The tetraspanin family member CD63, also referred to as LAMP3, is widely expressed on the membrane surface of macrophages and lymphocytes. CD63 engages in an array of cellular processes, most notably in the formation and release of exosomes.
As CD63 is expressed in a range of tumor cells, it has become central to current cancer diagnostics and therapeutics.
Expression of tetraspanin CD63 in different cell types. Image Credit: https://doi.org/10.1002/adbi.202300078
CD63 in cancer diagnostics
Exosomes are tiny vesicles expelled from cells through the cellular secretion system. These vesicles, especially those derived from tumor cells, contain proteins that mirror the state and progression of tumors, making them useful as diagnostic markers. A key protein, CD63, plays an essential role in the formation and release of exosomes, serving as a significant marker for their detection.
The increased expression of CD63 in various types of cancer, such as melanoma, breast cancer, and gastric cancer, highlights its potential as a biomarker. For example, elevated levels of CD63 and another protein, Caveolin-1, in plasma exosomes have shown potential in the early detection of melanoma.
Additionally, CD63 may serve as a prognostic marker in gastric cancer, providing valuable insights into disease progression and outcomes.
Schematic illustration of exosomes biogenesis and secretion. Image Credit: https://doi.org/10.1002/adbi.201970051
CD63 and the tumor microenvironment
CD63’s role in the Tumor Micro-Environment (TME) is primarily linked to its function in exosomes. CD63’s impact on the TME is characterized by the regulation of intercellular communication and the remodeling of matrices.
It also plays an important role in both cell migration and adhesion, as well as tumor cell proliferation and survival. CD63 is, therefore, considered a significant factor in tumor initiation, development and metastasis.
Intercellular communication
CD63 is a marker protein of exosomes, with exosomes containing CD63 underpinning tumor cells’ ability to communicate with surrounding cells, for example, other tumor cells, immune cells, and stromal cells. CD63, therefore, notably impacts the composition and function of the TME.
Matrix remodeling
Exosomes are equipped with a variety of degrading enzymes, including Matrix metalloproteinases (MMPs), which play a crucial role in the degradation and remodeling of the extracellular matrix (ECM).
One significant protein, CD63, has been demonstrated to contribute to these processes by facilitating the lysosomal degradation of Membrane-type 1 matrix metalloproteinase (MT1-MMP).
Cell adhesion and migration
Epithelial-mesenchymal transition (EMT) is a process where epithelial cells lose their polarity and adhesion, transforming into mesenchymal cells that have increased motility and invasiveness. CD63 helps to reduce the migration and invasion of melanoma cells by inhibiting markers associated with EMT.
Tumor cell proliferation and survival
CD63 interacts with a range of signaling molecules and receptors, influencing various signaling pathways either by activation or inhibition. Specifically, when CD63 binds with Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), it activates the MAPK signaling pathway, which supports the proliferation and survival of tumor cells.
Schematic representation of the roles of exosome cargo in cancer progression. Image Credit: https://doi.org/10.1387/ijdb.210120nk
Roles of CD63 as a therapeutic target
CD63’s role in tumor formation is complex. It exhibits various properties across different cancer types, making it a potentially useful therapeutic target.
CD63 as a tumor suppressor
CD63 has the capacity to hinder the metastatic potential of melanoma cells through the inhibition of EMT markers. Overexpression of CD63 inhibits hepatocellular carcinoma cell migration via the downregulation of interleukin (IL-6 and IL-12).
Studies have shown that in head and neck squamous cell carcinoma, the expression of CD63 and its related protein keratin-1 have actually decreased at metastatic sites.
CD63 as a tumor promoter
CD63 contributes to tumor progression through its interactions with TIMP-1, whereby it activates signaling pathways that improve cell proliferation, survival, and migration. Effectively preventing this CD63/TIMP-1 interaction can, therefore, inhibit tumor formation.
The co-expression of CD63 and TIMP-1 has been shown to promote metastasis in cancers such as melanoma and ovarian cancer. TIMP-1 also enables melanoma metastasis via its interaction with the CD63/integrin β1 complex.
Insights such as these are key to better understanding the therapeutic potential of targeting CD63 in different cancer treatments.
CD63 as tumor suppressors. Image Credit: ACROBiosystems
CD63 as tumor promoters. Image Credit: ACROBiosystems
Conclusion
CD63’s potential applications in cancer diagnosis and therapy are explicitly linked to its centrality to exosome biology, matrix remodeling, and cell migration.
Its dual role in tumor progression means that additional research must be undertaken in order to better understand the precise function of CD63 in tumor progression. This research is also key to effectively utilizing CD63 in cancer diagnosis and treatment.
ACROBiosystems has successfully developed HEK293 expressed full-length CD63-VLP protein (Ala 2-Met 238) via “FLAG.” This protein has been specifically designed to support the development of drugs and therapies targeting CD63.
References and further reading
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
Acknowledgments
Produced from materials originally authored by ACROBiosystems.
About ACROBiosystems
ACROBiosystems is a cornerstone enterprise of the pharmaceutical and biotechnology industries. Their mission is to help overcome challenges with innovative tools and solutions from discovery to the clinic. They supply life science tools designed to be used in discovery research and scalable to the clinical phase and beyond. By consistently adapting to new regulatory challenges and guidelines, ACROBiosystems delivers solutions, whether it comes through recombinant proteins, antibodies, assay kits, GMP-grade reagents, or custom services. ACROBiosystems empower scientists and engineers dedicated towards innovation to simplify and accelerate the development of new, better, and more affordable medicine.
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