Abstract
Developmental endothelial locus-1 (Del-1) is a secretory, multifunctional domain protein. It can bind to integrins and phosphatidylserine. As a local tissue signal, it plays a regulatory role in the cancer microenvironment and inflammation. Del-1 has destructive effects in most cancers and is associated with the progression and invasion of some cancers. In contrast, Del-1 also plays a protective role in inflammation. Del-1 regulates inflammation by regulating the generation of neutrophils in bone marrow, inhibiting the recruitment and migration of neutrophils and accelerating the clearance of neutrophils by macrophages. Del-1 and IL-17 are reciprocally regulated, and their balance maintains immune system homeostasis. Del-1 is expected to become a new therapeutic target for inflammatory disorders such as multiple sclerosis.
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.
Availability of data and materials
Not applicable.
Abbreviations
- ALX/FPR2:
-
Lipoxin A4 receptor/formylpeptide receptor-2
- BBB:
-
Blood–brain barrier
- CAR:
-
CXCL-12-abundant reticular
- CNS:
-
Central nervous system
- C/EBPβ:
-
CCAAT enhancer-binding protein β
- Del-1:
-
Developmental endothelial locus-1
- DHA:
-
Docosahexaenoic acid
- EAE:
-
Experimental allergic encephalomyelitis
- ECM:
-
Extracellular matrix
- EDIL3:
-
EGF like repeats and discoidin domains 3
- EVs:
-
Circulating extracellular vesicles
- GPR32:
-
G-protein-coupled receptor 32
- GSK3β:
-
Glycogen synthase kinase 3β
- HSCs:
-
Hematopoietic stem cells
- ICAM-1:
-
Intercellular adhesion molecule-1
- PI3K:
-
Phosphatidylinositol 3-kinase
- PPA:
-
Postoperative peritoneal adhesions
- PS:
-
Phosphatidylserine
- RvD1:
-
Resolvin D1
- TGF-β:
-
Transforming growth factor β
- TNBC:
-
Triple-negative breast cancer
References
Matzinger P, Kamala T. Tissue-based class control: the other side of tolerance. Nat Rev Immunol. 2011;11(3):221–30.
Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011;12(11):1035–44.
Hajishengallis G, Chavakis T. Endogenous modulators of inflammatory cell recruitment. Trends Immunol. 2013;34(1):1–6.
Chung KJ, Chatzigeorgiou A, Economopoulou M, Garcia-Martin R, Alexaki VI, Mitroulis I, et al. A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat Immunol. 2017;18(6):654–64.
Oyler-Yaniv A, Oyler-Yaniv J, Whitlock BM, Liu Z, Germain RN, Huse M, et al. A tunable diffusion-consumption mechanism of cytokine propagation enables plasticity in cell-to-cell communication in the immune system. Immunity. 2017;46(4):609–20.
Hajishengallis G, Chavakis T. DEL-1-regulated immune plasticity and inflammatory disorders. Trends Mol Med. 2019;25(5):444–59.
Ho HK, Jang JJ, Kaji S, Spektor G, Fong A, Yang P, et al. Developmental endothelial locus-1 (Del-1), a novel angiogenic protein: its role in ischemia. Circulation. 2004;109(10):1314–9.
Choi EY, Lim JH, Neuwirth A, Economopoulou M, Chatzigeorgiou A, Chung KJ, et al. Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination. Mol Psychiatry. 2015;20(7):880–8.
Kourtzelis I, Li X, Mitroulis I, et al. DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat Immunol. 2019;20(1):40–9. https://doi.org/10.1038/s41590-018-0249-1.
Shin J, Maekawa T, Abe T, Hajishengallis E, Hosur K, Pyaram K, et al. DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates. Sci Transl Med. 2015;7(307):307ra155.
Hidai C, Zupancic T, Penta K, Mikhail A, Kawana M, Quertermous EE, et al. Cloning and characterization of developmental endothelial locus-1: an embryonic endothelial cell protein that binds the alphavbeta3 integrin receptor. Genes Dev. 1998;12(1):21–33.
Schurpf T, Chen Q, Liu JH, Wang R, Springer TA, Wang JH. The RGD finger of Del-1 is a unique structural feature critical for integrin binding. FASEB J. 2012;26(8):3412–20.
Hidai C, Kawana M, Kitano H, Kokubun S. Discoidin domain of Del1 protein contributes to its deposition in the extracellular matrix. Cell Tissue Res. 2007;330(1):83–95.
Choi EY, Chavakis E, Czabanka MA, Langer HF, Fraemohs L, Economopoulou M, et al. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science (New York, NY). 2008;322(5904):1101–4.
Bednarczyk M, Stege H, Grabbe S, Bros M. β2 integrins-multi-functional leukocyte receptors in health and disease. Int J Mol Sci. 2020;21(4):1402.
Vestweber D. How leukocytes cross the vascular endothelium. Nat Rev Immunol. 2015;15(11):692–704. https://doi.org/10.1038/nri3908.
Mitroulis I, Kang YY, Gahmberg CG, Siegert G, Hajishengallis G, Chavakis T, et al. Developmental endothelial locus-1 attenuates complement-dependent phagocytosis through inhibition of Mac-1-integrin. Thromb Haemost. 2014;111(5):1004–6.
Hanayama R, Tanaka M, Miwa K, Nagata S. Expression of developmental endothelial locus-1 in a subset of macrophages for engulfment of apoptotic cells. J Immunol (Baltimore, Md: 1950). 2004;172(6):3876–82.
Eskan MA, Jotwani R, Abe T, Chmelar J, Lim JH, Liang S, et al. The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat Immunol. 2012;13(5):465–73.
Fu Y, Tsauo J, Sun Y, Wang Z, Kim KY, Lee SH, et al. Developmental endothelial locus-1 prevents development of peritoneal adhesions in mice. Biochem Biophys Res Commun. 2018;500(3):783–9.
Mitroulis I, Chen LS, Singh RP, et al. Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche. J Clin Invest. 2017;127(10):3624–39. https://doi.org/10.1172/jci92571.
Kim DY, Lee SH, Fu Y, **g F, Kim WY, Hong SB, et al. Del-1, an endogenous inhibitor of TGF-β activation, attenuates fibrosis. Front Immunol. 2020;11:68.
Galdiero MR, Garlanda C, Jaillon S, Marone G, Mantovani A. Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol. 2013;228(7):1404–12.
Ribeiro R, Lopes C, Medeiros R. Leptin and prostate: implications for cancer prevention–overview of genetics and molecular interactions. Eur J Cancer Prev. 2004;13(5):359–68.
Penta K, Varner JA, Liaw L, Hidai C, Schatzman R, Quertermous T. Del1 induces integrin signaling and angiogenesis by ligation of alphaVbeta3. J Biol Chem. 1999;274(16):11101–9.
Niu JX, Zhang WJ, Ye LY, Wu LQ, Zhu GJ, Yang ZH, et al. The role of adhesion molecules, alpha v beta 3, alpha v beta 5 and their ligands in the tumor cell and endothelial cell adhesion. Eur J Cancer Prev. 2007;16(6):517–27. https://doi.org/10.1097/CEJ.0b013e3280145c00.
Moon PG, Lee JE, Cho YE, et al. Identification of developmental endothelial locus-1 on circulating extracellular vesicles as a novel biomarker for early breast cancer detection. Clin Cancer Res. 2016;22(7):1757–66. https://doi.org/10.1158/1078-0432.ccr-15-0654.
Lee JE, Moon PG, Cho YE, et al. Identification of EDIL3 on extracellular vesicles involved in breast cancer cell invasion. J Proteomics. 2016;131:17–28. https://doi.org/10.1016/j.jprot.2015.10.005.
Lee SJ, Lee J, Kim WW, Jung JH, Park HY, Park JY, et al. Del-1 expression as a potential biomarker in triple-negative early breast cancer. Oncology. 2018;94(4):243–56.
Lee J, Jeong JH, Jung JH, Kim WW, Lee SJ, Park JY, et al. Overcoming tamoxifen resistance by regulation of Del-1 in breast cancer. Oncology. 2019;97:180–8.
Sun JC, Liang XT, Pan K, et al. High expression level of EDIL3 in HCC predicts poor prognosis of HCC patients. World J Gastroenterol. 2010;16(36):4611–5. https://doi.org/10.3748/wjg.v16.i36.4611.
**a H, Chen J, Shi M, et al. EDIL3 is a novel regulator of epithelial-mesenchymal transition controlling early recurrence of hepatocellular carcinoma. J Hepatol. 2015;63(4):863–73. https://doi.org/10.1016/j.jhep.2015.05.005.
Oplawski M, Dziobek K, Zmarzly N, Grabarek B, Tomala B, Lesniak E, et al. Evaluation of changes in the expression pattern of EDIL3 in different grades of endometrial cancer. Curr Pharm Biotechnol. 2019;20(6):483–8.
Jiang SH, Wang Y, Yang JY, Li J, Feng MX, Wang YH, et al. Overexpressed EDIL3 predicts poor prognosis and promotes anchorage-independent tumor growth in human pancreatic cancer. Oncotarget. 2016;7(4):4226–40.
Beckham CJ, Olsen J, Yin PN, Wu CH, Ting HJ, Hagen FK, et al. Bladder cancer exosomes contain EDIL-3/Del1 and facilitate cancer progression. J Urol. 2014;192(2):583–92.
Zou X, Qiao H, Jiang X, Dong X, Jiang H, Sun X. Downregulation of developmentally regulated endothelial cell locus-1 inhibits the growth of colon cancer. J Biomed Sci. 2009;16:33.
Lee SH, Kim DY, **g F, Kim H, Yun CO, Han DJ, et al. Del-1 overexpression potentiates lung cancer cell proliferation and invasion. Biochem Biophys Res Commun. 2015;468(1–2):92–8.
Jeong D, Ban S, Oh S, ** Lee S, Yong Park S, Koh YW. Prognostic significance of EDIL3 expression and correlation with mesenchymal phenotype and microvessel density in lung adenocarcinoma. Sci Rep. 2017;7(1):8649.
Lee SH, Kim DY, Kang YY, Kim H, Jang J, Lee MN, et al. Developmental endothelial locus-1 inhibits MIF production through suppression of NF-kappaB in macrophages. Int J Mol Med. 2014;33(4):919–24.
Herault A, Binnewies M, Leong S, Calero-Nieto FJ, Zhang SY, Kang YA, et al. Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis. Nature. 2017;544(7648):53–8.
Manz MG, Boettcher S. Emergency granulopoiesis. Nat Rev Immunol. 2014;14(5):302–14.
Mitroulis I, Kalafati L, Hajishengallis G, Chavakis T. Myelopoiesis in the context of innate immunity. J Innate Immun. 2018;10(5–6):365–72.
Mendelson A, Frenette PS. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med. 2014;20(8):833–46.
Chen LS, Kourtzelis I, Singh RP, Grossklaus S, Wielockx B, Hajishengallis G, et al. Endothelial cell-specific overexpression of Del-1 drives expansion of haematopoietic progenitor cells in the bone marrow. Thromb Haemost. 2018;118:613–6.
Waisman A, Hauptmann J, Regen T. The role of IL-17 in CNS diseases. Acta Neuropathol. 2015;129(5):625–37.
Duffney PF, Falsetta ML, Rackow AR, Thatcher TH, Phipps RP, Sime PJ. Key roles for lipid mediators in the adaptive immune response. J Clin Investig. 2018;128(7):2724–31.
Maekawa T, Hosur K, Abe T, Kantarci A, Ziogas A, Wang B, et al. Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3beta-C/EBPbeta pathway. Nat Commun. 2015;6:8272.
Brostjan C, Oehler R. The role of neutrophil death in chronic inflammation and cancer. Cell Death Discov. 2020;6:26.
AlQranei MS, Chellaiah MA. Osteoclastogenesis in periodontal diseases: possible mediators and mechanisms. J Oral Biosci. 2020;62(2):123–30.
Shin J, Hosur KB, Pyaram K, et al. Expression and function of the homeostatic molecule Del-1 in endothelial cells and the periodontal tissue. Clin Dev Immunol. 2013;2013:617809. https://doi.org/10.1155/2013/617809.
Franceschi C, Zaikin A, Gordleeva S, Ivanchenko M, Bonifazi F, Storci G, et al. Inflammaging 2018: an update and a model. Semin Immunol. 2018;40:1–5.
Adriaensen W, Mathei C, Vaes B, van Pottelbergh G, Wallemacq P, Degryse JM. Interleukin-6 as a first-rated serum inflammatory marker to predict mortality and hospitalization in the oldest old: a regression and CART approach in the BELFRAIL study. Exp Gerontol. 2015;69:53–61.
Puzianowska-Kuznicka M, Owczarz M, Wieczorowska-Tobis K, Nadrowski P, Chudek J, Slusarczyk P, et al. Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study. Immunity Ageing. 2016;13:21.
Goris A, Sawcer S, Vandenbroeck K, Carton H, Billiau A, Setakis E, et al. New candidate loci for multiple sclerosis susceptibility revealed by a whole genome association screen in a Belgian population. J Neuroimmunol. 2003;143(1–2):65–9.
Ramanan VK, Risacher SL, Nho K, Kim S, Swaminathan S, Shen L, et al. APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study. Mol Psychiatry. 2014;19(3):351–7.
Lin Z, Bei JX, Shen M, Li Q, Liao Z, Zhang Y, et al. A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nat Genet. 2011;44(1):73–7.
Gravallese EM, Schett G. Effects of the IL-23-IL-17 pathway on bone in spondyloarthritis. Nat Rev Rheumatol. 2018;14(11):631–40.
Yan S, Chen L, Zhao Q, Liu YN, Hou R, Yu J, et al. Developmental endothelial locus-1 (Del-1) antagonizes Interleukin-17-mediated allergic asthma. Immunol Cell Biol. 2018;96(5):526–35.
Wang G, Wu K, Li W, Zhao E, Shi L, Wang J, et al. Role of IL-17 and TGF-beta in peritoneal adhesion formation after surgical trauma. Wound Repair Regener. 2014;22(5):631–9.
Plewczyński D, Ginalski K. The interactome: predicting the protein-protein interactions in cells. Cell Mol Biol Lett. 2009;14(1):1–22.
Farhang N, Brunger JM, Stover JD, Thakore PI, Lawrence B, Guilak F, et al. (*) CRISPR-based epigenome editing of cytokine receptors for the promotion of cell survival and tissue deposition in inflammatory environments. Tissue Eng Part A. 2017;23(15–16):738–49.
Acknowledgements
Not applicable.
Funding
Not applicable.
Author information
Authors and Affiliations
Contributions
ML conceived the review article and drafted and finalized the article. The research direction of DZ is the molecular immunomodulation effects in neuroautoimmune diseases. She proposed searching for a molecule that has immunomodulatory functions in the local inflammatory tissues, and when we focused on the molecular Del-1, she proposed that its role in local inflammatory immune regulation had not been elucidated and the antagonistic effect between Del-1 and IL-17 in some inflammatory diseases deserves to be discussed, after which she reviewed and revised the manuscript many times. GL reviewed the manuscript and provided many comments. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Li, M., Zhong, D. & Li, G. Regulatory role of local tissue signal Del-1 in cancer and inflammation: a review. Cell Mol Biol Lett 26, 31 (2021). https://doi.org/10.1186/s11658-021-00274-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s11658-021-00274-9