/j.canlet.2015.06.030 · 5.62 Impact Factor
  • Source
    • "To investigate whether E-selectin-dependent interactions occur in prostate CTCs, we first used MDA, PC3, LNCaP, and C4-2 PCa cell lines to assess their rolling behavior in the presence of E-selectin-coated microtube surfaces. Out of the four PCa cell lines studied, we only detected robust rolling behavior in MDA cells (data not shown), consistent with prior studies [24,25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hematogenous metastasis accounts for the majority of cancer-related deaths, yet the mechanism remains unclear. Circulating tumor cells (CTCs) in blood may employ different pathways to cross blood endothelial barrier and establish a metastatic niche. Several studies provide evidence that prostate cancer (PCa) cell tethering and rolling on microvascular endothelium via E-selectin/E-selectin ligand interactions under shear flow theoretically promote extravasation and contribute to the development of metastases. However, it is unknown if CTCs from PCa patients interact with E-selectin expressed on endothelium, initiating a route for tumor metastases. Here we report that CTCs derived from PCa patients showed interactions with E-selectin and E-selectin expressing endothelial cells. To examine E-selectin-mediated interactions of PCa cell lines and CTCs derived from metastatic PCa patients, we used fluorescently-labeled anti-prostate specific membrane antigen (PSMA) monoclonal antibody J591-488 which is internalized following cell-surface binding. We employed a microscale flow device consisting of E-selectin-coated microtubes and human umbilical vein endothelial cells (HUVECs) on parallel-plate flow chamber simulating vascular endothelium. We observed that J591-488 did not significantly alter the rolling behavior in PCa cells at shear stresses below 3 dyn/cm(2). CTCs obtained from 31 PCa patient samples showed that CTCs tether and stably interact with E-selectin and E-selectin expressing HUVECs at physiological shear stress. Interestingly, samples collected during disease progression demonstrated significantly more CTC/E-selectin interactions than samples during times of therapeutic response (p=0.016). Analysis of the expression of sialyl Lewis X (sLe(x)) in patient samples showed that a small subset comprising 1.9-18.8% of CTCs possess high sLe(x) expression. Furthermore, E-selectin-mediated interactions between prostate CTCs and HUVECs were diminished in the presence of anti-E-selectin neutralizing antibody. CTC-Endothelial interactions provide a novel insight into potential adhesive mechanisms of prostate CTCs as a means to initiate metastasis.
    PLoS ONE 12/2013; 8(12):e85143. DOI:10.1371/journal.pone.0085143 · 3.23 Impact Factor
  • Source
    • "(Narasipura and King, 2009; Rana et al, 2009, 2012; Hsu et al, 2011. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: The interaction between human prostate cancer (PCa) cells and bone marrow (BM) endothelium follows a rolling-and-adhesion cascade mediated by E-selectin ligand (ESL): E-selectin. This adhesion is enabled by elevated expression of α-1,3-fucosyltransferases (FTs), enzymes responsible for ESL-mediated bone metastasis in humans. In contrast, the incidence of bone metastasis in mice is rare. Methods: FT 3, 6 and 7 were overexpressed in mouse PCa cells. The rolling cell number, cell-rolling velocity and transendothelial migration were characterised in vitro. Fucosyltransferases-transduced mouse PCa cells expressing luciferase were inoculated into mice via left ventricle to compare the capability of bone metastasis. Mass spectrometry and immunoprecipitation were utilised for identification of ESLs. Results: Overexpression of FT3, FT6 or FT7 restored ESLs and enabled mouse PCa cells to roll and adhere in E-selectin-functionalised microtubes, similar to trafficking of circulating PCa cells in BM vessels. Following intracardiac inoculation, FT6-transduced cells induced robust bone metastasis in mice. Inhibition of FT6 by a fucose mimetic significantly reduced bone metastasis. Importantly, comparison of FT3, FT6 and FT7 gene expression in existing clinical samples showed significant upregulation of FT6 in PCa-distant metastases. Conclusion: FT6 is a key mediator of PCa cells trafficking to the BM. It may serve as a viable drug target in preclinical tests of therapeutics for reduction of PCa bone metastasis.
    British Journal of Cancer 10/2013; 109(12). DOI:10.1038/bjc.2013.690 · 4.84 Impact Factor
Show more