Background

A wide variety of local tissue signals exist in the human body. Local tissues are believed to be passive recipients of immunity and cancer, but recent studies have found that they are active regulators [1]. Local tissue signals can remold immunity and play crucial roles in immune-driven inflammatory diseases and cancer [2]. Some signals exert different functions at different positions. In some circumstances, some local tissue signals can regulate the recruitment and activation of immune cells to control the initiation and termination of the immune response. In others, they can regulate the function and phenotype of local tissues and recruit immune cells. These signals are mainly secreted by local stromal and parenchymal cells, including cytokines, growth factors, antimicrobial peptides, and other locally acting factors [1, 3]. They promote or inhibit the interaction of local tissues with immune cells through direct effects or intercellular adhesion [4, 5]. Local tissue signals are essential in the local tissue microenvironment, and their compartmentalized expression is considered to optimize the spatial regulation of the body.

Developmental endothelial locus-1 (Del-1) is a representative of local tissue signals and exerts different regulatory functions in different expression areas [6]. For instance, Del-1 accelerates the process of inflammation resolution in inflammatory areas, but not in non-inflammatory areas. The functions of many other local tissue signals remain unclear. It is useful to study the role of Del-1 for understanding how local tissue signals regulate the local tissue microenvironment, including how they maintain homeostasis of the immune system, and regulate the invasion of cancer and other unknown functions. In this paper, we present a review of the regulatory role of local tissue signal Del-1 in cancer and inflammation.

Structure, ligands, and functions of Del-1

Del-1 is a 52 kDa extracellular matrix glycoprotein that is primarily produced by endothelial cells during embryological vascular development [7]. Macrophages, neuronal cells, osteoclasts, and some hematopoietic microenvironment cells can also produce Del-1 [8,9,10]. Del-1 consists of three N-terminal EGF-like repeats (E1, E2, and E3) and two C-terminal discoidin I-like domains (C1 and C2). EDIL3 (EGF like repeats and discoidin domains 3) is the gene encoding Del-1 [6]. Del-1 not only interacts with αv (αvβ3 and αvβ5) integrins through an RGD motif in the second EGF repeat [11, 12] but also interacts with glycosaminoglycans and phosphatidylserine (PS) through discoidin I-like domains [13]. See the Protein Data Bank (PDB) website for details of Del-1 3D structure (http://www.rcsb.org/structure/4d90). Del-1 can bind to β2 integrins, which have distinct CD11 subunits and a common CD18 subunit [14]. αLβ2 integrin (LFA-1, lymphocyte function-associated antigen 1; CD11a/CD18) mediates the process by which leukocytes adhere firmly to the vascular endothelium and transmigrate through the vessel wall, which results in their recruitment to inflamed tissue [15]. In the vessel lumen, αMβ2 integrin (MAC-1, macrophage-1 antigen; CD11b/CD18) mediates not only the crawling of leukocytes on the endothelium, but also the process by which leukocytes search for a proper site to transmigrate from the vessel [16]. Del-1 can bind to αLβ2 and αMβ2 integrins and prevent them from binding to intercellular adhesion molecule-1 (ICAM-1), thus preventing binding between leukocytes and the endothelium [17]. Del-1 can also bind to αvβ3 integrin on the macrophage at one end and to PS on the apoptotic cell at the other end, thereby acting as a bridge to mediate the efferocytosis of apoptotic cells by macrophages [9, 18]. Genetic knockout of Del-1 has a unique phenotype. In mice with periodontitis, Del-1 deficiency is associated with inflammatory periodontal loss and neutrophil infiltration [19]. In experimental allergic encephalomyelitis (EAE), Del-1 deficiency increases disease severity, increases inflammation and immune cell infiltration in the central nervous system (CNS), increases IL-17 levels, and breaks down the blood–brain barrier (BBB) [8]. In endothelial cells, Del-1 deficiency increases LFA-1 dependent leukocyte adhesion in vitro and in vivo. Del-1 deficient mice display higher neutrophil accumulation during lung inflammation, but this condition can be reversed in Del-1/LFA-1 double-deficient mice [14]. In postoperative peritoneal adhesion (PPA) mice, Del-1 deficiency increases the incidence and severity of PPA, increases acute inflammation, and increases the deposition of extracellular matrix (ECM) proteins in the surgically traumatized peritoneum [20]. In hematopoietic stem cells (HSCs), Del-1 deficiency increases long-term HSC quiescence [21]. In mice with lung fibrosis, Del-1 deficiency activates transforming growth factor β (TGF-β), thereby increasing the production of collagen [22].

Elevated levels and progression-promoting effects of Del-1 in cancer

Previous studies have shown that under the effect of microenvironmental signals, tumor-related macrophages and leukocytes can differentiate into specific phenotypes to foster tumor progression and suppress adaptive immunity [23]. The growth and metastasis of cancer are associated with angiogenesis, and Del-1 is involved in angiogenesis [24]. In the original site, cancer cells interact with tumor-derived endothelial cells, and in the secondary site, cancer cells interact with normal tissue-derived endothelial cells. Studies have shown that the expression of Del-1 is upregulated in cancer cells; αvβ3, αvβ5, and their ligands Del-1 and L1-CAM (CD171) play essential roles in the process of cancer cell adhesion at the primary site [25, 26]. Since then, researchers have started to focus on the relationship between cancer and Del-1. The relationship between breast cancer and Del-1 has been most widely studied. Researchers examined the level of Del-1 in the plasma and circulating extracellular vesicles (EVs) of early stage breast cancer patients and found that the levels of Del-1 were upregulated both in the plasma and EVs compared to those of the controls. Furthermore, the sensitivity of Del-1 for early stage breast cancer diagnosis was higher than that of CA-153. Therefore, Del-1 in the plasma and EVs may be a sensitive biomarker that can identify early stage breast cancer and distinguish breast cancer from benign breast tumors and noncancerous diseases [27]. In another study, although the expression of Del-1 mRNA was found in all breast cancer cell lines, the rate and intensity were much higher in triple-negative breast cancer (TNBC), and Del-1 was correlated with cancer progression and worse survival trends [28]. Therefore, Del-1 is likely to act as a biomarker and progression predictor in patients with TNBC [29]. One study elucidated that tamoxifen-resistant breast cancer has a strong correlation with Del-1 overexpression, and its progression can be inhibited by Del-1 depletion, which means that the sensitivity of tamoxifen is restored [30]. Therefore, downregulating the level of Del-1 is a potential therapeutic strategy for some types of breast cancer.

In addition to breast cancer, EDIL3 expression increases in hepatocellular carcinoma and predicts a poor prognosis [31]. It also enhances the tumorigenic, metastatic, and angiogenic potential through TGF-β and ERK signaling in hepatocellular carcinoma [61]. Gene editing technology is also expected to be used to regulate the local tissue signals associated with Del-1, so as to change the tumor immune microenvironment or regulate the immune microenvironment of inflammatory diseases. These aspects may be new directions for future research.