Mechanisms of esophageal cancer metastasis and treatment progress

Abstract

Esophageal cancer is a prevalent tumor of the digestive tract worldwide. The detection rate of early-stage esophageal cancer is very low, and most patients are diagnosed with metastasis. Metastasis of esophageal cancer mainly includes direct diffusion metastasis, hematogenous metastasis, and lymphatic metastasis. This article reviews the metabolic process of esophageal cancer metastasis and the mechanisms by which M2 macrophages, CAF, regulatory T cells, and their released cytokines, including chemokines, interleukins, and growth factors, form an immune barrier to the anti-tumor immune response mediated by CD8+ T cells, impeding their ability to kill tumor cells during tumor immune escape. The effect of Ferroptosis on the metastasis of esophageal cancer is briefly mentioned. Moreover, the paper also summarizes common drugs and research directions in chemotherapy, immunotherapy, and targeted therapy for advanced metastatic esophageal cancer. This review aims to serve as a foundation for further investigations into the mechanism and management of esophageal cancer metastasis.

Keywords: anatomical mechanism; chemotherapy; esophageal cancer; immunotherapy; metastasis; molecular mechanism; targeted therapy.

Figure 1

Hematogenous transfer process. VEGF-A and VEGF-B bind to VEGFR-1 and VEGFR-2, initiating downstream signaling pathways that promote angiogenesis. Tumor-derived exosomes can enhance angiogenesis and facilitate the release and transport of MMPs, influencing angiogenesis. TGF-β1 released by tumors activates smad2/3 and inhibits smad7, leading to the production of N-calmodulin and Vimentin, and suppressing the expression of E-calmodulin, thereby inducing and accelerating the process of EMT. MMPs contribute to ECM disruption. Tumor cells enhance adhesion to the basement membrane through ITGα1 and E-calmodulin. Members of the ITGαβ family facilitate EC cell transmigration across the vascular endothelium. P-selectin interacts with talin1 to activate integrin αIIbβ3, which recruits platelets to peri-CTCs. P-selectin, fibronectin (FN), and platelet granules (PG) promote CTC clustering by inducing platelet aggregation around CTCs. Platelet adhesion and aggregation trigger the secretion of p-selectin and TGF-β1 via the TGF-β1-garp pathway, leading to increased FN synthesis. This provides mechanical protection against shear forces and immune cell attacks. Additionally, fibrin binding to leukocytes contributes to the formation of small clots, further enhancing the stability of CTC clusters.

Figure 2

Immunosuppressive mechanisms of EC. Tumor cells release TGF-β, activating CAFs, Tregs, and TAMs. CAFs release CXCL-like chemokines, promoting neutrophil aggregation. CAFs also release MCP-1, promoting monocyte aggregation and transformation. Furthermore, CAFs release FAP, activating AKT- and ERK-related signaling pathways, and promoting the release of CCL2, CXCL8, and IL-6. The amount of WNT2+ released from CAFs is inversely correlated with CD8+ T cell activity. WNT2+ inhibits the JAK2/STAT3 signaling cascade by affecting SOCS3 secretion, suppressing T cell differentiation and expression. CCL2, CXCL8, IL-4, IL-6, and IL-13 induce M2 macrophage polarization and TAM aggregation. M2 macrophages deplete CD8+ T cells, which have specific antitumor effects, and enhance the PD-1/PD-L1 pathway, increasing tumor cell immune escape. CCL17, CCL20, CCL21, and CCL22 promote Treg aggregation. Treg cells express high-affinity IL-2 receptors on their surface, competitively binding and depleting IL-2, inhibiting effector T cell proliferation. Treg cells secrete suppressive cytokines, including IL-32 and TGF-β, to inhibit T cell activation. Treg cells also secrete CTLA-4, reducing CD80/86 expression on APCs and inhibiting APC maturation, impairing immune function within the TME.