ADVANTAGES OF PATIENT-DERIVED XENOGRAFTING STUDIES
Xenografting of tumor cell lines grown in vitro has been a fundamental experimental technique in oncology for at least forty years, in order to study human cancers in a laboratory model organism. Although xenografts from tumor cell lines are more clinically relevant than animal tumors, the high passage numbers of most tumor cell lines mean they no longer behave as a typical human tumor cell. The most clinically relevant xenografts are those that use tumor tissue from patients, which has not been passaged repeatedly or allowed to degrade in any way. Tumor tissue from patients is expanded minimally in mice to allow for sufficient experimental material, then frozen as a stock for future experiments. These patient-derived xenografts are the best screening environment for potential cancer treatments. Although their stromal cells match the host, making the tumors not identical to their human counterpart, PDX tumors still retain many original tumor qualities including histology, malignant phenotypes, tumor vasculature, and biomolecular features. In addition, researchers are currently working on creating mice with humanized stromal cells, a scientific achievement that would enable PDX tumor models to match human tumors even more closely. Xenografts may be inserted in a variety of places in the host organism. For ease of use, frequently xenografts are inserted in the flank, however they are often placed orthotopically, in the specific host organ required. Orthotopic xenografting allows for more effective impersonation of the tumor macroenvironment, increasing the relevance of PDX data.
IMMUNOCOMPROMISED MICE
To eliminate the chances of xenograft rejection, patient-derived xenografts are typically done in mice engineered to remove immune responses. Xenografts are often performed in the following murine models:
- Severe combined immunodeficiency (SCID) mice: mice with an diminished capacity to make B and T cells, as well as impaired complement activation, allowing them to accept xenografts.
- Athymic nude mice: mice engineered to be without a thymus, preventing the production of mature T-cells and thus preventing xenograft rejection.
- SCID-Beige mice: mice that have the SCID gene mutations but also have another mutation that also disables Natural Killer (NK) cells
- Non-Obese Diabetic (NOD) SCID mice that are a cross of NOD and SCID mutations, and therefore are absent mature T and B cells as well has have other immune system dysfunctions
| Immune System Components | ||||||
|---|---|---|---|---|---|---|
| Mature B Cells | Mature T Cells | Dendritic Cells | Macrophages | Natural Killer Cells | Complement | |
| SCID* | Absent | Absent | Present | Present | Present | Present |
| Nude | Present | Absent | Present | Present | Present | Present |
| SCID-Beige* | Absent | Absent | Present | Present | Absent | Present |
| NOD/SCID* | Absent | Absent | Defective | Defective | Defective | Absent |
To further mimic the human tumor environment, NOD/SCID mice may be “humanized” via injection of human bone marrow or peripheral blood cells to produce human T cells, B cells and dendric cells.Selection of the proper mice for PDX experiments is a crucial factor in experimental success, and a search of current literature is always recommended as part of experiment design. Patient-Derived Xenograft Services has experienced scientists who assist our clients in selection of the optimum experimental conditions for their requirements.