Molecular mechanisms of lymphatic metastasis in solid tumors of the gastrointestinal tract

Abstract

Tumor cell dissemination from the primary tumor site to distant organs is one of the characteristic properties of malignant tumors and represents a crucial step in the progression of disease. Although the pattern of spread may vary in different types of carcinomas, dissemination via the lymphatic system represents a common event in metastasis. The extent of lymph node metastasis is one of the major determinants for the prognosis of patients with gastrointestinal carcinomas and guides the therapeutically management. During the last decades, significant attention has been given to the molecular mechanisms that control lymphatic metastasis. The process of lymphangiogenesis has come into the focus. Lymphangiogenesis, the formation of newly lymphatics, comprises a series of complex cellular events and is controlled by a balance between pro- and anti-lymphangiogenic signals. This article will briefly describe the lymphatic system and then provide an overview of the molecular players involved in tumor lymphangiogenesis.

Keywords: Lymphangiogenesis; gastrointestinal tumors; lymphangiogenic factors; lymphatic metastasis; molecular mechanisms.

Figure 1

Scheme of differentially expressed genes between the lymphatic endothelium and the blood endothelium. Abbreviations: signal transducer and activator of transcription 6 (Stat6), monocyte chemotactic protein-1 (MCP-1), interleukin 6/8 (IL-6/8), intracellular adhesion molecule (ICAM), angiopoietin-1 (Ang-1), vascular endothelial growth factor/receptor (VEGF/R), cluster of Differentiation 44 (CD-44), insulin like growth factor 1/2 (IGF-1/2), fibroblast growth factor 2 (FGF-2), hepatocyte growth factor (HGF), mesenchymal epithelial transition factor (c-MET), angiopoietin receptor 2 (Tie-2). Adapted from [46].

Figure 2

Structure of lymphatic vessels compared to blood vessel. Blood vessels are characterized by a complete basement membrane and are surrounded by pericytes and smooth muscle cells. Initial lymphatic vessels in contrast have no or an incomplete basement membrane and are characterized by lose intercellular junctions and anchoring filaments, which makes them suitable for uptake of fluid, particles and tumor cells. Collecting afferent lymphatic vessel consist like blood vessels of pericytes, which help to reduce lymphatic fluid extravasation and draining lymph fluid to lymph nodes. Adapted from [46].

Figure 3

Schematic overview of processes involved in tumor lymphangiogenesis and metastasis. To facilitate tumor cell entry into the lymphatic vasculature tumor cells could secreted various lymphangiogenic growth factors.

Figure 4

Immunohistochemistry for VEGF-C expression in CRC.