Potential therapeutic strategies for lymphatic metastasis

Abstract

Physiologically, the lymphatic system regulates fluid volume in the interstitium and provides a conduit for immune cells to travel to lymph nodes, but pathologically, the lymphatic system serves as a primary escape route for cancer cells. Lymphatic capillaries have a thin discontinuous basement membrane, lack pericyte coverage and often contain endothelial cell gaps that can be invaded by immune cells (or tumor cells). In addition, tumor cells and stromal cells in the tumor microenvironment secrete factors that stimulate lymphangiogenesis, the growth of lymphatic endothelial cells and the sprouting of lymphatic capillaries. As a result, many tumors are surrounded by large, hyperplastic, peri-tumoral lymphatic vessels and less frequently are invaded by intra-tumoral lymphatic vessels. Carcinoma cells commonly metastasize through these lymphatic vessels to regional lymph nodes. The presence of metastatic cells in the sentinel lymph node is a prognostic indicator for many types of cancer, and the degree of dissemination determines the therapeutic course of action. Lymphangiogenesis is currently at the frontier of metastasis research. Recent strides in this field have uncovered numerous signaling pathways specific for lymphatic endothelial cells and vascular endothelial cells. This review will provide an overview of tumor lymphangiogenesis and current strategies aimed at inhibiting lymphatic metastasis. Novel therapeutic approaches that target the tumor cells as well as the vascular and lymphatic endothelial compartments are discussed.

Figure 1

Structural diagram of the cutaneous lymphatic system under physiological and pathological (tumor-bearing) conditions. A. Interstitial fluid is drained through wide luminal capillaries (green color) that extend up near the epidermis (E, peach color). Capillaries are composed of thin layers of endothelial cells connecting to the extracellular matrix through anchoring filaments. Capillaries possess inter-endothelial cell gaps, discontinuous basement membrane, no valves, and no pericyte coverage. In the dermis (D, pink color), capillaries drain into lymphatic vessels called precollectors that have a continuous basement membrane (denoted by dark green line) and valves that prevent the reflux of lymph. At the border to the subcutis (SC, yellow color), precollectors drain into collecting lymphatic vessels that are surrounded with smooth muscle cells or pericytes (denoted by blue line) that constrict to propel the lymph along to regional lymph nodes. B. An invasive melanoma (dark brown color) is shown. Tumor cells metastasize through peri-tumoral and intratumor lymphatic capillaries. Lymphatic capillary density around the tumor is increased and tumor-associated lymphatic capillaries are dilated and hyperplastic. A few lymphatic capillaries have sprouted into the tumor. The sentinel lymph node is shown with lymphangiogenic vessels as well. Note: this diagram is not drawn exactly to scale.

Figure 2

Human melanoma (A, C) and human melanoma (A375SM) xenograft (B, D) are surrounded with large peri-tumoral lymphatics (arrows). A, B. Hematoxylin and eosin. C. Human podoplanin (D2-40 antibody, Signet Laboratories) staining (brown color). D. Murine podoplanin (Reliatech) staining (brown color). T = tumor, D = dermis.