Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Targeting CD47 Inhibits Tumor Development and Increases Phagocytosis in Oral Squamous Cell Carcinoma

Author(s): Xiao-Jing Ye, Jian-Guang Yang, Ya-Qin Tan, Xiao-Jie Chen and Gang Zhou*

Volume 21, Issue 6, 2021

Published on: 30 July, 2020

Page: [766 - 774] Pages: 9

DOI: 10.2174/1871520620999200730162915

Price: $65

Abstract

Background: Our previous work demonstrated upregulated CD47 in Oral Squamous Cell Carcinoma (OSCC).

Objective: In the present study, we aimed to investigate the effects of CD47 on tumor cell development and phagocytosis in OSCC and elucidate the underlying mechanisms.

Methods: The proliferation, apoptosis, migration, and invasion of oral cancer cells were analyzed after knocking down the expression of CD47. The effects of CD47 on tumor development were also evaluated using a murine model of OSCC. The involvement of CD47 in the phagocytosis of oral cancer cells was identified.

Results: Cell proliferation was suppressed by knocking down the expression of CD47 in human OSCC cell line Cal-27 cells but there was no change in the apoptosis rate. Moreover, impaired expression of CD47 inhibited the migration and invasion of Cal-27 cells. Furthermore, we found that nude mice injected with CD47 knockeddown Cal-27 cells displayed decreased tumor volumes at week 9 compared to xenograft transplantations of blank Cal-27 cells. In addition, in vitro phagocytosis of Cal-27 cells by macrophages was significantly enhanced after the knockdown of CD47, which positively correlated with compromised STAT3/JAK2 signaling.

Conclusion: In summary, the knockdown of CD47 downregulated the development of OSCC and increased the phagocytosis of Cal-27 cells, indicating that CD47 might be a promising therapeutic target.

Keywords: Cell proliferation, macrophage, xenograft transplantations, CD47, STAT3/JAK2 signaling, tumor development.

« Previous Next »
Graphical Abstract

[1]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[2]
Thompson, L. World Health Organization classification of tumours: Pathology and genetics of head and neck tumours. Ear Nose Throat J., 2006, 85(2), 74.
[http://dx.doi.org/10.1177/014556130608500201] [PMID: 16579185]
[3]
Sick, E.; Jeanne, A.; Schneider, C.; Dedieu, S.; Takeda, K.; Martiny, L. CD47 update: A multifaceted actor in the tumour microenvironment of potential therapeutic interest. Br. J. Pharmacol., 2012, 167(7), 1415-1430.
[http://dx.doi.org/10.1111/j.1476-5381.2012.02099.x] [PMID: 22774848]
[4]
Barclay, A.N.; Van den Berg, T.K. The interaction between Signal Regulatory Protein alpha (SIRPα) and CD47: Structure, function, and therapeutic target. Annu. Rev. Immunol., 2014, 32, 25-50.
[http://dx.doi.org/10.1146/annurev-immunol-032713-120142] [PMID: 24215318]
[5]
Sosale, N.G.; Spinler, K.R.; Alvey, C.; Discher, D.E. Macrophage engulfment of a cell or nanoparticle is regulated by unavoidable opsonization, a species-specific ‘Marker of Self’ CD47, and target physical properties. Curr. Opin. Immunol., 2015, 35, 107-112.
[http://dx.doi.org/10.1016/j.coi.2015.06.013] [PMID: 26172292]
[6]
Willingham, S.B.; Volkmer, J.P.; Gentles, A.J.; Sahoo, D.; Dalerba, P.; Mitra, S.S.; Wang, J.; Contreras-Trujillo, H.; Martin, R.; Cohen, J.D.; Lovelace, P.; Scheeren, F.A.; Chao, M.P.; Weiskopf, K.; Tang, C.; Volkmer, A.K.; Naik, T.J.; Storm, T.A.; Mosley, A.R.; Edris, B.; Schmid, S.M.; Sun, C.K.; Chua, M.S.; Murillo, O.; Rajendran, P.; Cha, A.C.; Chin, R.K.; Kim, D.; Adorno, M.; Raveh, T.; Tseng, D.; Jaiswal, S.; Enger, P.O.; Steinberg, G.K.; Li, G.; So, S.K.; Majeti, R.; Harsh, G.R.; van de Rijn, M.; Teng, N.N.; Sunwoo, J.B.; Alizadeh, A.A.; Clarke, M.F.; Weissman, I.L. The CD47-Signal Regulatory Protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc. Natl. Acad. Sci. USA, 2012, 109(17), 6662-6667.
[http://dx.doi.org/10.1073/pnas.1121623109] [PMID: 22451913]
[7]
Yoshida, K.; Tsujimoto, H.; Matsumura, K.; Kinoshita, M.; Takahata, R.; Matsumoto, Y.; Hiraki, S.; Ono, S.; Seki, S.; Yamamoto, J.; Hase, K. CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer. Cancer Med., 2015, 4(9), 1322-1333.
[http://dx.doi.org/10.1002/cam4.478] [PMID: 26077800]
[8]
Pan, Y.; Volkmer, J.P.; Mach, K.E.; Rouse, R.V.; Liu, J.J.; Sahoo, D.; Chang, T.C.; Metzner, T.J.; Kang, L.; van de Rijn, M.; Skinner, E.C.; Gambhir, S.S.; Weissman, I.L.; Liao, J.C. Endoscopic molecular imaging of human bladder cancer using a CD47 antibody. Sci. Transl. Med., 2014, 6(260)260ra148
[http://dx.doi.org/10.1126/scitranslmed.3009457] [PMID: 25355698]
[9]
Amoyel, M.; Anderson, A.M.; Bach, E.A. JAK/STAT pathway dysregulation in tumors: A Drosophila perspective. Semin. Cell Dev. Biol., 2014, 28, 96-103.
[http://dx.doi.org/10.1016/j.semcdb.2014.03.023] [PMID: 24685611]
[10]
Geiger, J.L.; Grandis, J.R.; Bauman, J.E. The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations. Oral Oncol., 2016, 56, 84-92.
[http://dx.doi.org/10.1016/j.oraloncology.2015.11.022] [PMID: 26733183]
[11]
Banerjee, K.; Resat, H. Constitutive activation of STAT3 in breast cancer cells: A review. Int. J. Cancer, 2016, 138(11), 2570-2578.
[http://dx.doi.org/10.1002/ijc.29923] [PMID: 26559373]
[12]
Dutta, P.; Sabri, N.; Li, J.; Li, W.X. Role of STAT3 in lung cancer. JAK-STAT, 2015, 3(4)e999503
[http://dx.doi.org/10.1080/21623996.2014.999503] [PMID: 26413424]
[13]
Lai, S.Y.; Johnson, F.M. Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: Implications for future therapeutic approaches. Drug Resist. Updat., 2010, 13(3), 67-78.
[http://dx.doi.org/10.1016/j.drup.2010.04.001] [PMID: 20471303]
[14]
Kowshik, J.; Baba, A.B.; Giri, H.; Deepak Reddy, G.; Dixit, M.; Nagini, S. Astaxanthin inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis in a hamster model of oral cancer. PLoS One, 2014, 9(10)e109114
[http://dx.doi.org/10.1371/journal.pone.0109114] [PMID: 25296162]
[15]
Toledano, N.; Gur-Wahnon, D.; Ben-Yehuda, A.; Rachmilewitz, J. Novel CD47: SIRPα dependent mechanism for the activation of STAT3 in antigen-presenting cell. PLoS One, 2013, 8(9)e75595
[http://dx.doi.org/10.1371/journal.pone.0075595] [PMID: 24073274]
[16]
Ye, X.; Wang, X.; Lu, R.; Zhang, J.; Chen, X.; Zhou, G. CD47 as a potential prognostic marker for oral leukoplakia and oral squamous cell carcinoma. Oncol. Lett., 2018, 15(6), 9075-9080.
[http://dx.doi.org/10.3892/ol.2018.8520] [PMID: 29805639]
[17]
Soto-Pantoja, D.R.; Stein, E.V.; Rogers, N.M.; Sharifi-Sanjani, M.; Isenberg, J.S.; Roberts, D.D. Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47. Expert Opin. Ther. Targets, 2013, 17(1), 89-103.
[http://dx.doi.org/10.1517/14728222.2013.733699] [PMID: 23101472]
[18]
Harrington, M. Blocking CD47 to stop tumor growth. Lab Anim. (NY), 2012, 41(5), 111.
[http://dx.doi.org/10.1038/laban0512-111b] [PMID: 22517079]
[19]
Kim, M.J.; Lee, J.C.; Lee, J.J.; Kim, S.; Lee, S.G.; Park, S.W.; Sung, M.W.; Heo, D.S. Association of CD47 with natural killer cell-mediated cytotoxicity of head-and-neck squamous cell carcinoma lines. Tumour Biol., 2008, 29(1), 28-34.
[http://dx.doi.org/10.1159/000132568] [PMID: 18497546]
[20]
Chan, K.S.; Espinosa, I.; Chao, M.; Wong, D.; Ailles, L.; Diehn, M.; Gill, H.; Presti, J., Jr; Chang, H.Y.; van de Rijn, M.; Shortliffe, L.; Weissman, I.L. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc. Natl. Acad. Sci. USA, 2009, 106(33), 14016-14021.
[http://dx.doi.org/10.1073/pnas.0906549106] [PMID: 19666525]
[21]
Sick, E.; Boukhari, A.; Deramaudt, T.; Rondé, P.; Bucher, B.; André, P.; Gies, J.P.; Takeda, K. Activation of CD47 receptors causes proliferation of human astrocytoma but not normal astrocytes via an Akt-dependent pathway. Glia, 2011, 59(2), 308-319.
[http://dx.doi.org/10.1002/glia.21102] [PMID: 21125662]
[22]
Hatherley, D.; Lea, S.M.; Johnson, S.; Barclay, A.N. Polymorphisms in the human inhibitory signal-regulatory protein α do not affect binding to its ligand CD47. J. Biol. Chem., 2014, 289(14), 10024-10028.http://www.jbc.org/cgi/doi/10.1074/jbc.M114.550558
[http://dx.doi.org/10.1074/jbc.M114.550558] [PMID: 24550402]
[23]
Kim, D.; Wang, J.; Willingham, S.B.; Martin, R.; Wernig, G.; Weissman, I.L. Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells. Leukemia, 2012, 26(12), 2538-2545.
[http://dx.doi.org/10.1038/leu.2012.141] [PMID: 22648449]
[24]
Oldenborg, P.A. CD47: A cell surface glycoprotein which regulates multiple functions of hematopoietic cells in health and disease. ISRN Hematol., 2013, 2013614619
[http://dx.doi.org/10.1155/2013/614619] [PMID: 23401787]
[25]
Lv, Z.; Bian, Z.; Shi, L.; Niu, S.; Ha, B.; Tremblay, A.; Li, L.; Zhang, X.; Paluszynski, J.; Liu, M.; Zen, K.; Liu, Y. Loss of cell surface CD47 clustering formation and binding avidity to SIRPα facilitate apoptotic cell clearance by macrophages. J. Immunol., 2015, 195(2), 661-671.
[http://dx.doi.org/10.4049/jimmunol.1401719] [PMID: 26085683]
[26]
Uno, S.; Kinoshita, Y.; Azuma, Y.; Tsunenari, T.; Yoshimura, Y.; Iida, S.; Kikuchi, Y.; Yamada-Okabe, H.; Fukushima, N. Antitumor activity of a monoclonal antibody against CD47 in xenograft models of human leukemia. Oncol. Rep., 2007, 17(5), 1189-1194.
[http://dx.doi.org/10.3892/or.17.5.1189] [PMID: 17390064]
[27]
Mateo, V.; Lagneaux, L.; Bron, D.; Biron, G.; Armant, M.; Delespesse, G.; Sarfati, M. CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia. Nat. Med., 1999, 5(11), 1277-1284.
[http://dx.doi.org/10.1038/15233] [PMID: 10545994]
[28]
Rivera, A.; Fu, X.; Tao, L.; Zhang, X. Expression of mouse CD47 on human cancer cells profoundly increases tumor metastasis in murine models. BMC Cancer, 2015, 15, 964.
[http://dx.doi.org/10.1186/s12885-015-1980-8] [PMID: 26674012]
[29]
Wang, Y.; Xu, Z.; Guo, S.; Zhang, L.; Sharma, A.; Robertson, G.P.; Huang, L. Intravenous delivery of siRNA targeting CD47 effectively inhibits melanoma tumor growth and lung metastasis. Mol. Ther., 2013, 21(10), 1919-1929.
[http://dx.doi.org/10.1038/mt.2013.135] [PMID: 23774794]
[30]
Tan, M.; Zhu, L.; Zhuang, H.; Hao, Y.; Gao, S.; Liu, S.; Liu, Q.; Liu, D.; Liu, J.; Lin, B. Lewis Y antigen modified CD47 is an independent risk factor for poor prognosis and promotes early ovarian cancer metastasis. Am. J. Cancer Res., 2015, 5(9), 2777-2787.
[PMID: 26609483]
[31]
Zhang, Y.; Sime, W.; Juhas, M.; Sjölander, A. Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration. Eur. J. Cancer, 2013, 49(15), 3320-3334.
[http://dx.doi.org/10.1016/j.ejca.2013.06.005] [PMID: 23810249]
[32]
Chao, M.P.; Tang, C.; Pachynski, R.K.; Chin, R.; Majeti, R.; Weissman, I.L. Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy. Blood, 2011, 118(18), 4890-4901.
[http://dx.doi.org/10.1182/blood-2011-02-338020] [PMID: 21828138]
[33]
Lo, J.; Lau, E.Y.; So, F.T.; Lu, P.; Chan, V.S.; Cheung, V.C.; Ching, R.H.; Cheng, B.Y.; Ma, M.K.; Ng, I.O.; Lee, T.K. Anti-CD47 antibody suppresses tumour growth and augments the effect of chemotherapy treatment in hepatocellular carcinoma. Liver Int., 2016, 36(5), 737-745.
[http://dx.doi.org/10.1111/liv.12963] [PMID: 26351778]
[34]
Xiao, Z.; Chung, H.; Banan, B.; Manning, P.T.; Ott, K.C.; Lin, S.; Capoccia, B.J.; Subramanian, V.; Hiebsch, R.R.; Upadhya, G.A.; Mohanakumar, T.; Frazier, W.A.; Lin, Y.; Chapman, W.C. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett., 2015, 360(2), 302-309.
[http://dx.doi.org/10.1016/j.canlet.2015.02.036] [PMID: 25721088]
[35]
Ye, X.; Zhang, J.; Lu, R.; Zhou, G. Signal regulatory protein α associated with the progression of oral leukoplakia and oral squamous cell carcinoma regulates phenotype switch of macrophages. Oncotarget, 2016, 7(49), 81305-81321.
[http://dx.doi.org/10.18632/oncotarget.12874] [PMID: 27793032]
[36]
Wang, T.; Niu, G.; Kortylewski, M.; Burdelya, L.; Shain, K.; Zhang, S.; Bhattacharya, R.; Gabrilovich, D.; Heller, R.; Coppola, D.; Dalton, W.; Jove, R.; Pardoll, D.; Yu, H. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat. Med., 2004, 10(1), 48-54.
[http://dx.doi.org/10.1038/nm976] [PMID: 14702634]
[37]
Mali, S.B. Review of STAT3 (Signal Transducers and Activators of Transcription) in head and neck cancer. Oral Oncol., 2015, 51(6), 565-569.
[http://dx.doi.org/10.1016/j.oraloncology.2015.03.004] [PMID: 25817923]
[38]
Ferguson, S.D.; Srinivasan, V.M.; Heimberger, A.B. The role of STAT3 in tumor-mediated immune suppression. J. Neurooncol., 2015, 123(3), 385-394.
[http://dx.doi.org/10.1007/s11060-015-1731-3] [PMID: 25700834]
[39]
Komohara, Y.; Horlad, H.; Ohnishi, K.; Ohta, K.; Makino, K.; Hondo, H.; Yamanaka, R.; Kajiwara, K.; Saito, T.; Kuratsu, J.; Takeya, M. M2 macrophage/microglial cells induce activation of Stat3 in primary central nervous system lymphoma. J. Clin. Exp. Hematop., 2011, 51(2), 93-99.
[http://dx.doi.org/10.3960/jslrt.51.93] [PMID: 22104307]

Rights & Permissions Print Cite
Article Metrics
39
1
© 2024 Bentham Science Publishers | Privacy Policy