Prognostic value and multifaceted roles of tetraspanin CD9 in cancer

Abstract

CD9 is a crucial regulator of cell adhesion in the immune system and plays important physiological roles in hematopoiesis, blood coagulation or viral and bacterial infections. It is involved in the transendothelial migration of leukocytes which might also be hijacked by cancer cells during their invasion and metastasis. CD9 is found at the cell surface and the membrane of exosomes affecting cancer progression and therapy resistance. High expression of CD9 is mostly associated with good patients outcome, with a few exceptions. Discordant findings have been reported for breast, ovarian, melanoma, pancreatic and esophageal cancer, which might be related to using different antibodies or inherent cancer heterogeneity. According to in vitro and in vivo studies, tetraspanin CD9 is not clearly associated with either tumor suppression or promotion. Further mechanistic experiments will elucidate the role of CD9 in particular cancer types and specific conditions.

Keywords: CD9; cancer; exosomes; immunohistochemistry; prognosis.

Figure 1

Structure of tetraspanin CD9 and its role in cancer, including exosome trafficking. (A) The CD9 protein consists of four transmembrane domains (–4), short (EC1, SEL) and long (EC2, LEL) extracellular loop, short intracellular loop and short intracellular N- and C-termini. There are several possible palmitoylation sites made up of membrane-proximal cysteines and a possible N-glycosylation site in the SEL. In the LEL, there are two disulfide bridges, each containing one cysteine of the CCG motif (152–154), a typical feature of the tetraspanin family. Based on UniProt (AC: P21926, cited 1.8.2022). (B) CD9 was implicated both in tumor promoting and suppressing mechanisms. Several studies have described its role in cell migration and invasion, e.g. by affecting actin-polymerization and reorganisation at the cell protrusions (5, 6) or by increasing the production of the proteinase MMP-2 which cleaves ECM components during cell invasion (6). Increased CD9 expression was also linked to increased signalling in the protumorigenic NF-κB pathway (7). However, increased CD9 expression was shown to attenuate EGFR signalling and thus suppress cell proliferation (8, 9). Another study described higher metastatic rate in cells with decreased CD9 expression (10). CD9 downregulation was also observed in cells which underwent EMT (11). CD9 can also affect tumor neoangiogenesis by promoting VEGFR3 signalling in endothelial cells (12). Last but not least, transendothelial migration of tumor cells is supported by CD9 reorganisation at points of contact between endothelial and tumor cells (13). (C) Exosomes can transport cargo between cells in the tumor microenvironment (other tumor cells, stromal cells, immune cells) and thus enable mutual communication (14, 15). They also help establish the premetastatic niche in the target organ before colonization (–20). Exosomes can also promote drug resistance via several mechanisms, e.g. by transporting drugs out of the tumor cells (21, 22) or by neutralisation of antibody-conjugated drugs (23).