CD99 at the crossroads of physiology and pathology

Abstract

CD99 is a cell surface protein with unique features and only partly defined mechanisms of action. This molecule is involved in crucial biological processes, including cell adhesion, migration, death, differentiation and diapedesis, and it influences processes associated with inflammation, immune responses and cancer. CD99 is frequently overexpressed in many types of tumors, particularly pediatric tumors including Ewing sarcoma and specific subtypes of leukemia. Engagement of CD99 induces the death of malignant cells through non-conventional mechanisms. In Ewing sarcoma, triggering of CD99 by specific monoclonal antibodies activates hyperstimulation of micropinocytosis and leads to cancer cells killing through a caspase-independent, non-apoptotic pathway resembling methuosis. This process is characterized by extreme accumulation of vacuoles in the cytoplasmic space, which compromises cell viability, requires the activation of RAS-Rac1 downstream signaling and appears to be rather specific for tumor cells. In addition, anti-CD99 monoclonal antibodies exhibit antitumor activities in xenografts in the absence of immune effector cells or complement proteins. Overall, these data establish CD99 as a new opportunity to treat patients with high expression of CD99, particularly those that are resistant to canonical apoptosis-inducing agents.

The molecular genetic background leading to the formation of the human erythroid-specific Xga/CD99 blood groups

“…38 In contrast to Xg a , CD99 is abundantly expressed in a wide range of tissues and has drawn considerable attention in recent years. [39][40][41] CD99 has been recognized to be 1 of the critical molecules involved in the leukocyte transendothelial migration signaling pathway; thus, it plays an important role in the recruitment of leukocytes into inflamed areas. 39,42,43 Particularly, subsets of CD34 1 hematopoietic stem cells with high or low CD99 expression levels have been identified; these subsets have different levels of transendothelial migration activity and show variation in the numbers of blood cells of several downstream lineages produced after differentiation.…”

Identification of Age-Specific and Common Key Regulatory Mechanisms Governing Eggshell Strength in Chicken Using Random Forests

“…ET-1 gene regulation is responsive to intracellular calcium and calmodulin [87]. The MIC2 signaling pathway, which was specifically enriched for ESS2, has CD99 as the main cell surface protein and has been implicated in apoptosis, adhesion, differentiation, and protein trafficking possibly by affecting actin cytoskeleton reorganization [88,89]. Another ESS2 specific pathway involves the inactivation of the nuclear factor Y (NF-Y) transcription factor by p73 proteins, a process that represses the promoter of the telomerase catalytic subunit and induces replicative senescence [90,91].…”

Genomics and Therapeutic Vulnerabilities of Primary Bone Tumors

“…Anti-CD99 antibodies exert additive/synergistic effects when combined with conventional agents, such as doxorubicin or vincristine [129], and are effective even against chemoresistant tumor cells. For more details, please refer to the recent reviews [130,131]. Despite these potentialities, the antibodies directed against CD99 have not reached the clinics yet.…”