Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Pathology & Oncology Research
Published in: Pathology & Oncology Research 2/2017

01-04-2017 | Review

Macrophage Migration Inhibitory Factor (MIF): Biological Activities and Relation with Cancer

Authors: Camila Cristina Guimarães Nobre, Josélio Maria Galvão de Araújo, Thales Allyrio Araújo de Medeiros Fernandes, Ricardo Ney Oliveira Cobucci, Daniel Carlos Ferreira Lanza, Vânia Sousa Andrade, José Veríssimo Fernandes

Published in: Pathology & Oncology Research | Issue 2/2017

Login to get access

Abstract

Macrophage migration inhibitory factor (MIF) emerged in recent years as an important inflammation mediator, playing a prominent role in the pathogenesis of various types of malignant neoplasm. MIF is a glycoprotein that presents a wide spectrum of biological activities and exerts a complex interaction with various cellular signaling pathways, causing imbalance of homeostasis. Experimental and clinical studies show that high levels of MIF are found in almost all types of human cancers and are implicated in seemingly all stages of development of the tumors. The production of MIF is triggered through an autocrine signal emitted by tumor cells, and stimulates the production of cytokines, chemokines, and growth as well as angiogenic factors that lead to growth of the tumor, increasing its aggressiveness and metastatic potential. MIF is produced by virtually all types of human body cells, in response to stress caused by different factors, leading to pathological conditions such as chronic inflammation and immunomodulation with suppression of immune surveillance and of immune response against tumors, angiogenesis, and carcinogenesis. In this review, we present recent advances on the biological activity of MIF, the signaling pathways with which it is involved and their role in tumorigenesis.
Literature
1.
Bloom BR, Bennett B (1966) Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science 153(731):80–82CrossRefPubMed
2.
Takahashi N, Nishihira J, Sato Y et al (1998) Involvement of macrophage migration inhibitory factor (MIF) in the mechanism of tumor cell growth. Mol Med 4(11):707–714PubMedPubMedCentral
3.
Onodera S, Nishihira J, Koyama Y et al (2004) Macrophage migration inhibitory factor up-regulates the expression of interleukin-8 messenger RNA in synovial fibroblasts of rheumatoid arthritis patients: common transcriptional regulatory mechanism between interleukin-8 and interleukin-1beta. Arthritis Rheum 50(5):1437–1447CrossRefPubMed
4.
Lerch JK, Puga DA, Bloom O, Popovich PG (2014) Glucocorticoids and macrophage migration inhibitory factor (MIF) are neuroendocrine modulators of inflammation and neuropathic pain after spinal cord injury. Semin Immunol 26(5):409–414CrossRefPubMed
5.
Bernhagen J, Calandra T, Bucala R (1998) Regulation of the immune response by macrophage migration inhibitory factor: biological and structural features. J Mol Med 76(3–4):151–161CrossRefPubMed
6.
Benigni F, Atsumi T, Calandra T et al (2000) The proinflammatory mediator macrophage migration inhibitory factor induces glucose catabolism in muscle. J Clin Invest 106(10):1291–1300CrossRefPubMedPubMedCentral
7.
Lolis E, Bucala R (2003) Macrophage migration inhibitory factor. Expert Opin Ther Targets 7:153–164CrossRefPubMed
8.
Shi X, Leng L, Wang T et al (2006) CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity 25(4):595–606CrossRefPubMedPubMedCentral
9.
Bifulco C, McDaniel K, Leng L, Bucala R (2008) Tumor growth-promoting properties of macrophage migration inhibitory factor. Curr Pharm Des 14(36):3790–3801CrossRefPubMed
10.
11.
Lue H, Thiele M, Franz J et al (2007) Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity. Oncogene 26(35):5046–5059CrossRefPubMed
12.
Binsky I, Haran M, Starlets D et al (2007) IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival. Proc Natl Acad Sci U S A 104(33):13408–13413CrossRefPubMedPubMedCentral
13.
Hoi AY, Iskander MN, Morand EF (2007) Macrophage migration inhibitory factor: a therapeutic target across inflammatory diseases. Inflamm Allergy Drug Targets 6(3):183–190CrossRefPubMed
14.
Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA (2013) Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 13(11):759–771CrossRefPubMed
15.
Bernhagen J, Calandra T, Mitchell RA et al (1993) MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365(6448):756–759CrossRefPubMed
16.
Hagemann T, Robinson SC, Thompson RG, Charles K, Kulbe H, Balkwill FR (2007) Ovarian cancer cell-derived migration inhibitory factor enhances tumor growth, progression, and angiogenesis. Mol Cancer Ther 6(7):1993–2002CrossRefPubMed
17.
Wu S-P, Leng L, Feng Z et al (2006) Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of scleroderma. Arthritis Rheum 54(11):3661–3669CrossRefPubMed
18.
Dambacher J, Staudinger T, Seiderer J et al (2007) Macrophage migration inhibitory factor (MIF) −173G/C promoter polymorphism influences upper gastrointestinal tract involvement and disease activity in patients with Crohn’s disease. Inflamm Bowel Dis 13(1):71–82CrossRefPubMed
19.
Tong X, Zheng B, Tong Q et al (2015) The MIF -173G/C gene polymorphism increase gastrointestinal cancer and hematological malignancy risk : evidence from a meta-analysis and FPRP test. Int J Clin Exp Med 8(9):15949–15957PubMedPubMedCentral
20.
Meyer-Siegler KL, Vera PL et al (2007) Macrophage migration inhibitory factor (MIF) gene polymorphisms are associated with increased prostate cancer incidence. Genes Immun 8(8):646–652CrossRefPubMed
21.
Arisawa T, Tahara T, Shibata T et al (2008) Functional promoter polymorphisms of the macrophage migration inhibitory factor gene in gastric carcinogenesis. Oncol Rep 19(1):223–228PubMed
22.
23.
Babu SN, Chetal G, Kumar S (2012) Macrophage migration inhibitory factor: a potential marker for cancer diagnosis and therapy. Asian Pac J Cancer Prev 13(5):1737–1744CrossRefPubMed
24.
Krockenberger M, Engel JB, Kolb J et al (2010) Macrophage migration inhibitory factor expression in cervical cancer. J Cancer Res Clin Oncol 136(5):651–657CrossRefPubMed
25.
Richard V, Kindt N, Saussez S (2015) Macrophage migration inhibitory factor involvement in breast cancer (review). Int J Oncol 47(5):1627–1633PubMedPubMedCentral
26.
Fingerle-Rowson GR, Bucala R (2001) Neuroendocrine properties of macrophage migration inhibitory factor ( MIF ). Immunol Cell Biol 79(4):368–375CrossRefPubMed
27.
Conroy H, Mawhinney L, Donnelly SC (2010) Inflammation and cancer: macrophage migration inhibitory factor (MIF)--the potential missing link. QJM 103(11):831–836CrossRefPubMedPubMedCentral
28.
Rendon BE, Willer SS, Zundel W, Mitchell RA (2009) Mechanisms of macrophage migration inhibitory factor (MIF)-dependent tumor microenvironmental adaptation. Exp Mol Pathol 86(3):180–185CrossRefPubMedPubMedCentral
29.
Rosado JDD, Rodriguez-Sosa M (2011) Macrophage migration inhibitory factor (MIF): a key player in protozoan infections. Int J Biol Sci 7(9):1239–1256CrossRef
30.
Lehmann LE, Weber SU, Fuchs D et al (2008) Oxidoreductase macrophage migration inhibitory factor is simultaneously increased in leukocyte subsets of patients with severe sepsis. Biofactors 33(4):281–291CrossRefPubMed
31.
Simpson KD, Templeton DJ, Cross JV (2012) Macrophage migration inhibitory factor promotes tumor growth and metastasis by inducing myeloid-derived suppressor cells in the tumor microenvironment. J Immunol 189(12):5533–5540CrossRefPubMedPubMedCentral
32.
Yaddanapudi K, Rendon BE, Lamont G et al (2016) MIF is necessary for late-stage melanoma patient MDSC immune suppression and differentiation. Cancer Immunol Res 4(2):101–112CrossRefPubMed
33.
Bucala R (1996) MIF rediscovered : cytokine, pituitary hormone, and glucocorticoid-induced regulator of the immune response. FASEB J 10(14):1607–1613PubMed
34.
Fingerle-Rowson G, Koch P, Bikoff R et al (2003) Regulation of macrophage migration inhibitory factor expression by glucocorticoids in vivo. Am J Pathol 162(1):47–56CrossRefPubMedPubMedCentral
35.
Mawhinney L, Armstrong ME, O′ Reilly C, et al (2015) Macrophage migration inhibitory factor (MIF) enzymatic activity and lung cancer. Mol Med 20:729–735.
36.
Gregory JL, Leech MT, David JR, Yang YH, Dacumos A, Hickey MJ (2004) Reduced leukocyte-endothelial cell interactions in the inflamed microcirculation of macrophage migration inhibitory factor-deficient mice. Arthritis Rheum 50(9):3023–3034CrossRefPubMed
37.
Bernhagen J, Krohn R, Lue H et al (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13(5):587–596CrossRefPubMed
38.
Nishino T, Bernhagen J, Shiiki H, Calandra T, Dohi K, Bucala R (1995) Localization of macrophage migration inhibitory factor (MIF) to secretory granules within the corticotrophic and thyrotrophic cells of the pituitary gland. Mol Med 1(7):781–788PubMedPubMedCentral
39.
Bando H, Matsumoto G, Bando M et al (2002) Expression of macrophage migration inhibitory factor in human breast cancer: association with nodal spread. Jpn J Cancer Res 93(4):389–396CrossRefPubMed
40.
Lue H, Kleemann R, Calandra T et al (2002) Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease. Microbes Infect 4(4):449–460CrossRefPubMed
41.
Suzuki M, Murata K, Tanaka E, Nishihira J, Sakai M (1994) Crystallization and a preliminar X-ray diffraction study of macrophage migration inhibitory factor from human lymphocytes. J Mol Biol 235(3):1141–1143CrossRefPubMed
42.
Rosengren E, Bucala R, Aman P et al (1996) The immunoregulatory mediator macrophage migration inhibitory factor (MIF) catalyzes a tautomerization reaction. Mol Med 2(1):143–149PubMedPubMedCentral
43.
Rosengren E, Åman P, Thelin S et al (1997) The macrophage migration inhibitory factor MIF is a phenylpyruvate tautomerase. FEBS Lett 417(1):85–88CrossRefPubMed
44.
Kleemann R, Kapurniotu A, Frank RW et al (1998) Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase. J Mol Biol 280(1):85–102CrossRefPubMed
45.
Matsunaga J, Sinha D, Solano F, Santis C, Wistow G, Hearing V et al (1999) Macrophage migration inhibitory factor (MIF)--its role in catecholamine metabolism. Cell Mol Biol (Noisy-le-grand) 45(7):1035–1040
46.
El-turk F, Cascella M, Ouertatani-sakouhi H et al (2008) The conformational flexibility of the carboxy terminal residues 105 − 114 is a key modulator of the catalytic activity and stability of macrophage migration inhibitory factor. Biochemistry 47(40):10740–10756CrossRefPubMedPubMedCentral
47.
Cooke G, Armstrong ME, Donnelly SC (2009) Macrophage migration inhibitory factor (MIF), enzymatic activity and the inflammatory response. Biofactors 35(2):165–168CrossRefPubMed
48.
49.
Jung H, Seong HA, Ha H (2008) Critical role of cysteine residue 81 of macrophage migration inhibitory factor (MIF) in MIF-induced inhibition of p53 activity. J Biol Chem 283(29):20383–20396CrossRefPubMed
50.
51.
Krockenberger M, Dombrowski Y, Weidler C et al (2008) Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D. J Immunol 180(11):7338–7348CrossRefPubMedPubMedCentral
52.
Nakaya K, Nabata Y, Ichiyanagi T, An WW (2012) Stimulation of dendritic cell maturation and induction of apoptosis in leukemia cells by a heat-stable extract from azuki bean (Vigna angularis), a promising immunopotentiating food and dietary supplement for cancer prevention. Asian Pac J Cancer Prev 13(2):607–611CrossRefPubMed
53.
54.
Yaddanapudi K, Putty K, Rendon BE, et al (2013) Control of tumor-associated macrophage alternative activation by macrophage migration inhibitory factor. J Immunol190(6):2984–2993.
55.
56.
Shen YC, Thompson DL, Kuah MK et al (2012) The cytokine macrophage migration inhibitory factor (MIF) acts as a neurotrophin in the developing inner ear of the zebrafish, Danio rerio. Dev Biol 363(1):84–94CrossRefPubMed
57.
Zhang X, Chen L, Wang Y et al (2013) Macrophage migration inhibitory factor promotes proliferation and neuronal differentiation of neural stem/precursor cells through Wnt/β-catenin signal pathway. Int J Biol Sci 9(10):1108–1120CrossRefPubMedPubMedCentral
58.
Massirer KB, Carromeu C, Griesi-Oliveira K, Muotri AR (2011) Maintenance and differentiation of neural stem cells. Wiley Interdiscip Rev Syst Biol Med 3(1):107–114CrossRefPubMed
59.
Fernandes JV, Fernandes TAAM, Azevedo JCV et al (2015) Link between chronic inflammation and human papillomavirus-induced carcinogenesis (review). Oncol Lett 9(3):1015–1026PubMedPubMedCentral
60.
61.
Fernandes JV, Cobucci RNO, Jatoba CAN, Fernandes TA, Azevedo JW, Araújo JM (2015) The role of the mediators of inflammation in cancer development. Pathol Oncol Res 21(3):527–534CrossRefPubMed
62.
Santos LL, Morand EF (2006) The role of macrophage migration inhibitory factor in the inflammatory immune response and rheumatoid arthritis. Wien Med Wochenschr 156(1–2):11–18CrossRefPubMed
63.
64.
Gordon-Weeks AN, Lim SY, Yuzhalin AE, Jones K, Muschel R (2015) Macrophage migration inhibitory factor : a key cytokine and therapeutic target in colon cancer. Cytokine Growth Factor Rev 26(4):451–461CrossRefPubMed
65.
Ren Y, Law S, Huang X, Lee PY, Bacher M, Srivastava G, Wong J (2005) Macrophage migration inhibitory factor stimulates angiogenic factor expression and correlates with differentiation and lymph node status in patients with esophageal squamous cell carcinoma. Ann Surg 242(1):55–63CrossRefPubMedPubMedCentral
66.
Cheng RJ, Deng WG, Niu CB, Li YY, Fu Y (2011) Expression of macrophage migration inhibitory factor and CD74 in cervical squamous cell carcinoma. Int J Gynecol Cancer 21(6):1004–1012CrossRefPubMed
67.
Tang W, Gou X, Liu Q (2011) Expression of macrophage migration inhibition factor (MIF) in serum of patients with prostate cancer and its clinical significance. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 27(1):97–98PubMed
68.
Ren Y, Tsui HT, Poon RT et al (2003) Macrophage migration inhibitory fator – roles in regulating tumor cell migration and expression. Of angiogenic factors in hepatocellular carcinoma. Int J Cancer 107(1):22–29CrossRefPubMed
69.
White ES, Flaherty KR, Carskadon S et al (2003) Macrophage migration inhibitory factor and CXC chemokine expression in non-small cell lung cancer: role in angiogenesis and prognosis. Clin Cancer Res 9(2):853–860PubMed
70.
Ren Y, Chan HM, Fan J et al (2006) Inhibition of tumor growth and metastasis in vitro and in vivo by targeting macrophage migration inhibitory factor in human neuroblastoma. Oncogene 25(25):3501–3508CrossRefPubMed
71.
Guo YS, Dai YP, Li W et al (2011) Expression and significance of macrophage migration inhibitory factor in bladder urothelial cell carcinoma. Zhonghua Zhong Liu Za Zhi 33(1):28–31PubMed
72.
Bondza PK, Metz CN, Akoum A (2008) Macrophage migration inhibitory factor up-regulates alpha(v)beta(3) integrin and vascular endothelial growth factor expression in endometrial adenocarcinoma cell line Ishikawa. J Reprod Immunol 77(2):142–151CrossRefPubMed
73.
Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW (2011) Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother 60(10):1419–1430CrossRefPubMedPubMedCentral
74.
Zea AH, Rodriguez PC, Atkins MB et al (2005) Arginase producing suppressor myeloid cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 65(8):3044–3048PubMed
75.
Cohen NA, Stewart ML, Gavathiotis E et al (2012) A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. Chem Biol 19(9):1175–1186CrossRefPubMedPubMedCentral
76.
Gore Y, Starlets D, Maharshak N et al (2008) Macrophage migration inhibitory factor induces B cell survival by activation of a CD74-CD44 receptor complex. J Biol Chem 283(5):2784–2792CrossRefPubMed
77.
Mitchell RA (2004) Mechanisms and effectors of MIF-dependent promotion of tumourigenesis. Cell Signal 16(1):13–19CrossRefPubMed
78.
Tarnowski M, Grymula K, Liu R et al (2011) Macrophage migration inhibitory factor is secreted by rhabdomyosarcoma cells, modulates tumor metastasis by binding to CXCR4 and CXCR7 receptors and inhibits recruitment of cancer-associated fibroblasts.Mol. Cancer Res 8(10):1328–1343
79.
80.
Ichihara E, Kiura K, Tanimoto M (2011) Targeting angiogenesis in cancer therapy. Acta Med Okayama 65(6):353–362PubMed
81.
Veillat V, Carli C, Metz CN, Al-Abed Y, Naccache PH, Akoum A (2010) Macrophage migration inhibitory factor elicits an angiogenic phenotype in human ectopic endometrial cells and triggers the production of major angiogenic factors via CD44, CD74, and MAPK signaling pathways. J Clin Endocrinol Metab 95(12):e403–e412. doi:10.​1210/​jc.​2010-0417 CrossRefPubMed
82.
Funamizu N, Hu C, Lacy C et al (2013) Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma. Int J Cancer 132(4):785–794CrossRefPubMedPubMedCentral
83.
84.
McClelland M, Zhao L, Carskadon S, Arenberg D (2009) Expression of CD74, the receptor for macrophage migration inhibitory factor, in non-small cell lung cancer. Am J Pathol 174(2):638–646CrossRefPubMedPubMedCentral
85.
Richard V, Kindt N, Decaestecker C et al (2014) Involvement of macrophage migration inhibitory factor and its receptor (CD74) in human breast cancer. Oncol Rep 32(2):523–529PubMedPubMedCentral
86.
Dietlin TA, Hofman FM, Lund BT, Gilmore W, Stohlman SA, van der Veen RC (2007) Mycobacteria-induced Gr-1+ subsets from distinct myeloid lineages have opposite effects on T cell expansion. J Leukoc Biol 81(5):1205–1212CrossRefPubMed
87.
Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S (2007) Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67(9):4507–4513CrossRefPubMed
88.
Movahedi K, Guilliams M, Van Den Bossche J et al (2008) Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell suppressive activity. Blood 111(8):4233–4244CrossRefPubMed
89.
Gasser S, Orsulic S, Brown EJ, Raulet DH (2005) The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436(7054):1186–1190CrossRefPubMedPubMedCentral
90.
Mittelbronn M, Platten M, Zeiner P et al (2011) Macrophage migration inhibitory factor (MIF) expression in human malignant gliomas contributes to immune escape and tumour progression. Acta Neuropathol 122(3):353–365CrossRefPubMed
91.
Pende D, Rivera P, Marcenaro S et al (2002) Major histocompatibility complex class I-related chain a and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res 62(21):6178–6186PubMed
92.
93.
Wu S, Lian J, Tao H, Shang H, Zhang L (2011) Correlation of macrophage migration inhibitory factor gene polymorphism with the risk of early-stage cervical cancer and lymphatic metastasis. Oncol Lett 2(6):1261–1267PubMedPubMedCentral
Metadata
Title
Macrophage Migration Inhibitory Factor (MIF): Biological Activities and Relation with Cancer
Authors
Camila Cristina Guimarães Nobre
Josélio Maria Galvão de Araújo
Thales Allyrio Araújo de Medeiros Fernandes
Ricardo Ney Oliveira Cobucci
Daniel Carlos Ferreira Lanza
Vânia Sousa Andrade
José Veríssimo Fernandes
Publication date
01-04-2017
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 2/2017
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-016-0138-6

Other articles of this Issue 2/2017

Pathology & Oncology Research 2/2017 Go to the issue

Original Article

Relationships between Common and Novel Interleukin-6 Gene Polymorphisms and Risk of Cervical Cancer: a Case-Control Study

Original Article

Combined Analysis of ChIP Sequencing and Gene Expression Dataset in Breast Cancer

Letter to the Editor

Normothermic and Hyperthermic Intraperitoneal Chemoperfusions with Cisplatin to Treat Advanced Ovarian Cancer in Experimental Settings

Letter to the Editor

Platelets, Micro-Particles and Elastase. A Review with Extrapolation to the Mechanism of Generation and Bio-Pathology of Platelet Fragments

Short Communication

The General Expression Analysis of WTX Gene in Normal and Cancer Tissues

Original Article

Region Specific Differences of Claudin-5 Expression in Pediatric Intracranial Ependymomas: Potential Prognostic Role in Supratentorial Cases
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits