Orthotopic Xenografts or Subcutaneous Tumor Models: Which Provides Better Insight into Cancer?

In cancer research, preclinical models play a crucial role in enabling scientists to study the complex dynamics of tumor growth, progression, and response to therapies. Two of the most commonly used are orthotopic xenografts and subcutaneous tumor models. 

Orthotopic xenografts entail the engraftment of tumor cells into the organ of origin, which allows the tumor to grow within its natural environment, interacting with stromal and immune cells specific to the tissue. In subcutaneous tumor models, the tumor cells are placed under the skin, which is a much simpler process but lacks the specific organ microenvironment.

Orthotopic Tumor Models

Orthotopic tumor models interact with the stromal cells of the host tissue, as well as tissue-specific immune cells, enabling a tumor growth pattern that is highly similar to that observed in human cancer patients. This cell-cell interaction plays a critical role in modulating tumor growth, differentiation, and drug sensitivity. However, the implantation of tumors into the organ of origin generally requires surgical intervention and specialized imaging methods to monitor tumor growth and progression within the body.

Advantages

• Clinically Relevant: Since these models allow tumors to grow within their organ of origin, they replicate the complex organ-specific Tumor Microenvironment (TME) observed in human patients, making them highly valuable for drug testing and other experimental interventions.
• Metastasis: Orthotopic tumors can metastasize with specificities comparable to the human situation, thus enabling a closer simulation of disease progression.
• Immunotherapeutic Potential: Orthotopic tumor models can generate more patient-relevant pharmacodynamic profiles for immunotherapeutic agents, which provides a relevant efficacy and resistance profile.

Challenges

• Technical Difficulty: The establishment of orthotopic tumor models requires advanced surgical skills, anesthesia, and longer timelines.
• Animal Welfare: The invasive nature of orthotopic tumor implantation raises important considerations around animal welfare and requires careful design and execution of experiments.
• Monitoring: Tracking tumor progression in orthotopic models can be difficult since the tumors are not always visible. Though bioluminescent imaging has improved this significantly, it still requires specialized equipment and data analysis expertise.

Use Cases

• Studies Requiring High Clinical Relevance: When a study aims to closely mimic the clinical condition of cancer patients, orthotopic xenograft models provide an organ-specific TME, enabling the study of tumor growth, progression, and metastasis in a realistic context. As orthotopic tumors can metastasize with specificities comparable to human cancer, these models are highly suitable for studies focusing on understanding and preventing cancer metastasis.
• Drug Testing and Immunotherapies: The high predictive therapeutic value of orthotopic models makes them an excellent choice for meaningful drug testing. They are particularly relevant for evaluating immunotherapeutics, as they provide a functional immune system and relevant microenvironment for interpreting data accurately.
• Developing Treatments for Drug-resistant Cancers: Given the resistance of certain cancers to common anticancer drugs as well as targeted agents and immunotherapies, there is a critical need for advanced preclinical models like orthotopic xenografts that include a human disease-relevant TME.

Subcutaneous Tumor Models

Subcutaneous tumor models are widely used due to their relative ease of establishment and the straightforward monitoring of tumor progression. However, the microenvironment in subcutaneous models does not accurately replicate the complex interaction of tumor cells with organ-specific stromal cells and immune cells found in the human body.

Models like Genetically Engineered Mouse Models (GEMMs), which spontaneously develop tumors due to disease-specific mutations, do offer some advantages in this regard, but are not typically ideal for large-scale in vivo pharmacology studies. The lack of a relevant microenvironment in these models can limit their clinical relevance and potentially skew the interpretation of drug testing results.

Advantages

• Ease of Use: No special surgical skills are required for the engraftment of tumor cells, making these models widely accessible.
• Monitoring: Tracking of tumor progression in subcutaneous models is straightforward since the tumors are readily visible and palpable under the skin.

Challenges

• Lack of Clinical Relevance: Subcutaneous models lack the organ-specific TME found in human patients, limiting their clinical relevance.
• Immunotherapeutic Response: Subcutaneous models do not accurately reflect the immune profiles of orthotopic tumors, which should be taken into consideration when evaluating immunotherapies.

Use Cases

• Initial Screening of Therapeutics: Due to their ease of setup and straightforward monitoring, subcutaneous models are often used for initial screening of therapeutics. This allows for quick and easy assessment of the potential efficacy of a drug before more complex and expensive models are utilized.
• Studies Requiring Rapid Results: The relatively simple setup and ease of monitoring in subcutaneous models can expedite the timeline of a study. This can be beneficial when rapid results are required, such as in early-stage drug development or exploratory research.
• Large-Scale In Vivo Pharmacology Studies: Subcutaneous models, including Genetically Engineered Mouse Models (GEMMs), can be employed for large-scale studies due to their relatively straightforward and cost-effective implementation.

The Crucial Role of Tumor Models in Preclinical Studies

Orthotopic xenograft and subcutaneous tumor models both serve as critical tools in cancer research, playing significant roles in shaping our understanding of cancer biology and the development of effective treatments. While each model possesses its unique advantages, the orthotopic xenograft model provides a more organ-specific and clinically relevant TME, closely mimicking the biological processes that occur in human cancers. Its utility in preclinical drug testing and its potential to generate more patient-relevant pharmacodynamic profiles underline its high predictive therapeutic value.

While advancements in tumor model technologies are driving significant progress, it's essential to acknowledge that both orthotopic xenograft and subcutaneous models will continue to play complementary roles in cancer research. By leveraging the strengths of each model and continuing to refine their use, researchers can accelerate the development of new and effective cancer treatments, ultimately improving patient outcomes.