CD55 in cancer: Complementing functions in a non-canonical manner

Abstract

CD55, or decay accelerating factor, is a membrane lipid microdomain-associated, GPI-anchored protein implicated in the shielding of cells from complement-mediated attack via accelerating decay of C3 and C5. Loss of CD55 is associated with a number of pathologies due to hyperactivation of the complement system. CD55 is also implicated in cancer progression thought to be driven via its role in cell shielding mechanisms. We now appreciate that CD55 can signal intracellularly to promote malignant transformation, cancer progression, cell survival, angiogenesis, and inhibition of apoptosis. Outside-in signaling via CD55 is mediated by signaling pathways including JNK, JAK/STAT, MAPK/NF-κB, and LCK. Moreover, CD55 is enriched in the cancer stem cell (CSC) niche of multiple tumors including breast, ovarian, cervical, and can be induced by chemotherapeutics and hypoxic environments. CSCs are implicated in tumor recurrence and chemoresistance. Here, we review the unexpected roles of CD55 in cancer including the roles of canonical and noncanonical pathways that CD55 orchestrates. We will highlight opportunities for therapeutic targeting CD55 and gaps in the field that require more in-depth mechanistic insights.

Keywords: CD55; Cancer stem cell; Complement pathway; DAF; Decay accelerating factor.

Fig. 1.. Canonical and non-canonical function of CD55

(A) CD55 structure and its role in complement mediated pathway. (B) Non-complement role of CD55 signaling in cancer. CD55 can signal from outside in leading to activation of diverse oncogenic signaling pathways. Growth factors, cytokines, and prostaglandins augment or activate CD55 signaling. As a ligand for CD97, an epidermal growth factor seven-span transmembrane (EGF-7TM) receptor, CD55 can trigger intracellular signaling via Janus kinase/signal transducer and activator of transcription (JAK/STAT3) and GSK3β. These pathways can activate cascades that drive oncogenesis via Myc, resistance to chemotherapy via BRCA1 and MLH1, and CSC self-renewal via SOX2, OCT4, and NANOG.

Fig. 2.

Timeline of CD55 discovery ^{[3, 8] [9] [10, 11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [–41]}