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CD63, also called LAMP3, is a tetraspanin family member that is widely expressed on the membrane surface of macrophages, lymphocytes. By engaging in various cellular processes, particularly in the formation and release of exosomes, CD63 plays a pivotal role in cancer diagnostics and therapeutics due to its expression in some tumor cells.
https://doi.org/10.1002/adbi.202300078
Expression of tetraspanin CD63 in different cell types
Exosomes are small vesicles released outside cells via cellular secretion system. Tumor-derived exosomes released by tumor cells carry proteins that reflect tumor status and progression and are therefore commonly used as diagnostic markers. CD63 is critical in exosome formation and release, making it a marker protein for the detection of exosomes.
The upregulation of CD63 in various cancers, including melanoma, breast cancer, and stomach cancer, underscores its potential as a biomarker. For instance, high levels of CD63 and Caveolin-1 in plasma exosomes have shown promise as tools for early detection of melanoma. CD63 might be a prognostic marker for patients with gastric cancer.
https://doi.org/10.1002/adbi.201970051
Schematic illustration of exosomes biogenesis and secretion
The role of CD63 in the Tumor micro-environment (TME) is mainly achieved through its function in exosomes. CD63 profoundly influences the TME by regulating intercellular communication, matrix remodeling, cell migration and adhesion, and tumor cell proliferation and survival, thus playing an important role in tumor initiation, development and metastasis.
- Intercellular Communication: As mentioned above, CD63 is one of the marker proteins of exosomes. Tumor cells communicate with surrounding cells (other tumor cells, immune cells, stromal cells, etc.) by releasing exosomes containing CD63, thereby affecting the composition and function of TME.
- Matrix remodeling: Exosomes carry a variety of degrading enzymes such as Matrix metalloproteinases (MMPs), which are involved in the degradation and remodeling of the extracellular matrix (ECM). CD63 has been shown to participate in the degradation and remodeling of ECM by promoting lysosomal degradation of Membrane-type 1 matrix metalloproteinase (MT1-MMP).
- Cell Adhesion and Migration: Epithelial-mesenchymal transformation (EMT) involves epithelial cells losing their polarity and adhesion to become mesenchymal cells, enhancing their motility and invasiveness. CD63 can reduce melanoma cell migration and invasion by inhibiting EMT markers.
- Tumor Cell Proliferation and Survival: CD63 can interact with a variety of signaling molecules and receptors, activating or inhibiting different signaling pathways. For example, the interaction of CD63 with Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) can activate the MAPK signaling pathway, promoting the proliferation and survival of tumor cells.
https://doi.org/10.1387/ijdb.210120nk
Schematic representation of the roles of exosome cargo in cancer progression
CD63 exhibits a complex role in tumor formation, exhibiting different properties across cancer types, making it a potential therapeutic target. For example:
- As a Tumor Suppressor: As mentioned above, CD63 can reduce the metastatic potential of melanoma cells by inhibiting EMT markers. Overexpression of CD63 inhibits hepatocellular carcinoma cell migration by down-regulating interleukin (IL-6 and IL-12). In head and neck squamous cell carcinoma, expression of CD63 and its related protein keratin-1 decreased at metastatic sites.
- As a Tumor Promoter: CD63 interacts with TIMP-1, activating signaling pathways that enhance cell proliferation, survival, and migration, thereby contributing to tumor progression. Blocking the CD63/TIMP-1 interaction can inhibit tumor formation. Co-expression of CD63 and TIMP-1 can promote metastasis in cancers such as ovarian cancer and melanoma. Additionally, TIMP-1 facilitates melanoma metastasis through interaction with the CD63/integrin β1 complex.
These insights highlight the therapeutic potential of targeting CD63 in cancer treatment.
| CD63 as tumor suppressors | CD63 as tumor promoters |
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CD63’s involvement in exosome biology, matrix remodeling, and cell migration, highlighting its potential applications in both cancer diagnosis and therapy. However, given its dual role in tumor progression, further research is needed to better understand the precise function of CD63 in tumor progression in order to effectively utilize its potential in cancer diagnosis and treatment.
ACROBiosystems has successfully developed HEK293 expressed full-length CD63-VLP protein (Ala 2-Met 238) via "FLAG" to support drugs and therapies R&D targeting CD63.
References
1. Dey S, Basu S, Ranjan A. Revisiting the Role of CD63 as Pro‐Tumorigenic or Anti‐Tumorigenic Tetraspanin in Cancers and its Theragnostic Implications[J]. Advanced Biology, 2023, 7(7): 2300078. https://doi.org/10.1002/adbi.202300078
2. Wang X, Huang J, Chen W, et al. The updated role of exosomal proteins in the diagnosis, prognosis, and treatment of cancer[J]. Experimental & Molecular Medicine, 2022, 54(9): 1390-1400. https://doi.org/10.1038/s12276-022-00855-4
3. Wang S, Wang J, Wei W, et al. Exosomes: The indispensable messenger in tumor pathogenesis and the rising star in antitumor applications[J]. Advanced Biosystems, 2019, 3(5): 1900008. https://doi.org/10.1002/adbi.201900008
4. Logozzi M, De Milito A, Lugini L, et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients[J]. PloS one, 2009, 4(4): e5219. https://doi.org/10.1371/journal.pone.0005219
5. Miki Y, Yashiro M, Okuno T, et al. Clinico-pathological significance of exosome marker CD63 expression on cancer cells and stromal cells in gastric cancer[J]. PLoS One, 2018, 13(9): e0202956. https://doi.org/10.1371/journal.pone.0202956
6. Takino T, Miyamori H, Kawaguchi N, et al. Tetraspanin CD63 promotes targeting and lysosomal proteolysis of membrane-type 1 matrix metalloproteinase[J]. Biochemical and biophysical research communications, 2003, 304(1): 160-166. https://doi.org/10.1016/S0006-291X(03)00544-8
7. Lupia A, Peppicelli S, Witort E, et al. CD63 tetraspanin is a negative driver of epithelial-to-mesenchymal transition in human melanoma cells[J]. Journal of Investigative Dermatology, 2014, 134(12): 2947-2956. https://doi.org/10.1038/jid.2014.258
8. Liu X W, Bernardo M M, Fridman R, et al. Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells against intrinsic apoptotic cell death via the focal adhesion kinase/phosphatidylinositol 3-kinase and MAPK signaling pathway[J]. Journal of Biological Chemistry, 2003, 278(41): 40364-40372. https://doi.org/10.1074/jbc.M302999200
9. Karampoga A, Tzaferi K, Koutsakis C, et al. Exosomes and the extracellular matrix: A dynamic interplay in cancer progression[J]. The International Journal of Developmental Biology, 2021, 66(1-2-3): 97-102. https://doi.org/10.1387/ijdb.210120nk
10. Warner R B, Najy A J, Jung Y S, et al. Establishment of structure-function relationship of tissue inhibitor of metalloproteinase-1 for its interaction with CD63: Implication for cancer therapy[J]. Scientific Reports, 2020, 10(1): 2099. https://doi.org/10.1038/s41598-020-58964-x
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