Regulation of tumor cell expression of the carbohydrate epitope sialyl Lewis X in the tumor microenvironment: implications for metastasis

Abstract

The association between inflammation and cancer has been recognized for almost 150 years. The processes of migration of cancer cells to metastatic sites and leukocyte recruitment to sites of inflammation have much in common. Both cell types display specialized carbohydrates modified with sialyl Lewis X (sLex) epitopes on their cell surfaces. These sLex epitopes are highly expressed on leukocytes and are ligands for selectin adhesion molecules present on activated vascular endothelium at sites of inflammation. The binding interactions between sLex ligands on leukocytes with endothelial selectins are well characterized and promote leukocyte trafficking to lymphoid tissues and sites of inflammation. Similarly, malignancy is associated with expression of sLex structures on cancer cells that aid tumor invasion and metastasis. High expression of sLex in many types of human carcinomas is associated with an advanced stage of disease and poor patient prognosis. Synthesis of sLex is dependent on activity of the glycosyltransferase enzymes α2,3-sialyltransferase and α1,3-fucosyltransferase-III (FucT-III). Exposure to the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) has been described to up-regulate FucT-III resulting in increased sLex in the airways of patients with respiratory disease, however, little is known about the molecular mechanisms involved in the regulation of sLex expression in the inflammatory lung tumor microenvironment. The overall objectives of this study are: 1) to investigate the role of cytokines and inflammatory cells in regulation of sLex expression on non small cell lung cancer cells, 2) to evaluate the role of FucT-III, sLex expression, and inflammatory cells in the acquisition of metastatic properties by lung cancer cells, and 3) to characterize the backbone protein and carbohydrate structures that display sLex on lung and colon cancer cells. Our major findings are presented in iv Chapters 2 and 3 and the conclusions drawn from this study are highlighted in Chapter 4. Our results suggest that FucT-III activity in non small cell lung cancers recruit neutrophils in the tumor microenvironment and enhance the metastatic potential of lung tumor cells through the promotion of sLex expression and acquisition of invasive and anchorage independent qualities. Thus, inhibition of FucT-III enzyme activity and sLex expression may represent promising therapeutic targets for the control of lung cancer metastasis.