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Differential Metastatic Adhesion Cascade Of Tumor Cells Bearing Selectin-Binding Ligands
A myriad of previous research has suggested that circulating tumor cells (CTCs) can adhere to the blood vessel wall to eventually extravasate and form secondary tumors in a step-wise process similar to the leukocyte adhesion cascade. These steps require the cell, whether CTC or leukocyte, to bear specific surface proteins which can form transient interactions with E- and/or P-selectin expressed on the inflamed endothelium. These interactions facilitate initial cell tethering and rolling which lead to firm cell adhesion and extravasation. However unlike leukocytes, CTCs can originate from various primary sites, e.g. breast, colon, lung, prostate, etc. Moreover, cancer cells from each particular site (and possibly even varying from each person with cancer) can exhibit unique phenotypic expressions of selectin ligands. Briefly from the cell lines studied here, COLO 205 (colon cancer) cells abundantly expressed E-selectin ligands and established stable cell rolling on E-selectin surfaces, however, this cell line proliferates in two separate populations with a differential degree of E-selectin binding capabilities. The MDA-MB-231 cell line (breast cancer) expressed E-selectin ligands, yet only interacted with E-selectin surfaces with cytokine treatments. The rare childhood eye cancer, retinoblastoma (RB), was found to metastasize without the expression of E-selectin ligands. The mechanism for the RB cell extravasation from the blood stream may proceed via the initial tethering of RB cells to circulating leukocytes where the RB:leukocyte aggregate adheres to the inflamed endothelium. Lastly, the ZR-75-1 cell line (breast cancer) also stably rolled on E-selectin surfaces largely due to the novel E-selectin ligand MUC1. The underglycosylated form of MUC1 was found to facilitate cell tethering when interacting with P-selectin, achieve stable cell rolling when interacting with E-selectin, and even produce firm cell adhesion events when interacting with intercellular adhesion molecule 1 (ICAM-1). Indeed, the challenge of CTC treatment is a major obstacle even when limited to the aspect of selectin ligand expression and cell adhesion to the endothelium. Fortunately, selectin:ligand based devices explored here and by other researchers may offer a viable method to capture CTCs from patient blood for further study and possible personalized treatments.
cancer metastasis; selectin; glycoprotein
King, Michael R.
Stroock, Abraham Duncan; Baird, Barbara Ann
Ph.D. of Biomedical Engineering
Doctor of Philosophy
dissertation or thesis