Overview of How Human Tumor Xenografts Are Used In Cancer Research and Pre-Clinical Trials
The growth of human tumors in a different species, eg., the mouse, requires immunodeficiency in the host animal to prevent rejection of the transplanted foreign tissue. There are a number of immunologically impaired mouse strains, and those that are more permissive can strongly increase the efficiency of xenotransplantation. We have selected the NSG mouse, one of the most permissive strains, to use in our resource core.
The basic xenotransplant procedure consists of implanting tumor fragments from human patients into NSG mice. When the tumors begin to grow, fragments from these mice are collected and implanted into a second set of expansion mouse recipients. The expansion can occur for several more passages and still keep the original tumor cell/stromal architecture in place. The implantation of a tumor fragment from a human patient into an immune deficient mouse is referred to as a patient derived xenograft (PDX). Mice carrying the expansion of tumor fragments derived from the same patient are designated as xenopatients.
Even though the “take” rate of implanted human tumor fragments into NSG mice is lower than implanting tumor cell lines, there are a number of clinically related advantages. The first is that there is a realistic representation of the heterogeneity of tumor cell subpopulations. A second advantage is that the stromal compartment is representative of the parental tumor in the early passages (3 to 4). A third advantage is the predictability of drug responses of human tumors. Because orthotopic implantation, ie., into the same tissue or organ, can be technically challenging, tumor fragments are generally implanted subcutaneously into the flank of each mouse.
The use of PDXs as a tool for preclinical studies demands that a particular PDX accurately reproduce the original patient’s tumor, and secondly, a PDX panel should accurately reproduce human cancers representing their various subcategories. Therefore, the PDX model system takes advantage of the high correlation between preclinical and clinical results in terms of therapeutic efficacy for PDXs that closely mimic and predict the clinical response of the patient’s tumor they derive from. A useful setting is development of the PDX models while the patient is undergoing first-line treatment, so that it is possible to acquire proof of concept information on the relative sensitivity or resistance to the different regimens to be correlated with molecular features and selection of the best second line treatment for the patient.
A second preclinical setting in which PDXs can be highly relevant is in the evaluation of new drugs in cancer treatment. New drugs can be tested, which can lead to the identification of the best treatment regimen for a specific subtype of tumor, as well as the identification of new biological pathways involved in tumor development, by taking advantage of the ability to develop a PDX panel that faithfully represents the heterogeneity of a cancer type.
A third preclinical setting for the PDX model is the investigation of the response of the tumor microenvironment to drug treatment. The presence of human stromal cells in early passage can be exploited to study interaction between tumor cells and the microenvironment and how anti-cancer drugs affect this interaction. In this regard, it is of interest to determine if the function or phenotype of these cells is modulated after treatment leading to more comprehensive knowledge of tumor development as well as mechanisms of drug resistance. Drug resistant cells could be responsible for tumor recurrence just as it frequently occurs in human patients after partial or complete response.
The biological relevance of the PDX model system is represented by the concept that cancer is the result of abnormal organogeneisis driven by cancer stem cells, defined as self-renewing tumor cells able to initiate tumor formation and to maintain tumor heterogeneity. PDXs for cancer stem cell studies provide an exciting and highly relevant research tool to develop an expanded appreciation for the cancer stem cell theory and the ability to leverage new findings that can be directly translated to the clinical setting.