Co-expression of TIMP-1 and Its Cell Surface Binding Partner CD63 in Glioblastomas

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2018 Mar 11

PMID 29523123

Citations 21

Authors

Charlotte Aaberg-Jessen

Mia D Sorensen

Ana L S A Matos

Jose M Moreira

Nils Brunner

Arnon Knudsen

Bjarne W Kristensen

Affiliations

Soon will be listed here.

Abstract

Background: We have previously identified tissue inhibitor of metalloproteinases-1 (TIMP-1) as a prognostic marker in glioblastomas. TIMP-1 has been associated with chemotherapy resistance, and CD63, a known TIMP-1-binding protein, has been suggested to be responsible for this effect. The aim of this study was to assess CD63 expression in astrocytomas focusing on the prognostic potential of CD63 alone and in combination with TIMP-1.

Methods: CD63 expression was investigated immunohistochemically in a cohort of 111 astrocytomas and correlated to tumor grade and overall survival by semi-quantitative scoring. CD63 expression in tumor-associated microglia/macrophages was examined by double-immunofluorescence with ionized calcium-binding adapter molecule 1 (Iba1). The association between CD63 and TIMP-1 was investigated using previously obtained TIMP-1 data from our astrocytoma cohort. Cellular co-expression of TIMP-1 and CD63 as well as TIMP-1 and the tumor stem cell-related markers CD133 and Sox2 was investigated with immunofluorescence. TIMP-1 and CD63 protein interaction was detected by an oligonucleotide-based proximity ligation assay and verified using co-immunoprecipitation.

Results: The expression of CD63 was widely distributed in astrocytomas with a significantly increased level in glioblastomas. CD63 levels did not significantly correlate with patient survival at a protein level, and CD63 did not augment the prognostic significance of TIMP-1. Up to 38% of the CD63+ cells expressed Iba1; however, Iba1 did not appear to impact the prognostic value of CD63. A significant correlation was found between TIMP-1 and CD63, and the TIMP-1 and CD63 proteins were co-expressed at the cellular level and located in close molecular proximity, suggesting that TIMP-1 and CD63 could be co-players in glioblastomas. Some TIMP-1+ cells expressed CD133 and Sox2.

Conclusion: The present study suggests that CD63 is highly expressed in glioblastomas and that TIMP-1 and CD63 interact. CD63 does not add to the prognostic value of TIMP-1. Co-expression of TIMP-1 and stem cell markers as well as the wide expression of CD63 might suggest a role for TIMP-1 and CD63 in glioblastoma stemness.

Citing Articles

Tissue Inhibitor of Metalloproteinases-1 Overexpression Mediates Chemoresistance in Triple-Negative Breast Cancer Cells.

Agnello L, dArgenio A, Caliendo A, Nilo R, Zannetti A, Fedele M Cells. 2023; 12(13).

PMID: 37443843 PMC: 10340747. DOI: 10.3390/cells12131809.

The invariant chain CD74 protein is a cell surface binding partner of TIMP-1 in breast cancer cells.

Hoeberg M, Noer J, Vistesen M, Bartels A, Bech E, Nygard S Mol Oncol. 2023; 17(8):1595-1612.

PMID: 37081824 PMC: 10399710. DOI: 10.1002/1878-0261.13436.

Recapitulating thyroid cancer histotypes through engineering embryonic stem cells.

Veschi V, Turdo A, Modica C, Verona F, Di Franco S, Gaggianesi M Nat Commun. 2023; 14(1):1351.

PMID: 36906579 PMC: 10008571. DOI: 10.1038/s41467-023-36922-1.

Yu H, Wang M, Wang X, Jiang X FEBS Open Bio. 2022; 13(2):307-322.

PMID: 36560848 PMC: 9900094. DOI: 10.1002/2211-5463.13541.

A CAF-Fueled TIMP-1/CD63/ITGB1/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells.

Dittmer A, Dittmer J Cancers (Basel). 2022; 14(20).

PMID: 36291767 PMC: 9599197. DOI: 10.3390/cancers14204983.

References

Singh S, Clarke I, Terasaki M, Bonn V, Hawkins C, Squire J . Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003; 63(18):5821-8. View

Gao Y, Zhu T, Mao C, Liu Z, Wang Z, Mao X . PPIC, EMP3 and CHI3L1 Are Novel Prognostic Markers for High Grade Glioma. Int J Mol Sci. 2016; 17(11). PMC: 5133809. DOI: 10.3390/ijms17111808. View

Cheng G, Fan X, Hao M, Wang J, Zhou X, Sun X . Higher levels of TIMP-1 expression are associated with a poor prognosis in triple-negative breast cancer. Mol Cancer. 2016; 15(1):30. PMC: 4851824. DOI: 10.1186/s12943-016-0515-5. View

Lai X, Gu Q, Zhou X, Feng W, Lin X, He Y . Decreased expression of CD63 tetraspanin protein predicts elevated malignant potential in human esophageal cancer. Oncol Lett. 2017; 13(6):4245-4251. PMC: 5453118. DOI: 10.3892/ol.2017.6023. View

Liang Y, Bollen A, Aldape K, Gupta N . Nuclear FABP7 immunoreactivity is preferentially expressed in infiltrative glioma and is associated with poor prognosis in EGFR-overexpressing glioblastoma. BMC Cancer. 2006; 6:97. PMC: 1479358. DOI: 10.1186/1471-2407-6-97. View

. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008; 455(7216):1061-8. PMC: 2671642. DOI: 10.1038/nature07385. View

Angelastro J, Lame M . Overexpression of CD133 promotes drug resistance in C6 glioma cells. Mol Cancer Res. 2010; 8(8):1105-15. PMC: 2923683. DOI: 10.1158/1541-7786.MCR-09-0383. View

Bao S, Wu Q, McLendon R, Hao Y, Shi Q, Hjelmeland A . Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006; 444(7120):756-60. DOI: 10.1038/nature05236. View

Kore R, Abraham E . Phosphorylation negatively regulates exosome mediated secretion of cryAB in glioma cells. Biochim Biophys Acta. 2015; 1863(2):368-77. PMC: 6374115. DOI: 10.1016/j.bbamcr.2015.11.027. View

10.

Tung J, Ko C, Yang S, Cheng C, Chen P, Chang C . Inhibition of pentraxin 3 in glioma cells impairs proliferation and invasion in vitro and in vivo. J Neurooncol. 2016; 129(2):201-9. DOI: 10.1007/s11060-016-2168-z. View

11.

Holten-Andersen M, Stephens R, Nielsen H, Murphy G, Christensen I, Brunner N . High preoperative plasma tissue inhibitor of metalloproteinase-1 levels are associated with short survival of patients with colorectal cancer. Clin Cancer Res. 2000; 6(11):4292-9. View

12.

Dahlrot R, Kristensen B, Hjelmborg J, Herrstedt J, Hansen S . A population-based study of low-grade gliomas and mutated isocitrate dehydrogenase 1 (IDH1). J Neurooncol. 2013; 114(3):309-17. DOI: 10.1007/s11060-013-1186-3. View

13.

Rauvala M, Puistola U, Turpeenniemi-Hujanen T . Gelatinases and their tissue inhibitors in ovarian tumors; TIMP-1 is a predictive as well as a prognostic factor. Gynecol Oncol. 2005; 99(3):656-63. DOI: 10.1016/j.ygyno.2005.07.009. View

14.

Giusti I, Delle Monache S, Di Francesco M, Sanita P, DAscenzo S, Gravina G . From glioblastoma to endothelial cells through extracellular vesicles: messages for angiogenesis. Tumour Biol. 2016; 37(9):12743-12753. DOI: 10.1007/s13277-016-5165-0. View

15.

Sorensen I, Fenger C, Winther H, Foged N, Lademann U, Brunner N . Characterization of anti-TIMP-1 monoclonal antibodies for immunohistochemical localization in formalin-fixed, paraffin-embedded tissue. J Histochem Cytochem. 2006; 54(10):1075-86. PMC: 3957804. DOI: 10.1369/jhc.5A6896.2006. View

16.

Santra M, Zheng X, Roberts C, Santra S, Lu M, Panda S . Single doublecortin gene therapy significantly reduces glioma tumor volume. J Neurosci Res. 2009; 88(2):304-14. PMC: 2795007. DOI: 10.1002/jnr.22207. View

17.

Zacher A, Kaulich K, Stepanow S, Wolter M, Kohrer K, Felsberg J . Molecular Diagnostics of Gliomas Using Next Generation Sequencing of a Glioma-Tailored Gene Panel. Brain Pathol. 2016; 27(2):146-159. PMC: 8029406. DOI: 10.1111/bpa.12367. View

18.

Wang Z, Chen J, Liu J, Tian L . Exosomes in tumor microenvironment: novel transporters and biomarkers. J Transl Med. 2016; 14(1):297. PMC: 5070309. DOI: 10.1186/s12967-016-1056-9. View

19.

Joo Y, Seo K, Kim H, Rew J, Park C, Kim S . Expression of tissue inhibitors of metalloproteinases (TIMPs) in gastric cancer. Dig Dis Sci. 2000; 45(1):114-21. DOI: 10.1023/a:1005421713137. View

20.

Radford K, Thorne R, Hersey P . Regulation of tumor cell motility and migration by CD63 in a human melanoma cell line. J Immunol. 1997; 158(7):3353-8. View