Suppression of Prostate Cancer Cell Rolling and Adhesion to Endothelium by 1α,25-Dihydroxyvitamin D3

Abstract

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.

Antineoplastic effects of 1,25(OH)2D3 and its analogs in breast, prostate and colorectal cancer

“…Loss of E-cadherin induces epithelial-mesenchymal cell transition via disruption of cell adhesion. Similar findings are reported in a study where increased levels of E-cadherin expression are accompanied with repressed cell rolling and reduced adhesion of the cancer cells to the endothelium (Hsu et al 2011).…”

Vitamin D in cancer chemoprevention

“…In this context, several in vitro studies have shown that the activity of CYP27B1 and its contribution to 1,25(OH) 2 D 3 production is lost in tumors with an aggressive phenotype (Fleet et al, 2012). On the other hand, Hsu et al (2011) reported that CYP27B1 was present in normal prostate epithelia cells (PECs). However, its enzyme activity was reduced in cells isolated from BPH while it was virtually absent in cells isolated from prostate cancer patients.…”

“…Although a direct inhibiting effect of these enzymes in prostate cell growth inhibition appears unlikely, it is reasonable to hypothesize that they may indirectly mediate the chemopreventive effects of 1,25(OH) 2 D 3 by preventing DNA damage caused by ROS. Finally, recent finding by Hsu et al (2011) show that Vit D may indirectly affect tumor cell invasion and metastasis by facilitating prostate cancer cell aggregation through the increase of E-cadherin expression. However, Ajibade et al (2014) recently reported that prolonged treatments with calcitriol in homozygous male TRAMP mice resulted in the development of a resistant and more aggressive form of prostate cancer associated with increased distant organ metastasis.…”

Cell–Cell Adhesion and Cytoskeleton Tension Oppose Each Other in Regulating Tumor Cell Aggregation

“…Both proand anti-aggregation forces contribute to promoting cancer dissemination: loss of cohesion forces in the primary tumor allows individual cancer cells or small groups of cells to escape into the lymphatic and circulatory systems (2), whereas the increased cellcell adhesiveness of metastatic cells allows them to form multicellular homotypic aggregates, which have an increased chance of survival once detached from the primary tumor (3). Formation of these malignant cell aggregates also enhances their probability of interacting with endothelial cells in small capillaries and of their extravasation into surrounding tissues, which are necessary steps for metastasis (4,5).…”