Preferential Adhesion of Prostate Cancer Cells to a Human Bone Marrow Endothelial Cell Line

Abstract

Background:In virtually all patients with advanced prostate cancer, the disease metastasizes to bone and causes osteoblastic growth. However, the mechanisms that contribute to bone metastasis are poorly understood. It has been hypothesized that the bone provides a favorable growth environment for prostate cancer cells, which nonselectively seed the bone marrow from the bloodstream. Alternatively, prostate cancer cells may preferentially bind to bone marrow endothelial cells. We developed an in vitro model of bone endothelium and tested the hypothesis that prostate cancer cells adhere preferentially to bone marrow endothelial cells. Methods: We isolated and characterized a human bone marrow endothelial (HBME-1) cell line. Cells were transfected with the simian virus 40 large T antigen for immortalization. Cell surface receptors were characterized by immunohistochemistry and flow cytometry. The adhesion of cancer cells to HBME-1 and to endothelial cell lines from other organs was tested in an in vitro binding assay as were inhibitors of adhesion. Results: The immortalized HBME-1 cell line demonstrated many properties characteristic of endothelial cells, including positive staining for von Willibrand factor and rapid formation of tubule structures when exposed to extracellular matrices. In an in vitro assay, prostate cancer cells adhered preferentially to human bone marrow endothelium when compared with endothelium derived from other sources. Preferential adhesion was blocked, in part, by antibodies to galectin-3 and LFA-1. Implications: These data suggest that the propensity of prostate cancer cells to establish themselves in bone is due, at least in part, to their preferential adhesion to human bone marrow endothelial cells. [J Natl Cancer Inst 1998;90:118-23]

Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

“…It has been shown that prostate epithelial cells interact directly with the BME cells, initially via selectins and this interaction is then stabilised by integrin binding (Orr et al, 2000). These are not the only binding steps, since antibodies to CD11a, CD18, LFA-1 and CD31 have also been shown to interfere with the binding process (Lehr and Pienta, 1998). Once bound, prostate epithelial cells induce endothelial cell retraction.…”

Cell adhesion and chemotaxis in prostate cancer metastasis to bone: a minireview

“…Galectin-3, VCAM-1, CD11a, CD18, integrins and LFA-1 have been implicated in prostate cancer adhesion to bone derived endothelial cells. 28 Alpha-2 beta-1 and alpha-3 beta-1 were responsible for prostate cancer cell adhesion to collagen I, and these integrins' expression was upregulated in prostate cancer cells with TGF-beta treatment (Table 3). 37,38 To study the mechanisms involved in bone metastases, several animal models are under development.…”

“…Using antibodies, Lehr and Pienta were able to reduce PC-3 cell adhesion with galactose rich modi®ed citrus pectin and the following antibodies: galectin-3, vascular cell adhesion molecule (VCAM), CD11a (alpha-L), CD18 (beta-2), and leukocyte functional antigen-1 (LFA-1) (Figure 3). 28 Another study showed that galectin-3 is expressed on the surface of a variety of rodent microvessel endothelium, and a subsequent study in our lab showed that PC-3 cells expressed galectin-3 (Pacis et al, manuscript submitted). 29 This data suggests that the galectin-3, VCAM, alpha-L, beta 2, and LFA-1 all may play partial role in tumor cell adhesion to HBME-1.…”

“…28 The ability of prostatic cancer cell lines and others to adhere to HBME-1 and human umbilical vein endothelial cells (HUVEC) were evaluated by adhesion assays. All cell lines tested adhered preferentially to HBME compared to HUVEC (Figure 2).…”

“…31 Lehr and Pienta demonstrated that a high concentration (0.5 mM) of peptides containing arginine ± glycine ± aspartic (RGD) sequences blocked adhesion by 70%, suggesting integrins are important for tumor cell interaction with HBME-1. 28 Another investigation demonstrated that nude mice injected intravenously with Chinese hamster ovary cells transfected with alpha-4 beta-1 produced bone metastasis. 32 Bone metastasis was inhibited by antibody to alpha-4 or VCAM-1, a ligand for alpha-4 beta-1 integrins.…”