In August this year, Jia et al., from the School of Life and Pharmacy of the Dalian University of Technology, published a paper entitled "CD93 Promotes Acute Myoid Leukemia Development and IS A Potential Therapeutic Target" in the Journal of Experimental Cell Research . It is pointed out that CD93 is highly expressed in patients with M4 and M5 subtypes of Acute Myeloid Leukemia (AML), and in leukemia stem cells, AML progenitor cells, and more differentiated AML cells. The study found that CD93 monoclonal antibody combined with αMFc-NC-DM1 targeted CD93 could inhibit the proliferation of AML cells. For the refractory AML, CD93 is expected to become a rising star in the treatment of leukemia.
In recent years, there have been many reports about CD93, and this target has been pointed out to play an important role in cell proliferation, cell migration, and tumor angiogenesis. What is CD93? How does CD93 work? Let's look down with questions.
1. What is CD93?
CD93(C1qRp) is a C-type lectin-like type I single transmembrane protein, and the C-type lectin domain in the extracellular region can bind to MMRN2, belonging to the Group XIV C-Type lectin family . XIV family members share similar molecular structures, including a C-type lectin-like domain, a series of EGF-like repeats, and a highly glycosylated mucin domain (Figure 1).
Figure 1. Structure of CD93
TM, thrombomodulin (TM), a family of CD93 and XIV, is considered a homolog and TM is a natural tissue anticoagulant and modulator of the innate immune response. In addition to TM, CD93 also shares structural homology with endosialin, a member of the Group XIV family. CD93 is expressed mainly in a variety of cell types involved in the inflammatory cascade and hematopoiesis, including bone marrow cells, hematopoietic stem cells, NK cells, platelets, neurons, microglia, and endothelial cells.
2. Regulatory mechanism of CD93
In 2021, Stefano's authors identified the existence of a pathway for CD93 to regulate the migration of blood vessels and endothelial cells: CD93 adaptor protein (Cbl and Crk) and as well as rho family GTP enzymes: Rac1,Cdc42,RhoA, and, as regulatory factors of cytoskeletal movement, responsible for the process of endothelial cell migration. During this process, Cbl interacted with Crk after phosphorylation on 774 tyrosine, and Crk played the role of downstream integron in CD93-mediated signal transduction to regulate cell polarity and migration. In addition, confocal microscopic analysis of the GTP enzyme biosensor revealed that CD93 drives the synergistic activation of rho protein at the edge of migrating endothelial cells. In summary, the activation and regulation of the Rho GTPase signaling pathway triggered by CD93 have proved that CD93 plays a key role in the migration of living cells.
Figure 2. Shows the migration of the CD93 signaling pathway in ECs.
images quoted from Stefano et al., 2022; https://doi.org/10.1016/j.matbio.2021.05.006
As a transmembrane receptor, CD93 is up-regulated in tumor blood vessels of many cancers. Studies have proved that during tumor angiogenesis, transmembrane glycoprotein CD93 can interact with the extracellular matrix to activate the signaling pathway regulating cell adhesion, migration and vascular maturation , which activates fibronectin fibrous tissue by regulating β1 integrin signal. In endothelial cells, CD93 is expressed in endothelial filaments and promotes filament formation, inhibiting proteolysis by and interaction with MMRN2. In the latest study, through a comparison of tumor gene expression analysis based on data from VEGF inhibitors in vivo, CD93 is a candidate receptor for down-regulation in VEGF inhibition and a potential target for mediating vascular normalization, also confirming the angiogenic effect of CD93 in endothelial cells.
3. Ligand for CD93
On April 13, 2021, a research paper entitled INTERLEUKIN-17DRREGULATIES GROUP 3 INNOTE LYMPHOID CELL FUNCTION THROUGH ITS RECEPTOR CD93 was published in the top immunology journal "Immunity" by the Chen Dong academician team from the Tsinghua University Institute of Immunology. This study first identified the functional receptor as CD93 and revealed that IL-17D regulated the function of IL-C3 cells by binding to CD93 and was involved in the maintenance of intestinal homeostasis.
IL-17D is necessary for intestinal hemostasis, and its deficiency leads to the defect of IL-22 produced by IL-C3. IL-17D expressed by intestinal epithelial cells is critical to the IL-C3 response through regulated production and is necessary to fight DSS-induced colitis. Purification studies in protein have shown that IL-17D binds not to a typical IL-17 receptor but to a glycoprotein CD93 expressed on mature IL-C3. In colitis experiments, mice lacking CD93 in ILC3 showed impaired IL-22 production and increased colonic inflammation. Therefore, IL-17D-CD93 regulates IL-C3 function to maintain intestinal homeostasis.
Another study found that CD93 was expressed in IL-C progenitor cells , indicating that IL-17D regulated the maturation of IL-C3 immediately after the migration of precursor cells to the intestine. The function of IL-C3 interacting with its receptor CD93 increases our understanding of the biology of ILC3 and the interaction of the tissue immune system, and provides new treatments for infectious and autoimmune diseases.
Figure 3. Intestinal epithelial cell-derived IL-17D becomes a key factor for regulating the function of ILC3s and intestinal homeostasis by binding to the receptor CD93
Image quoted from Huang et al., 2021 (https://doi.org/10.1016/j.immuni.2021.03.018
4. CD93 and disease treatment
4.1 CD93 and chronic immune diseases
The typical case of chronic immune-related diseases is psoriasis; Inflammation, high epidermal proliferation and angiogenesis are its main pathological features. However, CD93 (Cluster of Discrimination 93) is an angiogenic element that plays a role in the regulation of cell adhesion. In the endothelial cell environment, CD93 plays a role in regulating cell adhesion and homing of skin inflammatory cells , which is the main step of inflammation in psoriasis. Wafaa et al. studied the changes of CD93 in serum, peripheral blood mononuclear cells and skin of patients with psoriasis and the control group. We also evaluated the allele frequency of CD93 SNPs rs2749812 and rs2749817 in psoriasis patients and control groups, and the effect of narrow-band ultraviolet B (NB-UVB) treatment on the expression of CD93 gene in the skin of psoriasis patients . Patients with psoriasis had significantly higher CD93 gene expression levels in both lesional and non-lesional skin compared to the control group. Its relationship with rs2749817 gene polymorphism suggests that CD93 plays an important role in the pathogenesis of psoriasis and is expected to become a specific therapeutic target for psoriasis, providing an encouraging method for the future treatment of psoriasis.
4.2 CD93 and Tumor
An acknowledged key feature of malignant tumors is abnormal angiogenesis. The morphologically changed blood vessels may present with permeability disorder and dysfunction, leading to hypoxia, lactic acid accumulation, pH reduction, and difficulty in normal drug delivery to the tumor microenvironment (TME). CD93 plays a key role in the anti-angiogenic therapy of cancer. It is necessary for tumor angiogenesis and integrity for CD93 to participate in the activation process of β1 integrin .
Until 2021, Chen Lieping team found that CD93 was inhibited and down-regulated by VEGF and Insulin-like growth factor binding protein 7(IGFBP7, insulin-like growth factor binding protein 7), just dig out the more important role of CD93 –that is, blocking CD93 can promote the normalization of tumor vascular system, thus promoting drug delivery and improving the effect of immunotherapy.
In 2022, Zheng et al. also analyzed the immune effect of CD93 in bladder cancer in TCGA pan-cancer in 2022. The association of CD93 with BLCA clinical and tumor microenvironment features, predicted immunotherapeutic pathways, molecular subtypes, treatment features, and mutation status was assessed in the TCGA-BLCA and two additional BLCA cohorts. The effect of CD93 on the immunotherapeutic response was demonstrated by five real-world cohorts and the chemotherapeutic response was evaluated with an IC50. The verification results prove that CD93 is related to the clinical and pathological features, immune regulation and molecular subtypes of BLCA disease , and can effectively participate in the immune response.
In addition, gene set enrichment analysis (GSEA) showed that patients with low CD93 expression were more sensitive to immunotherapy for urothelial carcinoma.
To sum up, CD93 is involved in various immune responses, controls the infiltration of immune cells and affects the malignant characteristics of various cancer types. Therefore, CD93 has potential value as a biomarker for determining the prognosis and immune infiltration of a variety of cancers.
5. Clinical application prospect of CD93
CD93 is limited in expression in bone marrow cells, platelets, early B cell precursors, and endothelial cells and is listed as one of the top 20 genes that are common features of angiogenesis in human tumors. In addition to the fact that overexpression of CD93 in tumor vessels can be observed in pancreatic tumors as well as in human renal, head and neck, and colon cancers, the CD93 signaling pathway has also been shown to induce proliferation of AML LSCs harboring MLL gene rearrangement and to promote AML progression. In recent years, targeted angiogenic genes have become a hot topic in the study of tumor treatment and prevention of tumor expansion. DCBY02 drug antibody from Dynamicure Biotechnology has entered clinical phase I. Pre-clinical drug antibody study is also being conducted at Stanford University. CD93 plays a key role in tumor vascular maturation and is a potential therapeutic target. The development of CD93 protein from different species is of great significance for studying the molecular function of CD93 and speeding up the research and development of new drugs.
In order to assist pharmaceutical companies in the research and development of drugs targeting CD93 for diseases such as cancer and acute myeloid leukemia, CUSABIO has launched the CD93 active protein product (Code: CSB-MP865099HU) to assist your research on the mechanism of CD93 or its potential clinical value.
Recombinant Human Complement component C1q receptor(CD93),partial (Active)
● High Purity Validated by SDS-PAGE
(Tris-Glycine gel) Discontinuous SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel. Greater than 90% as determined by SDS-PAGE.
● Excellent Bioactivity Validated by Functional ELISA
Measured by its binding ability in a functional ELISA. Immobilized Human CD93 at 2 μg/ml can bind Anti-CD93 recombinant antibody (CSB-RA865099MA1HU), the EC50 is 0.6639-1.173 ng/mL.
Measured by its binding ability in a functional ELISA. Immobilized Human CD93 at 2 μg/ml can bind Human IGFBP7 (CSB-MP620956HU), the EC50 is 20.34-26.92 ng/mL.
 Jia J, Liu B, Wang D, et al. CD93 promotes acute myeloid leukemia development and is a potential therapeutic target[J]. Experimental Cell Research, 2022, 420(2): 113361.
 Dean, Y.D., McGreal, E.P., Akatsu, H., and Gasque, P. (2000). Molecular and cellular properties of the rat AA4 antigen, a C-type lectin-like receptor with structural homology to thrombomodulin. J. Biol. Chem. 275, 34382–34392.
 R. Pellicani, E. Poletto, E. Andreuzzi, A. Paulitti, R. Doliana, D. Bizzotto, P. Braghetta, R. Colladel, G. Tarticchio, P. Sabatelli, F. Bucciotti, G. Bressan, R.V. Iozzo, A. Colombatti, P. Bonaldo, M. Mongiat, Multimerin-2 main tains vascular stability and permeability, Matrix Biol 87 (2020) 11–25.
 lose, C.S.N., Flach, M., Mo¨ hle, L., Rogell, L., Hoyler, T., Ebert, K., Fabiunke, C., Pfeifer, D., Sexl, V., Fonseca-Pereira, D., et al. (2014). Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell line ages. Cell 157, 340–356.
 Kao YC, Jiang SJ, Pan WA, et al. The epidermal growth factor-like domain of CD93 is a potent angiogenic factor. PLoS One. 2012; 7(12):e51647.https://doi.org/10.1371/journal.pone.0051647
 Shehata W A, Maraee A H, Tayel N, et al. CD93 has a crucial role in pathogenesis of psoriasis[J]. Journal of Cosmetic Dermatology, 2022, 21(4): 1616-1624.
 M.De Palma, D. Biziato, T.V. Petrova, Microenvironmental regulation of tumour angiogenesis, Nature reviews, Cancer 17 (2017) 457–474.
 R. Lugano, K. Vemuri, D. Yu, M. Bergqvist, A. Smits, M. Essand, S. Johansson, E. Dejana, A. Dimberg, CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis, J. Clin. Invest. 128 (2018) 3280–3297.
 Y. Sun, W. Chen, R.J. Torphy, S. Yao, G. Zhu, R. Lin, R. Lugano, E.N. Miller, Y. Fujiwara, L. Bian, L. Zheng, S. Anand, F. Gao, W. Zhang, S.E. Ferrara, A. E. Goodspeed, A. Dimberg, X.-J. Wang, B.H. Edil, C.C. Barnett, R.D. Schulick, L. Chen, Y. Zhu, Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy, Sci. Transl. Med. 13 (2021).
 Zheng X, Xu H, Lin T, et al. CD93 orchestrates the tumor microenvironment and predicts the molecular subtype and therapy response of bladder cancer[J]. Computers in Biology and Medicine, 2022, 147: 105727.