Lymphangiogenesis in gastric cancer: function and mechanism

Abstract

Increased lymphangiogenesis and lymph node (LN) metastasis are thought to be important steps in cancer metastasis, and are associated with patient's poor prognosis. There is increasing evidence that the lymphatic system may play a crucial role in regulating tumor immune response and limiting tumor metastasis, since tumor lymphangiogenesis is more prominent in tumor metastasis and diffusion. Lymphangiogenesis takes place in embryonic development, wound healing, and a variety of pathological conditions, including tumors. Tumor cells and tumor microenvironment cells generate growth factors (such as lymphangiogenesis factor VEGF-C/D), which can promote lymphangiogenesis, thereby inducing the metastasis and diffusion of tumor cells. Nevertheless, the current research on lymphangiogenesis in gastric cancer is relatively scattered and lacks a comprehensive understanding. Therefore, in this review, we aim to provide a detailed perspective on molecules and signal transduction pathways that regulate gastric cancer lymphogenesis, which may provide new insights for the diagnosis and treatment of cancer.

Keywords: Gastric cancer; Lymph node metastasis; Lymphangiogenesis; Therapeutics.

Fig. 1

Represents the structure of the lymphatic system and tumor cells entering and leaving the draining LNs. a represents the hierarchical structure of lymphatic subtypes. Various cells (including cancer cells and immune cells) derived from the tumor microenvironment enter the LNs with the interstitial fluid passing through the initial lymphatic, the pre-collective lymphatic and the collecting lymphatic in turn. b represents the cancer cells into and out of the drainage LNs. With the interstitial fluid, the cancer cells begin at the blind end of the lymphatic, and then enter the afferent lymphatic, medullary sinus and efferent lymphatic of the draining LNs in turn, and finally the efferent lymphatic become the afferent lymphatic of other LNs

Fig. 2

Represents the signaling pathways that may be involved in lymphangiogenesis

Fig. 3

Molecular pathways that promote lymphangiogenesis in GC. SHH protein-mediated PI3K/AKT signaling pathway and TAMs and T cells in stromal microenvironment promote tumor lymphangiogenesis by inducing VEGFA/C/D expression. CCL21 expressed by LECs can induce CCR7-dependent cancer cells into lymphatic vessels. PDGF-BB secreted by tumor cells can directly induce tumor lymphangiogenesis. SHH sonic hedgehog, CCL21 CC-chemokine ligand 21, CCR7 C–C receptor 7, PDGF-BB platelet-derived growth factor BB, TAMs tumor-associated Macrophage