Tumor Lymphangiogenesis as a Potential Therapeutic Target

Abstract

<jats:p>Metastasis the spread of cancer cells to distant organs, is the main cause of death for cancer patients. Metastasis is often mediated by lymphatic vessels that invade the primary tumor, and an early sign of metastasis is the presence of cancer cells in the regional lymph node (the first lymph node colonized by metastasizing cancer cells from a primary tumor). Understanding the interplay between tumorigenesis and lymphangiogenesis (the formation of lymphatic vessels associated with tumor growth) will provide us with new insights into mechanisms that modulate metastatic spread. In the long term, these insights will help to define new molecular targets that could be used to block lymphatic vessel-mediated metastasis and increase patient survival. Here, we review the molecular mechanisms of embryonic lymphangiogenesis and those that are recapitulated in tumor lymphangiogenesis, with a view to identifying potential targets for therapies designed to suppress tumor lymphangiogenesis and hence metastasis.</jats:p>

SIX1 Promotes Tumor Lymphangiogenesis by Coordinating TGFβ Signals That Increase Expression of VEGF-C

“…Similar to tumor angiogenesis, lymphangiogenesis is mainly influenced by the tumor microenvironment (3). Among a variety of factors, VEGF-C and VEGF-D are considered the key drivers of lymphangiogenesis (4)(5)(6)(7)(8). VEGF-C is essential for the migration, survival, and proliferation of lymphatic endothelial cells (LEC; refs.…”

Prospero homeobox 1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis

“…PROX1 knockdown decreased the expression of lymphangiogenic inducers VEGF-C, VEGF-D, and COX-2 in human gastric cancer cells. Previous studies have shown that VEGF-C and VEGF-D induce the proliferation and migration of LECs by activating VEGFR-3, and that overexpression of VEGF-C, VEGF-D, or VEGFR-3 is associated with lymphatic metastasis and poor clinical outcomes of various cancers [25][26][27]. Further, COX-2 promotes tumor lymphangiogenesis and lymph node metastasis [28].…”

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

“…BMP9 expression is increased dramatically during malignant progression in the RIP1-Tag2 transgenic mouse model of multistep tumorigenesis, and reduced ALK1 gene dosage can inhibit tumor growth and progression in this model by inhibiting angiogenesis (24). In addition, the BMP9/BMP10/ALK1 pathway regulates development of lymphatic vessels (25), with implications for metastatic spread of tumor cells through lymphatic vasculature (26). Together, these findings indicate that inhibitors of BMP9/BMP10/ALK1 signaling may be promising therapeutic candidates for treatment of cancer and related diseases.…”