A novel intraperitoneal metastatic xenograft mouse model for survival outcome assessment of esophageal adenocarcinoma

Abstract

Esophageal adenocarcinoma (EAC) has become the dominant type of esophageal cancer in United States. The 5-year survival rate of EAC is below 20% and most patients present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Improvement of EAC patient outcome requires well-characterized animal models in which to evaluate novel therapeutics. In this study we aimed to establish a peritoneal dissemination xenograft mouse model of EAC that would support survival outcome analyses. To find the best candidate cell line from 7 human EAC cell lines of different origin named ESO26, OE33, ESO51, SK-GT-2, OE19, OACM5.1C and Flo-1 were injected intraperitoneally/subcutaneously into SCID mice. The peritoneal/xenograft tumor formation and mouse survival were compared among different groups. All cell lines injected subcutaneously formed tumors within 3 months at variable rates. All cell lines except OACM5.1C formed intraperitoneal tumors within 3 months at variable rates. Median animal survival with peritoneal dissemination was 108 days for ESO26 cells (5X106), 65 days for OE33 cells (5X106), 88 days for ESO51 cells (5X106), 76 days for SK-GT-2 cells (5X106), 55 days for OE19 cells (5X106), 45 days for OE19 cells (10X106) and 82 days for Flo-1 cells (5X106). Interestingly, only in the OE19 model all mice (7/7 for 5X106 and 5/5 for10X106) developed bloody ascites with liver metastasis after intraperitoneal injection. The median survival time of these animals was the shortest (45 days for 10X106 cells). In addition, median survival was significantly increased after paclitaxel treatment compared with the control group (57 days versus 45 days, p = 0.0034) along with a significant decrease of the relative subcutaneous tumor volume (p = 0.00011). Thus peritoneal dissemination mouse xenograft model for survival outcome assessment after intraperitoneal injection of OE19 cells will be very useful for the evaluation of cancer therapeutics.

Superior Therapeutic Efficacy of Nanoparticle Albumin Bound Paclitaxel Over Cremophor-Bound Paclitaxel in Experimental Esophageal Adenocarcinoma

“…WST-1 in vitro colorimetric cell proliferation assay revealed that single agent treatment of nab-paclitaxel is more effective in inhibiting both OE19 and OE33 human EAC cancer cell proliferation than PT. We found that OE33 cells are more sensitive to the antiproliferative effect of the anticancer drug treatments we used including nab-paclitaxel than OE19 cells, supporting the more aggressive phenotype of OE19 as we mentioned previously [30] . In addition, nab paclitaxel combination with CP showed stronger inhibition of cell proliferation compared to that of PT combination with CP.…”

“…We evaluated the impact of drug treatments on the survival of mice harboring OE19 and OE33 peritoneal disseminated xenograft tumors as described earlier by us [30] . Kaplan-Meier curves of different treatment groups and the comparison are shown in Figure 6 A (OE19) and Figure 6 B (OE33).…”

“…Cell viability of esophageal adenocarcinoma OE19 and OE33 cell line was evaluated by the colorimetric WST-1 assay as previously described [30] , [31] . The measurement is based on the ability of viable cells to cleave the sulfonated tetrazolium salt WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate) by mitochondrial dehydrogenases.…”

“…Animal survival studies were performed using 6- to 8-week-old female non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice bought from Charles River [30] . Mice were intraperitoneally injected with OE19 or OE33 (10X10 10 ).…”

“…Animals were examined daily for signs of distress or development of jaundice, and body weight was measured once a week. Animals were euthanized when they became moribund according to predefined criteria like rapid weight loss (>20%) or weight gain (>20% due to ascites), loss of ability to ambulate, labored respiration, or inability to drink or feed to avoid animal suffering [30] in line with the local animal care committee protocol.…”