Assessment of a mouse xenograft model of primary colorectal cancer with special reference to perfluorooctane sulfonate

Abstract

Colorectal cancer ranks third among the most commonly diagnosed cancers in the United States. Current therapies have a range of side effects, and the development of a reliable animal model to speed the discovery of safe effective preventative therapies would be of great value. A cross-sectional study in a large Appalachian population recently showed an association between low circulating levels of perfluorooctane sulfonate (PFOS) and a reduced prevalence of colorectal cancer. A study using APCmin (C57BL/6J-ApcMin/J) mice prone to familial adenomatous polyposis found PFOS was protective when exposure occurred during tumor development. To test the possible benefit of PFOS on spontaneous colorectal cancer, we developed a mouse model utilizing primary patient colorectal cancer implants into NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/Sz) mice. Study goals included: (1) to assess potential factors supporting the successful use of colorectal cancer from heterogeneous tumors for PDX studies; and, (2) evaluate PFOS as a therapy in tumor matched pairs of mice randomized to receive PFOS or vehicle. The time in days for mice to grow primary tumors to 5 mm took almost 2 months (mean = 53.3, se = 5.7, range = 17–136). Age of mice at implantation, patient age, gender and race appeared to have no discernable effect on engraftment rates. Engraftment rates for low and high-grade patient tumors were similar. PFOS appeared to reduce tumor size dramatically in one group of tumors, those from the right ascending colon. That is, by 5 weeks of treatment in two mice, PFOS had eliminated their 52.4 mm3 and 124.6 mm3 masses completely, an effect that was sustained for 10 weeks of treatment; in contrast, their corresponding matched vehicle control mice had tumors that grew to 472.7 mm3 and 340.1 mm3 in size respectively during the same period. In a third xenograft mouse, the tumor growth was dramatically blunted although not eliminated, and compared favorably to their matched vehicle controls over the same period. These preliminary findings suggested that this mouse model may be advantageous for testing compounds of potential value in the treatment of colorectal cancer, and PFOS may have utility in selected cases.

Establishment of a Patient-Derived Xenograft Model of Colorectal Cancer in CIEA NOG Mice and Exploring Smartfish Liquid Diet as a Source of Omega-3 Fatty Acids

“…In this study the total successful engraftment rate was 50%, which is comparable to the engraftment rates reported in the studies by Chijiwa et al (58% for gastrointestinal tumors) [ 21 ] and Katsiampoura et al (56% for CRC) [ 11 ]. However, when using surgically removed CRC tumors for engraftment, Katsiampoura et al found an engraftment rate of 72% [ 11 ], which is comparable to the study by Cho et al and Wimsatt et al that reported an engraftment rate of 67% and 64%, respectively [ 20 , 22 ]. When engrafting different types of cancer tissue in CIEA NOG mice, Fujii et al found that CRC tissue had the highest engraftment rate at approximately 32% [ 23 ].…”

SLCO1B3 promotes colorectal cancer tumorigenesis and metastasis through STAT3

“…Female BALB/c nude mice (five weeks old) were purchased from Beijing Vital River Laboratory Animal Technology (Beijing, China). The mouse model was established following the previously published protocol [ 22 ]. The mice were randomly assigned to two groups (n=6 per group) to receive HCT116 cells with stable SLCO1B3 knockdown or an equal number of negative controls HCT116 cells by subcutaneous injection into the front flank.…”

Genetic Alterations of NF-κB and Its Regulators: A Rich Platform to Advance Colorectal Cancer Diagnosis and Treatment

“…The subcutaneous PDX CRC model is commonly used as it is easy to operate, monitor, and resect with good tumor engraftment, while rarely generate metastases [ 66 ]. In contrast, the orthotopic PDX CRC model is more invasive, labor intensive, and difficult to monitor longitudinally; however, they are better models of metastases because they generate primary tumors and distant lung and liver metastases at similar rates observed in patients [ 64 , 66 , 67 , 68 , 69 ]. As such, orthotopic PDX CRC models are helpful to evaluate local invasive growth of primary tumors, study tumor–host interactions and therapeutic responses in their anatomical context, but preclinical therapeutic studies currently exclusively utilize subcutaneous PDX CRC models [ 70 ].…”

“…sive, and difficult to monitor longitudinally; however, they are better models of metastases because they generate primary tumors and distant lung and liver metastases at similar rates observed in patients [64,[66][67][68][69]. As such, orthotopic PDX CRC models are helpful to evaluate local invasive growth of primary tumors, study tumor-host interactions and therapeutic responses in their anatomical context, but preclinical therapeutic studies currently exclusively utilize subcutaneous PDX CRC models [70].…”