Abstract
ABSTRACTSyngeneic, immunocompetent allograft tumor models recapitulate important aspects of the tumor microenvironment and have short tumor latency with predictable growth kinetics, making them useful for trialing novel therapeutics. Here, we describe surgical techniques for orthotopic and heterotopic pancreatic ductal adenocarcinoma (PDAC) tumor implantation and characterize phenotypes based on implantation site.Mice (n=8 per group) were implanted with 104 cells in the pancreas or flank. Hy15549 and Han4.13 cell lines were derived from primary murine PDAC (Ptf1-Cre; LSL-KRAS-G12D; Trp53 Lox/+) on C57BL/6 and FVB strains, respectively. Single-cell suspension and solid tumor implants were compared. Tumors were treated with two intravenous doses of FOLFIRINOX and responses evaluated.All mice developed pancreatic tumors within 7 days. Orthotopic tumors grew faster and larger than heterotopic tumors. By 3 weeks, orthotopic mice began losing weight, and showed declines in body condition requiring euthanasia starting at 4 weeks. Single-cell injection into the pancreas had near 100% engraftment, but solid tumor implant engraftment was ∼50% and was associated with growth restriction. Orthotopic tumors were significantly more responsive to intravenous FOLFIRINOX compared with heterotopic tumors, with greater reductions in size and increased apoptosis. Heterotopic tumors were more desmoplastic and hypovascular. However, drug uptake into tumor tissue was equivalent regardless of tumor location or degree of fibrosis, indicating that microenvironment differences between heterotopic and orthotopic tumors influenced response to therapy.Our results show that orthotopic and heterotopic allograft locations confer unique microenvironments that influence growth kinetics, desmoplastic response and angiogenesis. Tumor location influences chemosensitivity to FOLFIRINOX and should inform future preclinical trials.This article has an associated First Person interview with the first author of the paper.
Highlights
Syngeneic, immunocompetent allograft tumor models recapitulate important aspects of the tumor microenvironment and have short tumor latency with predictable growth kinetics, making them useful for trialing novel therapeutics
Multiple surgical approaches have been proposed for pancreatic ductal adenocarcinoma (PDAC) orthotopic tumor implantation, detailed evaluations of the strengths and weaknesses of different techniques are lacking
An erroneous injection of tumor cells in the retroperitoneal space defeats the purpose of an orthotopic model but is likely to result in extravasation of contents into the peritoneal cavity, resulting in carcinomatosis (Figure 1C)
Summary
Immunocompetent allograft tumor models recapitulate important aspects of the tumor microenvironment and have short tumor latency with predictable growth kinetics, making them useful for trialing novel therapeutics. Drug uptake into tumor tissue was equivalent regardless of tumor location or degree of fibrosis, indicating that microenvironment differences between heterotopic and orthotopic tumors influenced response to therapy. Conclusion: Orthotopic and heterotopic allograft locations confer unique microenvironments that influence growth kinetics, desmoplastic response, and angiogenesis. Recent evidence suggests that primary tumor xenografts undergo significant genetic changes that diverge from the evolutionary course observed in human disease, calling into question the degree of translatability.[11,12] In addition, immunotherapy response rates in human PDAC have far been poor, there is strong evidence to indicate that immune infiltrates play an important role in shaping the tumor microenvironment and course of disease.[13] stromal cells and carcinoma cells are from different species in xenografts, which may influence cell-cell interactions. Immunodeficient models are limited by an incomplete tumor microenvironment
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