Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

Abstract

Identification and characterization of cancer stem cells (CSCs) in gastric cancer are difficult owing to the lack of specific markers and consensus methods. In this study, we show that cells with the CD90 surface marker in gastric tumors could be enriched under non-adherent, serumfree and sphere-forming conditions. These CD90 þ cells possess a higher ability to initiate tumor in vivo and could re-establish the cellular hierarchy of tumors from singlecell implantation, demonstrating their self-renewal properties. Interestingly, higher proportion of CD90 þ cells correlates with higher in vivo tumorigenicity of gastric primary tumor models. In addition, it was found that ERBB2 was overexpressed in about 25% of the gastric primary tumor models, which correlates with the higher level of CD90 expression in these tumors. Trastuzumab (humanized anti-ERBB2 antibody) treatment of hightumorigenic gastric primary tumor models could reduce the CD90 þ population in tumor mass and suppress tumor growth when combined with traditional chemotherapy. Moreover, tumorigenicity of tumor cells could also be suppressed when trastuzumab treatment starts at the same time as cell implantation. Therefore, we have identified a CSC population in gastric primary tumors characterized by their CD90 phenotype. The finding that trastuzumab targets the CSC population in gastric tumors suggests that ERBB2 signaling has a role in maintaining CSC populations, thus contributing to carcinogenesis and tumor invasion. In conclusion, the results from this study provide new insights into the gastric tumorigenic process and offer potential implications for the development of anticancer drugs as well as therapeutic treatment of gastric cancers.

Gastric tumor-initiating CD44+ cells and epithelial-mesenchymal transition are inhibited by γ-secretase inhibitor DAPT

“…CSCs exhibit increased resistance against conventional chemotherapy (14,15), and they may initiate tumors at limiting dilu tions in animals (5). A number of previous studies have validated the CSC hypothesis by isolating CSCs from gastric cancer patients, and CD44 has been identified as a surface marker of GCSCs (16)(17)(18)(19)(20). In the present study, CD44 + MKN45 cells were sorted by FACS.…”

Identification of CD90 as Putative Cancer Stem Cell Marker and Therapeutic Target in Insulinomas

“…More research is needed to determine whether the link between CD90 expression and increased tumorigenicity in INS cells is a causative or merely an associative link. For instance, Jiang et al demonstrated that expression of CD90 on gastric CSCs was correlated with ERBB2 expression, and that trastuzumab (Herceptin, mAb against ERBB2) targeted gastric CSCs characterized by the CD90 phenotype [32]. On the other hand, another study, while still mainly descriptive, demonstrated that transfection of a liver cancer cell line with a CD90 expression vector paralleled a decrease in E-cadherin expression and thereby increased migration and invasion of the liver cancer cells, implying a causal effect of CD90 expression and increased tumorigenicity [33].…”

Identifying and targeting cancer stem cells in the treatment of gastric cancer

“…These include cluster of differentiation 44 (CD44, and its variants); CD24/CD44; CD54/CD44; CXCR4; epithelial cell adhesion molecule (EpCAM)/CD44; aldehyde dehydrogenase 1 (ALDH1); CD90; CD71‐negative; CD133; CD166; leucine‐rich, repeat‐containing, G‐protein–coupled receptor 5 (LGR5), Oct4; and sex‐determining region Y‐box 2 (Sox2). Table 1 lists examples of the CSC markers that have been studied in gastric cancer 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35. When CSCs are positive for several of these markers, the cells display a phenotype of tumorigenicity and chemoresistance.…”