Mouse-Derived Isograft (MDI) In Vivo Tumor Models II. Carcinogen-Induced cMDI Models: Characterization and Cancer Therapeutic Approaches.

Janette Beshay,Thomas Lemarchand,Cynthia Obodozie,Peter Jantscheff,Holger Weber,Christoph Schächtele

doi:10.3390/cancers11020242

Abstract

In this second study, we established syngeneic in vivo models named carcinogen-induced mouse-derived isografts (cMDIs). Carcinogen-induced tumors were obtained during short-term observation (3–9 months) of CBA/J mice treated with various administration routes with 3-methylcholanthrene (MCA) or N-methyl-N-nitrosourea (MNU) as carcinogens. During necropsy, primary tumors and suspicious tissues were assessed macroscopically and re-transplanted (in PDX-like manner) into sex-matched syngeneic animals. Outgrowing tumors were histologically characterized as either spinocellular carcinoma (1/8) or various differentiated sarcomas (7/8). Growth curves of four sarcomas showed striking heterogeneity. These cMDIs were further characterized by flow cytometry, RNA sequencing, or efficacy studies. A variable invasion of immune cells into the tumors, as well as varying expression of tyrosine kinase receptor, IFN-γ signature, or immune cell population marker genes could be observed. Immune checkpoint inhibitor treatment (anti-mPD-1, anti-mCTLA-4, or a combination thereof) showed different responses in the various cMDI models. In general, cMDI models are carcinogen-induced tumors of low passage number that were propagated as tissue pieces in mice without any tissue culturing. Therefore, the tumors contained conserved tumor characteristics and intratumoral immune cell populations. In contrast to the previously described spontaneous MDI, carcinogen induction resulted in a greater number of individual but histologically related tumors, which were preferentially sarcomas.

Highlights

In the accompanying paper, the establishment and characterization of a new type of experimental in vivo cancer model, so-called mouse-derived isografts (MDIs) from spontaneous tumors, have been reported for the first time [1]
In the first part of this study, we introduced the establishment of nine histopathologically different sMDI tumor models in various mouse strains of both sexes, i.e., on different H-2 MHC class I haplotype backgrounds
In the present two papers, we introduced new mouse-derived isograft models and described their establishment, characteristics, and potential for future research

Summary

Introduction

The establishment and characterization of a new type of experimental in vivo cancer model, so-called mouse-derived isografts (MDIs) from spontaneous tumors (sMDIs), have been reported for the first time [1]. The new models increased the quantity and quality of available syngeneic in vivo tumor models, since we generated novel primary adenocarcinomas, lymphomas, and histiocytic sarcoma/histiocyte-associated lymphomas. These new spontaneous tumor models enable studying the causes and molecular mechanisms of tumor development, as well as new therapeutic approaches, especially regarding the interaction between the immune system and the tumors

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