Targeting lymphatic vessel functions through tyrosine kinases

Abstract

The lymphatic vascular system is actively involved in tissue fluid homeostasis, immune surveillance and fatty acid transport. Pathological conditions can arise from injury to the lymphatics, or they can be recruited in the context of cancer to facilitate metastasis. Protein tyrosine kinases are central players in signal transduction networks and regulation of cell behavior. In the lymphatic endothelium, tyrosine kinases are involved in processes such as the maintenance of existing lymphatic vessels, growth and maturation of new vessels and modulation of their identity and function. As such, they are attractive targets for both existing inhibitors and the development of new inhibitors which affect lymphangiogenesis in pathological states such as cancer. RNAi screening provides an opportunity to identify the functional role of tyrosine kinases in the lymphatics. This review will discuss the role of tyrosine kinases in lymphatic biology and the potential use of inhibitors for anti-lymphangiogenic therapy.

Figure 1

Different functions of LECs in active lymphatic vessels. This schematic outlines some of the cellular processes that occur in lymphatic vessels under pathological conditions such as cancer. In this diagram a tumor (and/or infiltrating immune cells) secretes factors that induce changes in the lymphatic vasculature. Growth factors binding to the different receptors expressed on the surface of the LECs may induce sprouting of new lymphatic vessels from existing lymphatic capillaries. The leading 'tip cell' detects a gradient of growth factors by means of cell surface receptors, and migrates towards the tumor. Behind the tip cell are the stalk cells, responding to proliferation stimuli. The formation of a lumen and maturation of the vessel is required to create a functional vessel. Other aspects of the vessel such as vessel dilation and vessel permeability to fluid and cells may also be altered. These characteristics may be exaggerated in the context of a tumor, to create the abnormal vessels often associated with cancer and enhance the ease with which lymphogenous metastasis occurs. Many of these responses are induced by signaling pathways involving tyrosine kinases.

Figure 2

Protein tyrosine kinase signaling pathways are potential targets in lymphatic endothelial cells. Protein tyrosine kinases are a diverse group of proteins that act in different subcellular compartments of the cell. Outlined in the diagram are some examples of the types of signaling pathways involving tyrosine kinases: a) Receptor tyrosine kinases are expressed on the cell surface and bind their specific ligands. Ligand binding activates the intrinsic protein tyrosine kinase domain and triggers the signaling cascade. (For example VEGFR-3 signalling). b) Non-PTK cell surface receptors can be associated with cytoplasmic tyrosine kinases. The cytoplasmic tyrosine kinase may be brought into contact with the receptor by direct binding, an example of which is the JAK kinases. Alternatively, the PTK may be tethered to the plasma membrane allowing it to rapidly interact with the activated receptor. The Src family kinases act in this manner. c) Other cytosolic PTKs act downstream in the signaling pathway or more broadly throughout the cell. The c-Abl kinase is an example of a PTK with activity in various subcellular locations. d) In some circumstances, the intracellular domain of a receptor tyrosine kinase may be cleaved and translocate to the nucleus where it is able to phosphorylate different targets. (For example ErbB4 can signal in this manner). e) Nuclear associated tyrosine kinases are localized to the nucleus; their activity may be modulated in response to signaling pathways. (An example of this is the fyn-related kinase). The types of inhibitors that could be used to target each tyrosine kinase pathway are listed on the right of the figure.