<p>Esophageal Microenvironment: From Precursor Microenvironment to Premetastatic Niche</p>

Abstract

Esophageal cancer (EC) is the sixth most deadly cancer, and its incidence is still increasing year by year. Although the researches on the molecular mechanisms of EC have been widely carried out and incremental progress has been made, its overall survival rate is still low. There is cumulative evidence showing that the esophageal microenvironment plays a vital role in the development of EC. In precancerous lesions of the esophagus, high-risk environmental factors can promote the development of precancerous lesions by inducing the production of inflammatory factors and the recruitment of immune cells. In the tumor microenvironment, tumor-promoting cells can inhibit anti-tumor immunity and promote tumor progression through a variety of pathways, such as bone marrow-derived suppressor cells (MDSCs), tumor-associated fibroblasts (CAFs), and regulatory T cells (Tregs). The formation of extracellular hypoxia and acidic microenvironment and the change of extracellular matrix stiffness are also important factors affecting tumor progression and metastasis. Simultaneously, primary tumor-derived cytokines and bone marrow-derived immune cells can also promote the formation of pre-metastasis niche of EC lymph nodes, which are beneficial to EC lymph node metastasis. Further research on the specific mechanism of these processes in the occurrence, development, and metastasis of each EC subtype will support us to grasp the overall pre-cancerous prevention, targeted treatment, and metastatic assessment of EC.

Understanding the immuno-biology of oesophageal adenocarcinoma: Towards improved therapeutic approaches

“…MDSCs are a heterogeneous population of cells that are produced in response to chronic inflammatory states such as cancer [90]. They exhibit a strong inhibitory effect on anti-tumour immunity in OC via inhibition of T-cell and NK-cell function, Treg and TAM activation, and promotion of fibroblast evolution to CAFs [91,92] (Fig. 2).…”

“…IL-4 and IL-13 along with other Th2-and CAF-derived cytokines, such as interleukin-6 (IL-6), have also been shown to polarise macrophages into the immunosuppressive M2 phenotype [95]. In OC, TAM infiltration is associated with a poor prognosis [91,[96][97][98]. M1-like macrophages on the other hand, display an anti-tumour, pro-inflammatory phenotype, and are associated with a Th1 response [96].…”

ECM Remodeling in Squamous Cell Carcinoma of the Aerodigestive Tract: Pathways for Cancer Dissemination and Emerging Biomarkers

“…Cells that succeed in surviving in the blood or lymphatic circulation harsh conditions extravasate into the stroma, colonizing the metastatic site [ 36 ]. The pre-metastatic niche is established before the arrival of tumor cells from the primary tumor and facilitates the seeding of malignant cells [ 42 ]. Its formation is mediated by secreted factors deriving from the primary tumor, which mainly act recruiting immune cells and inducing ECM remodeling due to the increased activity of lysis oxidase (LOX) and metalloproteases [ 42 , 43 , 44 ].…”

Targeting the Microenvironment in Esophageal Cancer

“…In addition, TME has several important characteristics, including hypoxia, acidosis, chronic inflammation, and immunosuppression, which are associated with tumor proliferation, migration, apoptosis, immune evasion, and angiogenesis ( Sung and Chung, 2002 ; Whiteside, 2008 ). Moreover, TME is not invariant, but involves constant remodeling of cells and their secretions to make them more suitable for tumor survival ( Han et al, 2020 ). This is partly responsible for the development of resistance to conventional treatments ( Luan et al, 2021 ).…”

“…In addition, anti-inflammatory reoxygenation combined with radiotherapy or photodynamic therapy, tumor vaccine, blocking microenvironment signal transduction, and other new therapies prevent occurrence and improve the prognosis of EC ( Huang and Fu, 2019 ; Liu J. et al, 2020 ; Yamamoto and Kato, 2020 ; Yang Y. M. et al, 2020 ). Moreover, many cells and factors in the microenvironment can be used as important indicators to judge the prognosis of EC ( Lin et al, 2016 ; Han et al, 2020 ). This review summarizes the EC microenvironment and related targeted therapies.…”