E- and P-Selectins Are Essential for Repopulation of Chronic Myelogenous and Chronic Eosinophilic Leukemias in a Scid Mouse Xenograft Model

Abstract

In chronic myelogenous (CML) and chronic eosinophilic leukemia (CEL), neoplastic cells spread via the circulation into various extramedullary organs. As E- and P-selectin constitute the starting point for the leucocyte adhesion/invasion cascade, and CEL and CML cells share many properties with normal granulocytes, we investigated the role of these selectins in CEL and CML cell expansion and organ invasion in a xenotransplantation model using scid mice. Using two human leukemic cell lines (EOL-1 and K562), we were able to show that E- and P-selectins mediate leukemia cell tethering and adherence in a laminar flow assay. While E-selectin binding depended on sialylated carbohydrate moieties, P-selectin binding was completely (K562) or partially (EOL-1) independent of these carbohydrates indicating the involvement of non-canonical selectin ligands. In a xenograft model in scid mice, both cell lines invaded the bone marrow and other organs, formed chloromas, and ultimately produced an overt leukemia. In contrast, in E- and P-selectin knockout scid mice, the cells failed to show engraftment in 8 out of 10 animals and even if they did engraft, they produced only little organ invasion and chloroma formation. Together, these data suggest that E- and P-selectins play an important role in leukemic dissemination in CML and CEL.

Aberrant Presentation of HPA-Reactive Carbohydrates Implies Selectin-Independent Metastasis Formation in Human Prostate Cancer

“…Likewise, engraftment and organ invasion of human eosinophilic leukemia cells (EOL-1) are remarkably reduced in selectin-deficient mice (16). Furthermore, the importance of HPA-reactive glycoconjugates as intermediates of selectin ligand synthesis has also been shown previously, as preincubation of human breast cancer cells with HPA inhibits their adhesion toward vascular endothelium (7,21).…”

“…4,11) are common intermediates for the synthesis of selectin ligands (7,21), extravasation of CTCs is not crucially dependent on selectin-selectin ligand interactions in prostate cancer. Again, this is a peculiarity of prostate cancer and contrary to different other human malignancies (13)(14)(15)(16). Interestingly, one recent study on the glycosylation potential of human prostate cancer also demonstrates a low mRNA expression of different polypeptide-GalNActransferases (pp-GalNAc-T's) in prostate cancer (34), suggesting a minor relevance of O-glycosylation initiation in prostate cancer in general.…”

“…14, 22; see also Supplementary Table S1; refs. 16,23). VCaP (prostate cancer) cells were obtained from American Type Culture Collection and cultured in RPMI-1640 supplemented with 2 mmol/L L-glutamine, 10% fetal calf serum, 100 U/mL penicillin, and 100 mg/mL streptomycin (all Invitrogen) at 37 C in a humidified atmosphere of 5% CO 2 (24).…”

“…1A, these glycans are common intermediates for the synthesis of sialylated Lewis X and A antigens (sLe X and sLe A ; ref. 12), which are presented at the surface of human breast and gastrointestinal adenocarcinoma (13)(14)(15) as well as leukemia cells (16). sLeX and sLeA are the main ligands for E-and P-selectin and therefore crucially involved in the adhesion cascade of leukocytes into inflamed tissues (17).…”

Studying Side Effects of Tyrosine Kinase Inhibitors in a Juvenile Rat Model with Focus on Skeletal Remodeling

“…The aim of the animal model described in this chapter was to evaluate side effects on bone remodeling rather than gaining further insight into the biology of CML (e.g., to study elementary mechanisms of CML disease progression) or on a more efficient antileukemic treatment exerted by new drugs (e.g., exploring why resistance develops under TKI therapy) [114,115]. For these essential questions, the reader is kindly referred to the detailed body of literature on establishing and maintaining acute lymphatic or myeloid leukemic cells in xenograft models, transgenic models, and syngeneic models using a broad range of species [116][117][118][119], whereas mice are used mostly in orthotopic animal models [120][121][122][123].…”