Introduction

Esophageal cancer (ESCA) is the seventh most common cancer in the world and the sixth most common cause of cancer-related death, according to new research [1]. Globally, one of the countries with the highest burden of ESCA is China [2]. ESCA can be classified into esophagus adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) by histopathology. The main treatment methods of ESCA include surgery, radiotherapy, chemotherapy, and comprehensive treatment [3]. The overall 5-year survival rate of patients with ESCA is about 20% [4]. The main cause of death is the invasion and metastasis of ESCA cells [5]. However, the 5-year survival rate of patients with early ESCA can exceed 95% if treated promptly [6]. Therefore, it is of great clinical significance to evaluate the biological changes related to ESCA at the molecular level and find the regulatory targets related to the malignant phenotype of cancer invasion and metastasis, to improve the survival rate of ESCA patients.

Chemokines were first described as factors inducing neutrophil migration in 1984 [7]. Chemokines are small cytokines or signal proteins secreted by cells and play an important role in their biology [8, 9]. Chemokines are a family of soluble proteins with a low molecular weight of 8–15 kDa. Studies have shown that human chemokines contain about 50 different types and 20 chemokine receptors [10]. According to the position of the first two N-terminal cysteine residues, chemokines are divided into four major subfamilies, including CC, CXC, C, and CX3C. Chemokine receptors are G-protein-coupled receptors. G-protein-coupled receptors have seven transmembrane domains on the surface of leukocytes. So far, about 20 different chemokine receptors have been identified. According to the type of chemokine they bind, they are also divided into four families, including CCR and CC chemokine binding and CXCR and CXC chemokine binding (Fig. 1). The CC and CXC chemokine are two major chemokine subfamilies, which are mainly expressed in tumor microenvironment (TME) and play an important role in tumor progression, tumor-related inflammation, immunity, and tumor invasion [11, 12]. Therefore, this review focuses on the role of CC and CXC in ESCA.

Fig. 1
figure 1

CC and CXC chemokines and their receptors

Full size image

Tumor-associated macrophages (TAMs) are macrophages that infiltrate tumor tissue, and their proportion in the TME is highly correlated with tumor occurrence, development, severity, and prognosis. Research has found that TAMs can secrete chemokines. Tumor cells secrete chemokines in the form of autocrine or paracrine. Chemokines mediate host response to cancer by guiding leukocytes into TME. In fact, TME is composed of a wide and diverse mixture of CC and CXC chemokines, which regulate tumor growth, angiogenesis, invasion, and leukocyte infiltration into tumors [13]. Chemokines can directly regulate tumor growth by inducing tumor cells proliferation and preventing tumor cells apoptosis (Fig. 2). The role of chemokines in tumors has been reported in various types of cancers, including breast [14], colon [15], ovarian [16], lung [17], as well as ESCA [18].

Fig. 2
figure 2

Tumor-associated macrophages in the tumor microenvironment secrete chemokines that act on the migration and invasion of esophageal cancer cells

Full size image

More and more evidences show that uncontrolled inflammation is related to the formation of ESCA [19,20,21]. Chemokines and their receptors play an important role in inflammation and malignant diseases [22,23,24]. The expression of chemokine in tumor tissue is decreased or up-regulated, which has protective and promoting effects on tumor occurrence. The purpose of this study is to explore the mechanism of chemokine-induced invasion and metastasis of ESCA and to provide a strong theoretical and experimental basis for revealing the pathogenesis of ESCA, finding molecular markers for diagnosis of ESCA, identifying, and developing drug targets for clinical treatment, and formulating effective treatment plans.

CC and CXC Chemokine Subfamily in ESCA

We reviewed articles on CC and CXC chemokines and their receptors in ESCA identified by PubMed database (Fig. 3). In the CC chemokines subfamily, there are 28 chemokines, from CCL1 to CCL28. We have not found any research reports on CCL6, CCL7, CCL9, CCL10, CCL12, CCL13, CCL14, CCL16, and CCL27 of ESCA. The role of CC chemokines in ESCA is summarized in Table 1. Most CC chemokines were highly expressed in ESCC and were related to the prognosis of patients. The pathways of CCL1/CCR8 and CCL3/CCR5 in the ESCA are illustrated in Fig. 4. CXC chemokine subfamily includes 17 chemokines from CXCL1 to CXCL17. We did not find the relationship between CXCL4, CXCL7, CXCL15, CXCL17, and ESCA. The role of CXC chemokines in ESCA is summarized in Table 1. Most CXC chemokines were highly expressed in ESCC. The pathways of CXCL6/CXCR2 and CXCR12/CXCR4 in the ESCA are illustrated in Fig. 4.

Fig. 3
figure 3

Diagram of CC and CXC chemokines in the esophageal cancer search

Full size image
Table 1 The CC and CXC chemokines play a role in the ESCA
Full size table
Fig. 4
figure 4

Schematic model of the CCL1/CCR8, CCL3/CCR5, CXCL6/CXCR2, and CXCL12/ CXCR4 axes in esophageal squamous cell carcinoma. CCL1 binds to the receptor CCR8 on cancer cells, and CCL1/CCR8 interaction promotes cancer cell migration and inhibits cancer cell apoptosis by activating Akt signaling pathway. CCL3 promotes tumor progression and poor prognosis in esophageal squamous cell carcinoma patients by binding to CCR5 on esophageal squamous cell carcinoma cells, activating the PI3K/AKT and MEK/ERK pathways, and promoting cell proliferation, migration, and angiogenesis. CXCL6 enhances transcription by activating the STAT3 pathway and enhances the growth and metastasis of esophageal squamous cell carcinoma cells. CXCL12/CXCR4 is one of the main mechanisms that esophageal squamous cell carcinoma cells transfer through ERK1/2 signaling pathway

Full size image

Chemokines and the Invasion and Migration in ESCA

CCL1, CCL3, CCL8, CCL21, CCL25, CXCL5, CXCL8, CXCL12, and CXCL14 are associated with the invasion and migration of ESCA. CCL1 is overexpressed in TAMs, CCR8 (CCL1 receptor) is expressed on the surface of ESCC cells, and the interaction between stromal CCL1 and CCR8 promotes ESCC progression of migration and invasion through Akt/PRAS40/mTOR pathway, thus providing a new therapeutic target [25]. CCL3, derived from TAMs and esophageal cancer cells, promotes cell migration and invasion by binding to CCR5 and phosphorylated Akt and ERK, thus promoting the progression of ESCC and poor prognosis [26]. It is CCL8 that can activate the NF-κB signaling pathway, induce the epithelial-mesenchymal transition, and promote the migration and invasion of ESCC cells in vitro [27]. CCL21 can significantly improve the migration ability of ESCC cell line, can induce the formation of pseudopodia, and can significantly enhance the motility of esophageal carcinoma cells [28]. Among the differentially expressed genes, CCL25 is highly associated with PCSK9, and thus, it is speculated that PCSK9 may promote the migration and invasion of ESCC by affecting the secretion of CCL25 [29]. The results showed that the enhanced expression of miR-145-3p inhibited the proliferation, migration, invasion, and stimulated apoptosis of ESCA by inhibiting CXCL5 [30]. CXCL8 up-regulated in the microenvironment may contribute to ESCC migration and invasion by the phosphorylation of Akt and ERK1/2 [31]. Developmentally down-regulated 9 maintained the stemness of ESCC cells and regulated CXCL8 through the ERK pathway to recruit myeloid-derived suppressor cells into the tumor [32]. Maelstrom could up-regulate CXCL8 through Akt1/RelA to direct myeloid-derived suppressor cells homing into ESCC [33]. Anti-CXCL8 autoantibody had good diagnostic value and may become a candidate biomarker for ESCC [34]. It suggested the potential usefulness of CXCL8 in the diagnosis and progression of ESCA [35, 36]. The decrease of CXCL12 contributes to the inhibition of proliferation and invasion of esophageal cancer cells in vitro [37]. Growth inhibitor 5 inhibits ESCC cells migration and invasion by down-regulating IL-6/CXCL12 signaling pathway [38]. Targeting CXCL12/CXCR4 is also summarized to provide a reference for the clinical diagnosis and treatment of ESCC [39]. Ectopic expression of CXCL14 inhibited the proliferation, invasion, tumor growth, and lung metastasis of ESCC cells [40]. FAM129A aggravates the progression of ESCA by negatively regulating the CXCL14 level [41].

Chemokines and the Survival in ESCA

The chemokines associated with the survival of ESCA are CCL4, CCL5, CCL11, CCL15, CCL18, CCL20, CCL22, CCL23, CCL25, CCL26, CCL28, CXCL1, CXCL5, CXCL6, CXCL10, CXCL11, and CXCL12. The study showed that CCL4 and CCL20 recruit functionally different T lymphocyte subsets and high levels of CCL4 in the lesions of ESCC patients predicting prolonged survival [42]. High CCL5 expression is associated with poor prognosis in low-grade esophageal cancer, and the therapeutic potential of targeting the CCL5-CCR5 axis in ESCC [43]. CCL5 served as the key chemokine to recruit CD8(+) T lymphocytes into ESCC tissue and may play a role in patient survival [44]. Autocrine CCL5 signaling may promote the progress of ESCC, and targeting CCL5/CCR5 axis may be a potential treatment strategy for ESCC [45]. CCL11 and CXCL10 in tumor tissues of ESCA patients after treatment are related to prognosis, and low levels indicate a good prognosis [46]. CCL15/MIP1D were associated with ESCA [47]. Overexpression of CCL18 was associated with a worse survival in patients with ESCC, and CCL18-induced hox transcript antisense intergenic RNA upregulation promotes malignant progression through the miR-130a-5p-ZEB1 axis [48]. Fusobacterium nucleatum might also contribute to aggressive tumor behavior through activation of CCL20 and be associated with shorter survival in ESCA [49]. CCL20 had been found to be overactivated in EAC tissue infected with the fusobacterium nucleatum [50]. High CCL22 expression was associated with poor patient survival, L1 cell adhesion molecule (L1CAM) promoted CCL22 expression by activating the PI3K/AKT/NF-κB signaling pathway, and CCL22 promoted the recruitment of Treg to ESCA sites, and Tregs secreted TGF-β and then Smad2/3 can promote the expression of L1CAM with a positive feedback mode [51]. Seven biomarkers (CXCL6, CCL23, CXCL5, TGFA, CXCL1, OSM, and CCL4) were inversely associated with HRs 0.57–0.72 in ESCC [52]. ESCA associated with CCL25 as a biomarker for predicting outcome in upper gastrointestinal tumors [53]. Elevated CCL26 was associated with improved overall survival in EAC [54]. The expression levels of CCL28 in the serum of early ESCC were significantly up-regulated [55], and CCL28 is a potential predictor of treatment response in EAC [56]. Histone deacetylase 2 promotes the development of ESCC by down-regulating microRNA-503-5p and promoting CXCL10 [57]. CXCL11/I-TAC was associated with ESCA for prevention and treatment [47]. ESCA patients with high CXCL12 tended to have worse overall and disease-free survival [58].

Chemokines and the Angiogenesis in ESCA

CXCL10 is associated with the survival of ESCA. Poly (A)-binding protein cytoplasmic 1 regulates the stability of interferon alpha (IFN-α) inducible protein 27 mRNA by interacting with eIF4G and promotes angiogenesis through the exosome miR-21-5p/CXCL10, playing a key role in the malignant progression of ESCC [59].

Chemokines and Metastasis in ESCA

CCL21, CXCL6, and CXCL12 are associated with the metastasis of ESCA. The CCL21/CCR7 receptor ligand system may play a role in the lymph node metastasis of ESCC by up-regulating MUC1 [28]. CXCL6 can enhance the growth and metastases of ESCC cells both in vivo and in vitro and promote epithelial–mesenchymal transition by up-regulating PD-L1 expression through activation of the STAT3 pathway [60]. Autocrine CXCL12/CXCR4 was one of the main mechanisms of metastasis of ESCA stem cells through ERK1/2 signaling pathway and may become a therapeutic target for ESCA patients [61].

Chemokines and Immune in ESCA

The chemokines found to be immune related to ESCA are CCL2, CCL17, CCL19, CCL20, CCL24, CXCL2, CXCL3, CXCL9, CXCL10, CXCL11, CXCL13, and CXCL16. CCL2/CCR2 axis recruits tumor-associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis [62]. Since CCL2 expressed by tumor cells recruits myeloid cells (monocytes, TAMs, and myeloid-derived suppressor cells) to TME, inhibition of the CCL2-CCR2 axis has been shown to enhance the immune response to tumors [63]. Levels of the chemokines CCL17 in tumors were significantly higher than in tumor-free tissues, and the CCL17/CCR4 axis might play an important role in Th17 cell infiltration of ESCC [64]. CCL17 and CCL22 within the tumor were associated with an increased population of Foxp3(+) Tregs in ESCC [65]. Responders were associated with lower baseline levels of CCL19 of toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in locally advanced resectable ESCC [66]. Study had shown that CCL20 can chemically regulate T cells (Tregs) through CCR6 (CCL20 receptor), thereby promoting the proliferation of ESCA [67]. The results showed that CCL20 induced by hypomethylation promoted the progression of ESCA and immune disorders [68]. CCL24 might be promising therapeutic targets for EAC [69]. Interleukin (IL)-17 stimulated ESCC cells to release more of the CXCL2 and CXCL3, which are involved in neutrophil migration [70]. The CXCR3 ligands Mig/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11 are angiostatic and attract anti-tumoral T lymphocytes and may therefore mediate ESCA growth retardation and regression [71]. CXCL10 has been indicated to have anti-tumor effects in ESCC [18]. The high expression of CXCL10 is a clinically useful marker for patients with advanced thoracic ESCC who need adjuvant chemotherapy after surgery [72]. CXCL10, as a key chemokine to recruit CD8 ( +) T lymphocytes into ESCC tissues, may play a role in the survival of patients [44]. IL-17A can promote ESCC tumor cells to produce more chemokine CXCL13, which was related to the migration of B cells [73]. CXCL16 induced the expression of CD38 in myeloid-derived suppressor cells in vitro in ESCA [74].

Chemokines and Radioresistance in ESCA

Chemokine CXCL1 is associated with radioresistance in ESCA. Recent studies have shown that cancer-associated fibroblast (CAF)-derived type 1 collagen (Col1) and tumor cell-derived CXCL1 are enriched in unresponsive patient-derived xenografts. Col1 not only promotes radiation tolerance of tumor cells by enhancing DNA repair ability but also induces CXCL1 secretion of tumor cells. In addition, CXCL1 further activated CAFs through the CXCR2-STAT3 pathway, establishing a positive feedback loop. Direct interference with tumor cell-derived CXCL1 or inhibition of CXCL1-CXCR2 pathway can effectively restore radiosensitivity in vivo [75]. Previous studies have shown that CAF-secreted CXCL1 inhibited reactive oxygen species (ROS)-clearing enzyme superoxide dismutase 1, leading to increasing ROS accumulation after radiation and enhancing DNA damage repair mediated by radiation resistance. CXCL1 secreted by CAFs also mediates radiation resistance by activating the crosstalk of CAFs and ESCC cells through the MEK/ERK pathway to induce CXCL1 expression signal cycle in autocrine/paracrine, which further enhances tumor radiationresistance [76].

Summary

ESCA is a highly aggressive tumor with a low survival rate. Chemokines have autocrine, paracrine, and hormone effects and are associated with tumor growth and distant organ metastasis, among others. Understanding their mechanisms of action may provide new therapeutic approaches for a wide range of human malignancies. The role of different chemokines and their receptors in the development of ESCA has been studied and they play a key role in the angiogenesis, growth, aggressiveness, and eventual metastasis of ESCA. It has been found that chemokines regulated the behavior of ESCA mainly by chemically attracting pre-tumor or anti-tumor leukocytes and forming new blood vessels. Wider studies are needed to unravel the complex chemokine network in the development of ESCA to provide more insights, which may enhance therapeutic applications for cancer patients. Further studies are needed to clarify the role of chemokines in ESCA, especially unstudied chemokines.