Tumor cell E-selectin ligands determine partialefficacy of bortezomib on spontaneous lung metastasis formation of solid human tumors in vivo.
CD44
E-selectin
MGAT5
bortezomib
endothelial adhesion
extravasation
lung metastasis
sialyl-Lewis A/X
solid tumor
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
06 04 2022
06 04 2022
Historique:
received:
21
10
2021
revised:
21
12
2021
accepted:
10
01
2022
pubmed:
16
1
2022
medline:
12
4
2022
entrez:
15
1
2022
Statut:
ppublish
Résumé
Extravasation of circulating tumor cells (CTCs) is critical for metastasis and is initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here, we show that the clinically approved proteasome inhibitor bortezomib (BZM; Velcade) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns. The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohistochemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and thus distant metastasis formation in malignancies expressing low-affinity E-selectin ligands.
Identifiants
pubmed: 35031433
pii: S1525-0016(22)00017-X
doi: 10.1016/j.ymthe.2022.01.017
pmc: PMC9077315
pii:
doi:
Substances chimiques
CA-19-9 Antigen
0
E-Selectin
0
Ligands
0
Oligosaccharides
0
Sialyl Lewis X Antigen
0
Bortezomib
69G8BD63PP
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1536-1552Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
Glycobiology. 2020 Aug 20;30(9):695-709
pubmed: 32103235
Molecules. 2018 Oct 30;23(11):
pubmed: 30380716
PLoS One. 2008 Mar 19;3(3):e1826
pubmed: 18350162
Oncotarget. 2015 May 10;6(13):11465-76
pubmed: 25888636
Cancer Res. 2005 Jul 1;65(13):5812-7
pubmed: 15994957
Cancer Cell. 2017 Sep 11;32(3):282-293
pubmed: 28898694
PLoS One. 2013 Jul 26;8(7):e70139
pubmed: 23922938
Clin Cancer Res. 2001 May;7(5):1419-28
pubmed: 11350913
N Engl J Med. 2004 Aug 19;351(8):781-91
pubmed: 15317891
Am J Physiol Lung Cell Mol Physiol. 2009 Jun;296(6):L1096-103
pubmed: 19304908
Histochem Cell Biol. 2011 May;135(5):499-512
pubmed: 21544708
Br J Cancer. 2010 Feb 2;102(3):602-9
pubmed: 20010946
Cell. 2017 Feb 9;168(4):670-691
pubmed: 28187288
PLoS One. 2013;8(1):e54959
pubmed: 23372803
Nat Cell Biol. 2014 Aug;16(8):717-27
pubmed: 25082194
Glycobiology. 2010 Feb;20(2):166-74
pubmed: 19846580
EMBO Mol Med. 2014 Nov 14;7(1):1-11
pubmed: 25398926
Br J Surg. 2003 Jul;90(7):882-8
pubmed: 12854118
Nat Rev Cancer. 2013 Dec;13(12):858-70
pubmed: 24263189
Gut. 2013 May;62(5):741-50
pubmed: 22490524
Clin Exp Metastasis. 1994 Nov;12(6):398-404
pubmed: 7923992
Oncogene. 2006 Oct 30;25(51):6680-4
pubmed: 17072321
Cell Commun Signal. 2008 Dec 04;6:10
pubmed: 19055814
PLoS One. 2014 Apr 03;9(4):e92327
pubmed: 24699516
Mol Oncol. 2017 Jan;11(1):40-61
pubmed: 28085223
Am J Physiol Cell Physiol. 2015 Jan 1;308(1):C68-78
pubmed: 25339657
Clin Cancer Res. 2017 Sep 15;23(18):5384-5393
pubmed: 28679772
Biochemistry. 1997 Oct 14;36(41):12412-20
pubmed: 9376344
J Hematol Oncol. 2018 May 10;11(1):64
pubmed: 29747682
Cancer Lett. 2012 Aug 1;321(1):89-99
pubmed: 22366582
Annu Rev Biomed Eng. 2008;10:39-57
pubmed: 18647111
Am J Physiol Cell Physiol. 2008 Sep;295(3):C701-7
pubmed: 18632734
Am J Pathol. 1996 Jan;148(1):165-75
pubmed: 8546203
Nat Rev Cancer. 2019 Oct;19(10):553-567
pubmed: 31455893
Front Biosci (Landmark Ed). 2011 Jun 01;16(9):3233-51
pubmed: 21622232
Clin Cancer Res. 1998 Feb;4(2):343-8
pubmed: 9516921
Cancer Manag Res. 2017 Mar 02;9:51-63
pubmed: 28280389
Blood. 2008 May 15;111(10):5205-14
pubmed: 18270324
Cancer Res. 2008 Mar 1;68(5):1443-50
pubmed: 18316608
Neoplasia. 2014 Nov 20;16(11):950-60
pubmed: 25425969
Cancer Res. 2004 Aug 15;64(16):5702-11
pubmed: 15313910
Clin Cancer Res. 2014 Apr 1;20(7):1791-802
pubmed: 24526735
J Immunol. 1996 Apr 1;156(7):2558-65
pubmed: 8786319
Cancer Lett. 2005 Jan 10;217(1):105-13
pubmed: 15596301
Front Cell Dev Biol. 2017 Mar 07;5:18
pubmed: 28326306
Br J Cancer. 2004 Jun 14;90(12):2312-6
pubmed: 15150588
Biochem Biophys Res Commun. 2011 Mar 18;406(3):423-9
pubmed: 21329670
Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3725-30
pubmed: 21321210
J Biol Chem. 1984 May 25;259(10):6253-60
pubmed: 6725252
Hepatogastroenterology. 1999 Mar-Apr;46(26):905-8
pubmed: 10370636