Development and Histopathological Characterization of Tumorgraft Models of Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic cancer is the one of the deadliest of all malignancies. The five year survival rate for patients with this disease is 3-5%. Thus, there is a compelling need for novel therapeutic strategies to improve the clinical outcome for patients with pancreatic cancer. Several groups have demonstrated for other types of solid tumors that early passage human tumor xenograft models can be used to define some genetic and molecular characteristics of specific human tumors. Published studies also suggest that murine tumorgraft models (early passage xenografts derived from direct implantation of primary tumor specimens) may be useful in identifying compounds with efficacy against specific tumor types. Because pancreatic cancer is a fatal disease and few well-characterized model systems are available for translational research, we developed and characterized a panel of pancreatic tumorgraft models for biological evaluation and therapeutic drug testing. Of the 41 primary tumor specimens implanted subcutaneously into mice, 35 produced viable tumorgraft models. We document the fidelity of histological and morphological characteristics and of KRAS mutation status among primary (F0), F1, and F2 tumors for the twenty models that have progressed to the F3 generation. Importantly, our procedures produced a take rate of 85%, higher than any reported in the literature. Primary tumor specimens that failed to produce tumorgrafts were those that either contained <10% tumor cells or that were obtained from significantly smaller primary tumors. In view of the fidelity of characteristics of primary tumor specimens through at least the F2 generation in mice, we propose that these tumorgraft models represent a useful tool for identifying critical characteristics of pancreatic tumors and for evaluating potential therapies.

The Tumor-Associated Glycosyltransferase ST6Gal-I Regulates Stem Cell Transcription Factors and Confers a Cancer Stem Cell Phenotype

“…PDX models were maintained as in (23). Briefly, resected human pancreatic tumors were implanted into immunocompromised mice.…”

Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

“…Furthermore, the subcutaneous transplantation model failed to metastasize at the level of the peritoneum and of the liver [ 173 ]. Garcia and coworkers have reported an efficient methodology to obtain the frequent engraftment (85% of cases) of primary pancreatic cancer tissue fragments into SCID mice (tumor tissue was implanted at the base of the tail) [ 174 ]. The tumor xenotransplants can be propagated into secondary and tertiary mice and exhibit pathological and molecular features like the tumors from which they were derived [ 174 ].…”

“…Garcia and coworkers have reported an efficient methodology to obtain the frequent engraftment (85% of cases) of primary pancreatic cancer tissue fragments into SCID mice (tumor tissue was implanted at the base of the tail) [ 174 ]. The tumor xenotransplants can be propagated into secondary and tertiary mice and exhibit pathological and molecular features like the tumors from which they were derived [ 174 ]. The 15% of cases unable to engraft immunodeficient mice have either a low percentage of tumor cells or have a low tumoral mass [ 174 ].…”

“…The tumor xenotransplants can be propagated into secondary and tertiary mice and exhibit pathological and molecular features like the tumors from which they were derived [ 174 ]. The 15% of cases unable to engraft immunodeficient mice have either a low percentage of tumor cells or have a low tumoral mass [ 174 ]. Wennerstrom and coworkers have reported the successful growth of primary pancreatic cancer specimens in NOD/SCID mice IL-2Rγ null (NSG mice) through subcutaneous injection of tumor cells [ 175 ].…”

Translational pancreatic cancer research: A comparative study on patient-derived xenograft models

“…Neither collagenase nor Matrigel were used to facilitate their implantation[ 22 , 23 ]. These steps, along with rapid implantation, facilitates the procedure and eliminates the influence of factors related to the processing of tumour cells such as DNA aberrations and cell death[ 24 , 25 ].…”