Mouse xenograft models vs GEM models for human cancer therapeutics

Abstract

If one wants to know whether a patient's tumor will respond to a specific therapeutic regime, one must examine the response of that human tumor, not a mouse tumor, to the therapy Numerous murine models have been developed to study human cancer. These models are used to investigate the factors involved in malignant transformation, invasion and metastasis, as well as to examine response to therapy. One of the most widely used models is the human tumor xenograft. In this model, human tumor cells are transplanted, either under the skin or into the organ type in which the tumor originated, into immunocompromised mice that do not reject human cells. For example, the xenograft will be readily accepted by athymic nude mice, severely compromised immunodeficient (SCID) mice, or other immunocompromised mice (Morton and Houghton, 2007). Depending upon the number of cells injected, or the size of the tumor transplanted, the tumor will develop over 1-8 weeks (or in some instances 1-4 months, or longer), and the response to appropriate therapeutic regimes can be studied in vivo. Another type of animal model for studying human cancer is the genetically engineered mouse (GEM) model. The genetic profile of these mice is altered such that one or several genes thought to be involved in transformation or malignancy are mutated, deleted or overexpressed; subsequently, the effect of altering these genes is studied over time and therapeutic responses to these tumors may be followed in vivo. Both athymic nude mice and mouse xenograft models that use human tumor cell lines have been used for decades to increase our understanding of factors affecting tumor growth; however, recent information regarding the key influence of the tumor microenvironment on tumor progression and growth has led to greater reliance on GEM tumor models using immunocompetent mice, as well as use of primary human tumor xenografts in humanized mouse models. In fact, the xenograft models are often regarded as inferior to the GEM models. In this article, I hope to show that each model has its use in cancer diagnostics and in preclinical therapeutic modalities.Several criteria have recently been suggested for GEM models of human cancers: (1) mice must carry the same mutation that occurs in human tumors; (2) mutations should be engineered within the endogenous locus, and not expressed as a transgene; (3) mutated genes should be silent during embryogenesis and early postnatal development, except for in models of inherited pediatric tumors; (4) mutations should be within the specific target tissues in selected cell types; and (5) mutations must occur in a limited number of cells. Additional 'desired features' are that the tumor type and anatomopathology should be as similar as possible to that observed in human tumors, and that tumor development should proceed through the same, or similar, 'preneoplastic' stages (M. Barbacid, Keystone Symposium on Inflamation, Microenvironment and Cancer, 2008, and personal communication). Another important criterion, which is difficult t...

Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts

“…Several preclinical models are currently being used in studies of PDAC, including genetically engineered mouse (GEM) models, ectopic or orthotopic patient-derived xenograft models, and subcutaneous cell line-derived xenograft models [32]. GEM models have the advantage that the tumors arise spontaneously in the pancreas of immune-competent mice, allowing studies of the interaction between the tumor microenvironment, the pancreas, and an intact immune system [33].…”

3D tumour models: novel in vitro approaches to cancer studies

“…A great advantage of this method is the capability to transplant both cancer tissue and surrounding stroma to mimic the complexity of the human tumour environment. Mice used for xenografts are immunocompromised so they do not reject human cells and include: athymic nude mice, severely compromised immunodeficient (SCID) mice or non-obese diabetic (NOD)/SCID humanized mice (Richmond and Su 2008). Tumour growth is often challenging in athymic nude mice, with no tumour progress observed even after 6 months (Elkas et al 2002).…”

De-Risking Immunotherapy: Report of a Consensus Workshop of the Cancer Immunotherapy Consortium of the Cancer Research Institute

“…Although mice are clearly necessary and useful for discovering new biology and dissecting biologic mechanisms (13,14), they have some limitations when it comes to predicting the efficacy of potential immunotherapies, identifying predictive biomarkers, and selecting indications, among other variables (15,16).…”