Orthotopic Patient-Derived Xenografts of Gastric Cancer to Decipher Drugs Effects on Cancer Stem Cells and Metastatic Dissemination

Abstract

Gastric cancer is the third leading cause of cancer mortality worldwide. Cancer stem cells (CSC) are at the origin of tumor initiation, chemoresistance, and the formation of metastases. However, there is a lack of mouse models enabling the study of the metastatic process in gastric adenocarcinoma (GC). The aims of this study were to develop original mouse models of patient-derived primary GC orthotopic xenografts (PDOX) allowing the development of distant metastases as preclinical models to study the anti-metastatic efficiency of drugs such as the phosphatidylinositol 3-kinase (PI3K) inhibitor Buparlisib (BKM120). Luciferase-encoding cells generated from primary GC were injected into the stomach wall of immunocompromised mice; gastric tumor and metastases development were followed by bioluminescence imaging. The anti-CSC properties of BKM120 were evaluated on the GC cells’ phenotype (CD44 expression) and tumorigenic properties in vitro and in vivo on BKM120-treated mice. After eight weeks, PDOX mice formed tumors in the stomach as well as distant metastases, that were enriched in CSC, in the liver, the lung, and the peritoneal cavity. BKM120 treatment significantly inhibited the CSC properties in vitro and reduced the number of distant metastases in mice. These new preclinical models offer the opportunity to study the anti-metastatic efficiency of new CSC-based therapeutic strategies.

TAZ Controls Helicobacter pylori-Induced Epithelial–Mesenchymal Transition and Cancer Stem Cell-Like Invasive and Tumorigenic Properties

“…The MKN45 cell line showed the highest TAZ/YAP expression ratio among the different cell lines, because only TAZ was expressed and not YAP. The NCI-N87 cell line and the GC07 cell line established from patient-derived GC xenografts showed a high TAZ/YAP ratio and were also selected to perform the following experiments ( Figure 1 B) [ 45 ]. Then, kinetics of TAZ protein expression and TAZ/YAP-mediated TEAD transcriptional activity were performed in these three gastric cell lines in response to infection with the cag A-positive 7.13 wild type (WT) H. pylori strain ( Figure 1 C,D).…”

“…MKN45 (RIKEN, BRC Cell Engineering Division, Japan) and MKN74 (HSRR Bank JCRB0255) were cultivated in Roswell park memorial institute (RPMI) 1640 Glutamax medium (Thermo Fisher Scientific, Courtaboeuf, France), and NCI-N87 (ATCC CRL-5822), Kato-III (ATCC HTB-103), and GC07 were cultivated in Dulbecco’s modified eagle medium (DMEM-F12) medium (Thermo Fisher Scientific), as previously described [ 12 , 15 , 45 ]. GC07 was derived from a patient-derived GC xenograft (PDX), which was successfully established by serial transplantation in non-obese diabetous severe combined immunodeficiency Interleukin 2 gamma null (NSG) mice, as previously described [ 15 ].…”

Gastric Cancer: Advances in Carcinogenesis Research and New Therapeutic Strategies

“…Drug repositioning was also used as strategy to target signalling pathways exacerbated in CD44+ GCSCs. Buparlisib (BKM120, a pan-class I PI3K inhibitor), first line treatment of metastatic head and neck epidermoid carcinomas, was found to decrease GCSC tumorigenic properties in vitro and to decrease GC metastasis in vivo [ 109 ]. Verteporfin, an FDA-approved drug for age-related macular degeneration, was repositioned in the GCSC context for its capacity to decrease YAP/TEAD transcriptional activity, cell proliferation, CD44 expression and number of tumorsphere-forming CD44+ALDHhigh GCSCs in vitro.…”

“…Likewise, subcutaneous xenograft of PDX cells reflect the heterogeneity of patient tumours but still do not metastasize to distant organs [ 55 ]. In a recent study, Giraud et al developed orthotopic PDX models in which patient-derived GC cells were xenografted directly into the stomach wall of immunodeficient mice and led after 8 weeks to distant metastases [ 109 ]. In these pre-clinical models, luciferase-encoding GC cells were traced all through the in vivo experiment allowing the monitoring of primary tumour establishment and kinetic of GC cells spread and metastasis development.…”

Application of Animal Models in Cancer Research: Recent Progress and Future Prospects

“… 79 The success rate of PDX modeling was also different among different tumor types, and the success rate of colorectal cancer and lung cancer was significantly higher than that of prostate cancer. 80 These shortcomings promote the emergence of some improved PDX models.…”