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Progress and challenges in experimental models for pheochromocytoma and paraganglioma
Arthur S Tischler1, Judith Favier2
1Department of Pathology and Laboratory Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts, USA.
Abstract:
Experimental models for pheochromocytoma and paraganglioma are needed for basic pathobiology research and for preclinical testing of drugs to improve treatment of patients with these tumors, especially patients with metastatic disease. The paucity of models reflects the rarity of the tumors, their slow growth, and their genetic complexity. While there are no human cell line or xenograft models that faithfully recapitulate the genotype or phenotype of these tumors, the past decade has shown progress in development and utilization of animal models, including a mouse and a rat model for SDH-deficient pheochromocytoma associated with germline Sdhb mutations. There are also innovative approaches to preclinical testing of potential treatments in primary cultures of human tumors. Challenges with these primary cultures include how to account for heterogeneous cell populations that will vary depending on the initial tumor dissociation and how to distinguish drug effects on neoplastic vs normal cells. The feasible duration for maintaining cultures must also be balanced against time required to reliably assess drug efficacy. Considerations potentially important for all in vitro studies include species differences, phenotype drift, changes that occur in the transition from tissue to cell culture, and the O2 concentration in which cultures are maintained.
Insights
Developing accurate models for pheochromocytoma and paraganglioma is crucial for understanding tumor biology and testing new treatments, especially for metastatic disease. Progress includes new animal models and innovative primary culture techniques, despite existing challenges.
Area of Science:
- Endocrinology
- Oncology
- Translational Research
Background:
- Pheochromocytoma and paraganglioma are rare neuroendocrine tumors requiring better experimental models for research.
- Existing models often fail to fully replicate tumor genotype and phenotype, hindering progress, particularly for metastatic disease.
- Genetic complexity, slow growth, and rarity contribute to the paucity of effective experimental models.
Purpose of the Study:
- To review the current state and challenges of experimental models for pheochromocytoma and paraganglioma research.
- To highlight advancements in animal models and primary human tumor cultures for preclinical studies.
- To identify key considerations for developing and utilizing these models effectively.
Main Methods:
- Review of existing literature on pheochromocytoma and paraganglioma models.
- Analysis of progress in animal model development (e.g., Sdhb-deficient models).
- Evaluation of innovative approaches using primary human tumor cultures for drug testing.
Main Results:
- Development of mouse and rat models for SDH-deficient pheochromocytoma linked to Sdhb mutations.
- Emergence of primary human tumor cultures as a viable preclinical testing strategy.
- Identification of challenges in primary cultures, including cell heterogeneity, distinguishing drug effects, and culture duration.
- Recognition of critical factors for in vitro studies: species differences, phenotype drift, tissue-to-culture transition, and oxygen concentration.
Conclusions:
- Significant progress has been made in developing animal models and primary culture systems for pheochromocytoma and paraganglioma.
- Addressing challenges related to model fidelity, heterogeneity, and standardization is essential for advancing research and treatment.
- Continued innovation in experimental models is vital for improving the therapeutic strategies for these rare tumors.
