Novel CD9-targeted therapies in gastric cancer

Abstract

There are 33 human tetraspanin proteins, emerging as key players in malignancy, the immune system, fertilization, cellular signaling, adhesion, morphology, motility, proliferation, and tumor invasion. CD9, a member of the tetraspanin family, associates with and influences a variety of cell-surface molecules. Through these interactions, CD9 modifies multiple cellular events, including adhesion, migration, proliferation, and survival. CD9 is therefore considered to play a role in several stages during cancer development. Reduced CD9 expression is generally related to venous vessel invasion and metastasis as well as poor prognosis. We found that treatment of mice bearing human gastric cancer cells with anti-CD9 antibody successfully inhibited tumor progression via antiproliferative, proapoptotic, and antiangiogenic effects, strongly indicating that CD9 is a possible therapeutic target in patients with gastric cancer. Here, we describe the possibility of CD9 manipulation as a novel therapeutic strategy in gastric cancer, which still shows poor prognosis.

Keywords: CD9; Gastric cancer; Tetraspanin; Therapeutic target; Tumorigenicity.

Figure 1

Structural features of CD9. CD9 has four putative transmembrane domains, which provide the short N- and C-terminal cytoplasmic domains, a small intracellular loop, and two extracellular loops. C: Cysteine; G: Glycine.

Figure 2

CD9 signaling. CD9-EGFR and CD9-β1 integrin co-localize on the cell surface. CD9 enhances the internalization of EGFR and reduces EGF-EGFR-induced signals[11]. CD9 ligation induced apoptosis via the selective activation of JNK and p38 MAPK pathway as well as caspase-3 and the p46 Shc isoform[26]. CD9 modulates integrin-dependent cell motility, cell migration, adhesion strengthening, and spreading[5,11]. EGFR: Epidermal growth factor receptor; p38 MAPK: p38 mitogen-activated-protein kinase; JNK: c-Jun NH₂-terminal kinase; FAK: Focal adhesion kinase.