In Vivo Modeling of Human Breast Cancer Using Cell Line and Patient-Derived Xenografts

Abstract

Historically, human breast cancer has been modeled largely in vitro using long-established cell lines primarily in two-dimensional culture, but also in three-dimensional cultures of varying cellular and molecular complexities. A subset of cell line models has also been used in vivo as cell line-derived xenografts (CDX). While outstanding for conducting detailed molecular analysis of regulatory mechanisms that may function in vivo, results of drug response studies using long-established cell lines have largely failed to translate clinically. In an attempt to address this shortcoming, many laboratories have succeeded in developing clinically annotated patient-derived xenograft (PDX) models of human cancers, including breast, in a variety of host systems. While immunocompromised mice are the predominant host, the immunocompromised rat and pig, zebrafish, as well as the chicken egg chorioallantoic membrane (CAM) have also emerged as potential host platforms to help address perceived shortcomings of immunocompromised mice. With any modeling platform, the two main issues to be resolved are criteria for “credentialing” the models as valid models to represent human cancer, and utility with respect to the ability to generate clinically relevant translational research data. Such data are beginning to emerge, particularly with the activities of PDX consortia such as the NCI PDXNet Program, EuroPDX, and the International Breast Cancer Consortium, as well as a host of pharmaceutical companies and contract research organizations (CRO). This review focuses primarily on these important aspects of PDX-related research, with a focus on breast cancer.

Molecular, Cellular, and Technical Aspects of Breast Cancer Cell Lines as a Foundational Tool in Cancer Research

“…The first xenograft technique was implemented in 1962 from human breast cancer to an immunodeficient mouse [135]. The technique of patient-derived xenografts (PDXs) has been conducted by numerous institutions for therapeutic and clinical trials [136]. This process involves the removal of cells from a patient with a known status of breast cancer and the injection of such cells into an immunodeficient mouse in a specific area that will show the growth of a tumor for analysis, as seen in Figure 6.…”

A Review of the Role of the Zebrafish (Danio reiro) in Preclinical and Clinical Models of Biomarker Identification and Drug Targeting, and Developments in Personalized Medicine in Breast Cancer

“…However, for medical reasons, using CDX is connected with some limitations. Multiple passaging leads to clonal selection and loss of tumor heterogeneity [ 39 ]. Differences in gene expression can be noticed even among the same cell line.…”

“…Thanks to that, the most efficient treatment can be applied for an individual patient, which promotes the development of personalized medicine. For BC, mice have been described as the most effective PDX model [ 39 , 45 – 47 ]. Although much research has been done on BC CDX using ZF, the number of zPDX (zebrafish PDX) is still, surprisingly, limited [ 16 , 48 , 49 ].…”

<i>In vivo</i> models in cancer research

“…Экспериментальные системы для изучения биологии опухолей включают клеточные культуры, первичные опухолевые линии, трехмерные модели органоидов, модели in vivo с использованием различных животных объектов, включая Drosophila melanogaster, куриные эмбрионы, рыбок данио-рерио (Danio rerio), мышей, крыс и свиней, а также компьютерные модели. Все это составляет основу для моделирования канцерогенеза и метастазирования и исследования молекулярно-генетических характеристик данных процессов [7].…”