CD63, a member of the transmembrane-4-superfamily of tetraspanin proteins, is a highly N-glycosylated type III lysosomal membrane protein. It plays crucial roles in multiple biological processes. CD63 is involved in extracellular vesicle (EV)-related functions, such as sorting cholesterol into endosomes for storage and distribution via exosomes [1]. It also contributes to EV secretion from cells, and is regulated by iron via the IRE-IRP system, which is important for ferritin secretion by EVs [2].

Some studies suggest that CD63 might have a role in cancer. In solid tumors, its expression shows a complex prognostic value. A meta-analysis indicated that CD63 expression may be a potential prognostic marker, being significantly associated with poor disease-specific survival in some subgroups [4]. It has been described as both a tumor promoter and suppressor in different cancers, and in breast cancer, CD63 + cancer-associated fibroblasts can confer CDK4/6 inhibitor resistance to breast cancer cells by exosomal miR-20 [5]. However, some research argues against a general role for CD63 in the sorting of proteins into EVs, and suggests that it is not required for the EV content-delivery process [3,6].

In conclusion, CD63 is a key protein in EV-related functions, including lipid sorting and ferritin secretion. Its role in cancer is complex, with potential as a prognostic marker and involvement in drug resistance. The study of CD63 using various models, such as in different cancer cell lines and through meta-analysis, helps to understand its diverse functions in biological processes and disease conditions.

References:

1. Palmulli, Roberta, Couty, Mickaël, Piontek, Melissa C, Raposo, Graça, van Niel, Guillaume. 2024. CD63 sorts cholesterol into endosomes for storage and distribution via exosomes. In Nature cell biology, 26, 1093-1109. doi:10.1038/s41556-024-01432-9. https://pubmed.ncbi.nlm.nih.gov/38886558/

2. Yanatori, Izumi, Richardson, Des R, Dhekne, Herschel S, Toyokuni, Shinya, Kishi, Fumio. . CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles. In Blood, 138, 1490-1503. doi:10.1182/blood.2021010995. https://pubmed.ncbi.nlm.nih.gov/34265052/

3. Fan, Yé, Pionneau, Cédric, Cocozza, Federico, Zimmermann, Pascale, Rubinstein, Eric. . Differential proteomics argues against a general role for CD9, CD81 or CD63 in the sorting of proteins into extracellular vesicles. In Journal of extracellular vesicles, 12, e12352. doi:10.1002/jev2.12352. https://pubmed.ncbi.nlm.nih.gov/37525398/

4. Koh, Hyun Min, Jang, Bo Gun, Kim, Dong Chul. . Prognostic Value of CD63 Expression in Solid Tumors: A Meta-analysis of the Literature. In In vivo (Athens, Greece), 34, 2209-2215. doi:10.21873/invivo.12031. https://pubmed.ncbi.nlm.nih.gov/32871743/

5. Dey, Saurabh, Basu, Soumya, Ranjan, Amit. 2023. Revisiting the Role of CD63 as Pro-Tumorigenic or Anti-Tumorigenic Tetraspanin in Cancers and its Theragnostic Implications. In Advanced biology, 7, e2300078. doi:10.1002/adbi.202300078. https://pubmed.ncbi.nlm.nih.gov/37142558/

6. Tognoli, Maria Laura, Dancourt, Julia, Bonsergent, Emeline, Vader, Pieter, Lavieu, Gregory. 2023. Lack of involvement of CD63 and CD9 tetraspanins in the extracellular vesicle content delivery process. In Communications biology, 6, 532. doi:10.1038/s42003-023-04911-1. https://pubmed.ncbi.nlm.nih.gov/37198427/

7. Sun, Jiahui, Du, Ruoxin, Li, Xiaoju, Gao, Yuan, Zhang, Cun. 2024. CD63+ cancer-associated fibroblasts confer CDK4/6 inhibitor resistance to breast cancer cells by exosomal miR-20. In Cancer letters, 588, 216747. doi:10.1016/j.canlet.2024.216747. https://pubmed.ncbi.nlm.nih.gov/38403110/