Patient-Derived Xenografts, often referred to as PDX models, are specialized research tools in cancer biology. These models are created by implanting tumor tissue directly from a patient into an immunocompromised mouse. This process allows human cancer cells to grow and thrive in a living system, serving as a “living avatar” of the patient’s tumor. The goal of PDX models is to provide a more accurate representation of human cancers than traditional laboratory methods. By growing patient tumors in mice, researchers can observe tumor behavior and explore potential treatments in conditions that closely resemble the human body.
Creating Patient Derived Xenografts
The creation of PDX models begins with obtaining fresh tumor tissue from a cancer patient, typically acquired during a biopsy or surgical procedure. Once collected, the tumor specimen is prepared, often by mechanically sectioning it into small fragments or dissociating it into a single-cell suspension. These fragments or cells are then implanted into an immunocompromised mouse.
Immunocompromised mice are used because their weakened immune systems prevent them from rejecting the foreign human tumor tissue. This allows human cancer cells to successfully engraft and grow within the mouse, mimicking their behavior in the patient’s body. Implantation can occur subcutaneously, just under the skin, or orthotopically, meaning the tissue is placed in the corresponding organ site in the mouse. After initial engraftment, the tumor grows, and portions of it can be serially transplanted, or “passaged,” into new immunocompromised mice. This process helps create a stable model while maintaining the original tumor’s genetic and histological characteristics over generations.
Why PDX Models are Important
PDX models offer significant advantages in cancer research due to their ability to closely mimic human tumors. Unlike traditional cancer cell lines grown in dishes, PDX models largely retain the genetic, molecular, and histological features of the original patient tumor, including tumor heterogeneity. This makes them more representative of the complex biology found in human cancers. This fidelity allows researchers to study tumor growth, metastasis, and the tumor microenvironment in a more physiologically relevant setting.
One of the most impactful applications of PDX models is in personalized medicine. They can be used to test various anti-cancer drugs on a patient’s specific tumor outside the body. This allows clinicians to predict individual drug responses and guide treatment decisions for individual patients, moving towards more precise oncology. PDX models are also invaluable in drug development, serving as a platform to screen new anti-cancer compounds and evaluate their efficacy. They help identify biomarkers that predict drug response and provide insights into mechanisms of drug resistance, bridging the gap between preclinical findings and clinical outcomes.
Considerations and Challenges
Despite their benefits, PDX models present several practical difficulties and limitations. A significant challenge is the engraftment success rate, as not all patient tumors will successfully grow in mice. The time and financial investment required to develop and maintain PDX models are substantial, making them costly and resource-intensive. These factors can limit their widespread accessibility, particularly for smaller research institutions.
Another key consideration is that while PDX models are superior to older methods, the mouse microenvironment is not identical to the human one. The use of immunodeficient mice means that interactions between the tumor and the human immune system are absent, which can affect studies involving immunotherapies. Researchers are developing humanized PDX models to address this by introducing components of the human immune system into the mice. Ethical considerations surrounding the use of animals in research are also present, necessitating strict ethical oversight and adherence to animal welfare guidelines. Additionally, the genetic characteristics of PDX tumors can change over successive passages in mice, potentially diverging from the original patient tumor.