Skip to main content
Top
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

Lentinan inhibits tumor angiogenesis via interferon γ and in a T cell independent manner

Authors: Shengming Deng, Guoxi Zhang, Jiajie Kuai, Peng Fan, Xuexiang Wang, Pei Zhou, Dan Yang, Xichen Zheng, Xiaomei Liu, Qunli Wu, Yuhui Huang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

Login to get access

Abstract

Background

Antiangiogenic agents are commonly used in lung and colon cancer treatments, however, rapid development of drug resistance limits their efficacy.

Methods

Lentinan (LNT) is a biologically active compound extracted from Lentinus edodes. The effects of LNT on tumor angiogenesis were evaluated by immunohistochemistry in murine LAP0297 lung and CT26 colorectal tumor models. The impacts of LNT on immune cells and gene expression in tumor tissues were determined by flow cytometry, qPCR, and ELISA. Nude mice and IFNγ blockade were used to investigate the mechanism of LNT affecting on tumor angiogenesis. The data sets were compared using two-tailed student’s t tests or ANOVA.

Results

We found that LNT inhibited tumor angiogenesis and the growth of lung and colon cancers. LNT treatments elevated the expression of angiostatic factors such as IFNγ and also increased tumor infiltration of IFNγ-expressing T cells and myeloid cells. Interestingly, IFNγ blockade, but not T cell deficiency, reversed the effects of LNT treatments on tumor blood vessels. Moreover, long-lasting LNT administration persistently suppressed tumor angiogenesis and inhibited tumor growth.

Conclusions

LNT inhibits tumor angiogenesis by increasing IFNγ production and in a T cell-independent manner. Our findings suggest that LNT could be developed as a new antiangiogenic agent for long-term treatment of lung and colon cancers.
Appendix
Available only for authorised users
Literature
1.
go back to reference Huang Y, Carbone DP. Mechanisms of and strategies for overcoming resistance to anti-vascular endothelial growth factor therapy in non-small cell lung cancer. Biochim Biophys Acta. 2015;1855:193–201.PubMed Huang Y, Carbone DP. Mechanisms of and strategies for overcoming resistance to anti-vascular endothelial growth factor therapy in non-small cell lung cancer. Biochim Biophys Acta. 2015;1855:193–201.PubMed
2.
go back to reference Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRef Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRef
3.
go back to reference Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307.CrossRef Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307.CrossRef
4.
go back to reference Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.CrossRef Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.CrossRef
5.
go back to reference Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.CrossRef Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.CrossRef
6.
go back to reference Park JS, Kim IK, Han S, Park I, Kim C, Bae J, Oh SJ, Lee S, Kim JH, Woo DC, He Y, Augustin HG, Kim I, Lee D, Koh GY. Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell. 2017;31:157–8.CrossRef Park JS, Kim IK, Han S, Park I, Kim C, Bae J, Oh SJ, Lee S, Kim JH, Woo DC, He Y, Augustin HG, Kim I, Lee D, Koh GY. Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell. 2017;31:157–8.CrossRef
7.
go back to reference Janne PA, Gray N, Settleman J. Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov. 2009;8:709–23.CrossRef Janne PA, Gray N, Settleman J. Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov. 2009;8:709–23.CrossRef
8.
go back to reference Beatty G, Paterson Y. IFN-gamma-dependent inhibition of tumor angiogenesis by tumor-infiltrating CD4+ T cells requires tumor responsiveness to IFN-gamma. J Immunol. 2001;166:2276–82.CrossRef Beatty G, Paterson Y. IFN-gamma-dependent inhibition of tumor angiogenesis by tumor-infiltrating CD4+ T cells requires tumor responsiveness to IFN-gamma. J Immunol. 2001;166:2276–82.CrossRef
9.
go back to reference Hayakawa Y, Takeda K, Yagita H, Smyth MJ, Van Kaer L, Okumura K, Saiki I. IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide. Blood. 2002;100:1728–33.PubMed Hayakawa Y, Takeda K, Yagita H, Smyth MJ, Van Kaer L, Okumura K, Saiki I. IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide. Blood. 2002;100:1728–33.PubMed
10.
go back to reference Kammertoens T, Friese C, Arina A, Idel C, Briesemeister D, Rothe M, Ivanov A, Szymborska A, Patone G, Kunz S, Sommermeyer D, Engels B, Leisegang M, Textor A, Fehling HJ, Fruttiger M, Lohoff M, Herrmann A, Yu H, Weichselbaum R, Uckert W, Hübner N, Gerhardt H, Beule D, Schreiber H, Blankenstein T. Tumour ischaemia by interferon-gamma resembles physiological blood vessel regression. Nature. 2017;545:98–102.CrossRef Kammertoens T, Friese C, Arina A, Idel C, Briesemeister D, Rothe M, Ivanov A, Szymborska A, Patone G, Kunz S, Sommermeyer D, Engels B, Leisegang M, Textor A, Fehling HJ, Fruttiger M, Lohoff M, Herrmann A, Yu H, Weichselbaum R, Uckert W, Hübner N, Gerhardt H, Beule D, Schreiber H, Blankenstein T. Tumour ischaemia by interferon-gamma resembles physiological blood vessel regression. Nature. 2017;545:98–102.CrossRef
11.
go back to reference Tian L, Goldstein A, Wang H, Ching Lo H, Sun Kim I, Welte T, Sheng K, Dobrolecki LE, Zhang X, Putluri N, Phung TL, Mani SA, Stossi F, Sreekumar A, Mancini MA, Decker WK, Zong C, Lewis MT, Zhang XH. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature. 2017;544:250–4.CrossRef Tian L, Goldstein A, Wang H, Ching Lo H, Sun Kim I, Welte T, Sheng K, Dobrolecki LE, Zhang X, Putluri N, Phung TL, Mani SA, Stossi F, Sreekumar A, Mancini MA, Decker WK, Zong C, Lewis MT, Zhang XH. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature. 2017;544:250–4.CrossRef
12.
go back to reference Huang Y, Kim BYS, Chan CK, Hahn SM, Weissman IL, Jiang W. Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol. 2018;18(3):195–203.CrossRef Huang Y, Kim BYS, Chan CK, Hahn SM, Weissman IL, Jiang W. Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol. 2018;18(3):195–203.CrossRef
13.
go back to reference Matsuoka H, Seo Y, Wakasugi H, Saito T, Tomoda H. Lentinan potentiates immunity and prolongs the survival time of some patients. Anticancer Res. 1997;17:2751–5.PubMed Matsuoka H, Seo Y, Wakasugi H, Saito T, Tomoda H. Lentinan potentiates immunity and prolongs the survival time of some patients. Anticancer Res. 1997;17:2751–5.PubMed
14.
go back to reference Ina K, Kataoka T, Ando T. The use of lentinan for treating gastric cancer. Anti Cancer Agents Med Chem. 2013;13:681–8.CrossRef Ina K, Kataoka T, Ando T. The use of lentinan for treating gastric cancer. Anti Cancer Agents Med Chem. 2013;13:681–8.CrossRef
15.
go back to reference Xu X, Yan H, Tang J, Chen J, Zhang X. Polysaccharides in Lentinus edodes: isolation, structure, immunomodulating activity and future prospective. Crit Rev Food Sci Nutr. 2014;54:474–87.CrossRef Xu X, Yan H, Tang J, Chen J, Zhang X. Polysaccharides in Lentinus edodes: isolation, structure, immunomodulating activity and future prospective. Crit Rev Food Sci Nutr. 2014;54:474–87.CrossRef
16.
go back to reference Ren L, Perera C, Hemar Y. Antitumor activity of mushroom polysaccharides: a review. Food Funct. 2012;3:1118–30.CrossRef Ren L, Perera C, Hemar Y. Antitumor activity of mushroom polysaccharides: a review. Food Funct. 2012;3:1118–30.CrossRef
17.
go back to reference Suga T, Shiio T, Maeda YY, Chihara G. Antitumor activity of lentinan in murine syngeneic and autochthonous hosts and its suppressive effect on 3-methylcholanthrene-induced carcinogenesis. Cancer Res. 1984;44:5132–7.PubMed Suga T, Shiio T, Maeda YY, Chihara G. Antitumor activity of lentinan in murine syngeneic and autochthonous hosts and its suppressive effect on 3-methylcholanthrene-induced carcinogenesis. Cancer Res. 1984;44:5132–7.PubMed
18.
go back to reference Zhou LD, Zhang QH, Zhang Y, Liu J, Cao YM. The shiitake mushroom-derived immuno-stimulant lentinan protects against murine malaria blood-stage infection by evoking adaptive immune-responses. Int Immunopharmacol. 2009;9:455–62.CrossRef Zhou LD, Zhang QH, Zhang Y, Liu J, Cao YM. The shiitake mushroom-derived immuno-stimulant lentinan protects against murine malaria blood-stage infection by evoking adaptive immune-responses. Int Immunopharmacol. 2009;9:455–62.CrossRef
19.
go back to reference Israilides C, Kletsas D, Arapoglou D, Philippoussis A, Pratsinis H, Ebringerova A, Hribalova V, Harding SE. In vitro cytostatic and immunomodulatory properties of the medicinal mushroom Lentinula edodes. Phytomedicine. 2008;15:512–9.CrossRef Israilides C, Kletsas D, Arapoglou D, Philippoussis A, Pratsinis H, Ebringerova A, Hribalova V, Harding SE. In vitro cytostatic and immunomodulatory properties of the medicinal mushroom Lentinula edodes. Phytomedicine. 2008;15:512–9.CrossRef
20.
go back to reference Sano B, Sugiyama Y, Kunieda K, Sano J, Saji S. Antitumor effects induced by the combination of TNP-470 as an angiogenesis inhibitor and lentinan as a biological response modifier in a rabbit spontaneous liver metastasis model. Surg Today. 2002;32:503–9.CrossRef Sano B, Sugiyama Y, Kunieda K, Sano J, Saji S. Antitumor effects induced by the combination of TNP-470 as an angiogenesis inhibitor and lentinan as a biological response modifier in a rabbit spontaneous liver metastasis model. Surg Today. 2002;32:503–9.CrossRef
21.
go back to reference Huang P, Duda DG, Jain RK, Fukumura D. Histopathologic findings and establishment of novel tumor lines from spontaneous tumors in FVB/N mice. Comp Med. 2008;58:253–63.PubMedPubMedCentral Huang P, Duda DG, Jain RK, Fukumura D. Histopathologic findings and establishment of novel tumor lines from spontaneous tumors in FVB/N mice. Comp Med. 2008;58:253–63.PubMedPubMedCentral
22.
go back to reference Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, Martin MR, Vianello F, Vianello F, Leblanc P, Munn LL, Huang P, Duda DG, Fukumura D, Jain RK, Poznansky MC. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012;109:17561–6.CrossRef Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, Martin MR, Vianello F, Vianello F, Leblanc P, Munn LL, Huang P, Duda DG, Fukumura D, Jain RK, Poznansky MC. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012;109:17561–6.CrossRef
23.
go back to reference Bodnar RJ, Yates CC, Wells A. IP-10 blocks vascular endothelial growth factor-induced endothelial cell motility and tube formation via inhibition of calpain. Circ Res. 2006;98:617–25.CrossRef Bodnar RJ, Yates CC, Wells A. IP-10 blocks vascular endothelial growth factor-induced endothelial cell motility and tube formation via inhibition of calpain. Circ Res. 2006;98:617–25.CrossRef
24.
go back to reference Wang D, Wang H, Brown J, Daikoku T, Ning W, Shi Q, Richmond A, Strieter R, Dey SK, DuBois RN. CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. J Exp Med. 2006;203:941–51.CrossRef Wang D, Wang H, Brown J, Daikoku T, Ning W, Shi Q, Richmond A, Strieter R, Dey SK, DuBois RN. CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. J Exp Med. 2006;203:941–51.CrossRef
25.
go back to reference Huang Y, Lin L, Shanker A, Malhotra A, Yang L, Dikov MM, Carbone DP. Resuscitating cancer immunosurveillance: selective stimulation of DLL1-notch signaling in T cells rescues T-cell function and inhibits tumor growth. Cancer Res. 2011;71:6122–31.CrossRef Huang Y, Lin L, Shanker A, Malhotra A, Yang L, Dikov MM, Carbone DP. Resuscitating cancer immunosurveillance: selective stimulation of DLL1-notch signaling in T cells rescues T-cell function and inhibits tumor growth. Cancer Res. 2011;71:6122–31.CrossRef
26.
go back to reference Higashi D, Seki K, Ishibashi Y, Egawa Y, Koga M, Sasaki T, Hirano K, Mikami K, Futami K, Maekawa T, Sudo M. The effect of lentinan combination therapy for unresectable advanced gastric cancer. Anticancer Res. 2012;32:2365–8.PubMed Higashi D, Seki K, Ishibashi Y, Egawa Y, Koga M, Sasaki T, Hirano K, Mikami K, Futami K, Maekawa T, Sudo M. The effect of lentinan combination therapy for unresectable advanced gastric cancer. Anticancer Res. 2012;32:2365–8.PubMed
27.
go back to reference Yoshino S, Nishikawa K, Morita S, Takahashi T, Sakata K, Nagao J, Nemoto H, Murakami N, Matsuda T, Hasegawa H, Shimizu R, Yoshikawa T, Osanai H, Imano M, Naitoh H, Tanaka A, Tajiri T, Gochi A, Suzuki M, Sakamoto J, Saji S, Oka M. Randomised phase III study of S-1 alone versus S-1 plus lentinan for unresectable or recurrent gastric cancer (JFMC36-0701). Eur J Cancer. 2016;65:164–71.CrossRef Yoshino S, Nishikawa K, Morita S, Takahashi T, Sakata K, Nagao J, Nemoto H, Murakami N, Matsuda T, Hasegawa H, Shimizu R, Yoshikawa T, Osanai H, Imano M, Naitoh H, Tanaka A, Tajiri T, Gochi A, Suzuki M, Sakamoto J, Saji S, Oka M. Randomised phase III study of S-1 alone versus S-1 plus lentinan for unresectable or recurrent gastric cancer (JFMC36-0701). Eur J Cancer. 2016;65:164–71.CrossRef
28.
go back to reference Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 2013;73:2943–8.CrossRef Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 2013;73:2943–8.CrossRef
29.
go back to reference Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26:605–22.CrossRef Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26:605–22.CrossRef
30.
go back to reference Wang J, Li W, Huang X, Liu Y, Li Q, Zheng Z, Wang K. A polysaccharide from Lentinus edodes inhibits human colon cancer cell proliferation and suppresses tumor growth in athymic nude mice. Oncotarget. 2017;8:610–23.CrossRef Wang J, Li W, Huang X, Liu Y, Li Q, Zheng Z, Wang K. A polysaccharide from Lentinus edodes inhibits human colon cancer cell proliferation and suppresses tumor growth in athymic nude mice. Oncotarget. 2017;8:610–23.CrossRef
31.
go back to reference Oba K, Kobayashi M, Matsui T, Kodera Y, Sakamoto J. Individual patient based meta-analysis of lentinan for unresectable/recurrent gastric cancer. Anticancer Res. 2009;29:2739–45.PubMed Oba K, Kobayashi M, Matsui T, Kodera Y, Sakamoto J. Individual patient based meta-analysis of lentinan for unresectable/recurrent gastric cancer. Anticancer Res. 2009;29:2739–45.PubMed
32.
go back to reference Chihara G, Maeda Y, Hamuro J, Sasaki T, Fukuoka F. Inhibition of mouse sarcoma 180 by polysaccharides from Lentinus edodes (Berk.) sing. Nature. 1969;222:687–8.CrossRef Chihara G, Maeda Y, Hamuro J, Sasaki T, Fukuoka F. Inhibition of mouse sarcoma 180 by polysaccharides from Lentinus edodes (Berk.) sing. Nature. 1969;222:687–8.CrossRef
33.
go back to reference Fujimoto K, Tomonaga M, Goto S. A case of recurrent ovarian cancer successfully treated with adoptive immunotherapy and lentinan. Anticancer Res. 2006;26:4015–8.PubMed Fujimoto K, Tomonaga M, Goto S. A case of recurrent ovarian cancer successfully treated with adoptive immunotherapy and lentinan. Anticancer Res. 2006;26:4015–8.PubMed
34.
go back to reference Hamuro J. Anticancer immunotherapy with perorally effective lentinan. Gan To Kagaku Ryoho. 2005;32:1209–15.PubMed Hamuro J. Anticancer immunotherapy with perorally effective lentinan. Gan To Kagaku Ryoho. 2005;32:1209–15.PubMed
35.
go back to reference Zhang L, Ji Q, Ni ZH, Sun J. Prohibitin induces apoptosis in BGC823 gastric cancer cells through the mitochondrial pathway. Asian Pac J Cancer Prev. 2012;13:3803–7.CrossRef Zhang L, Ji Q, Ni ZH, Sun J. Prohibitin induces apoptosis in BGC823 gastric cancer cells through the mitochondrial pathway. Asian Pac J Cancer Prev. 2012;13:3803–7.CrossRef
36.
go back to reference Zheng X, Fang Z, Liu X, Deng S, Zhou P, Wang X, Zhang C, Yin R, Hu H, Chen X, , Han Y, Zhao Y, Lin SH, Qin S, Wang X, Kim BY, Zhou P, Jiang W, Wu Q, Huang Y: Increased vessel perfusion predicts the efficacy of immune checkpoint blockade. J Clin Invest 2018, 128:2104–2115.CrossRef Zheng X, Fang Z, Liu X, Deng S, Zhou P, Wang X, Zhang C, Yin R, Hu H, Chen X, , Han Y, Zhao Y, Lin SH, Qin S, Wang X, Kim BY, Zhou P, Jiang W, Wu Q, Huang Y: Increased vessel perfusion predicts the efficacy of immune checkpoint blockade. J Clin Invest 2018, 128:2104–2115.CrossRef
37.
go back to reference Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J, Snuderl M, Ancukiewicz M, Polaskova P, Pinho MC, Jennings D, Plotkin SR, Chi AS, Eichler AF, Dietrich J, Hochberg FH, Lu-Emerson C, Iafrate AJ, Ivy SP, Rosen BR, Loeffler JS, Wen PY, Sorensen AG, Jain RK. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A. 2013;110:19059–64.CrossRef Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J, Snuderl M, Ancukiewicz M, Polaskova P, Pinho MC, Jennings D, Plotkin SR, Chi AS, Eichler AF, Dietrich J, Hochberg FH, Lu-Emerson C, Iafrate AJ, Ivy SP, Rosen BR, Loeffler JS, Wen PY, Sorensen AG, Jain RK. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A. 2013;110:19059–64.CrossRef
38.
go back to reference Emblem KE, Mouridsen K, Bjornerud A, Farrar CT, Jennings D, Borra RJ, Wen PY, Ivy P, Batchelor TT, Rosen BR, Jain RK, Sorensen AG. Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat Med. 2013;19:1178–83.CrossRef Emblem KE, Mouridsen K, Bjornerud A, Farrar CT, Jennings D, Borra RJ, Wen PY, Ivy P, Batchelor TT, Rosen BR, Jain RK, Sorensen AG. Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat Med. 2013;19:1178–83.CrossRef
39.
go back to reference Gu YH, Belury MA. Selective induction of apoptosis in murine skin carcinoma cells (CH72) by an ethanol extract of Lentinula edodes. Cancer Lett. 2005;220:21–8.CrossRef Gu YH, Belury MA. Selective induction of apoptosis in murine skin carcinoma cells (CH72) by an ethanol extract of Lentinula edodes. Cancer Lett. 2005;220:21–8.CrossRef
Metadata
Title
Lentinan inhibits tumor angiogenesis via interferon γ and in a T cell independent manner
Authors
Shengming Deng
Guoxi Zhang
Jiajie Kuai
Peng Fan
Xuexiang Wang
Pei Zhou
Dan Yang
Xichen Zheng
Xiaomei Liu
Qunli Wu
Yuhui Huang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0932-y

Other articles of this Issue 1/2018

Journal of Experimental & Clinical Cancer Research 1/2018 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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