嗜铬细胞瘤和副神经节瘤的实验模型方面的进展和挑战。
Progress and challenges in experimental models for pheochromocytoma and paraganglioma.
发表日期:2023 Feb 01
作者:
Arthur S Tischler, Judith Favier
来源:
ENDOCRINE-RELATED CANCER
摘要:
对于基础病理生物学和药物临床前测试,需要炮制嗜铬细胞瘤和副神经节瘤的实验模型,以提高治疗这些肿瘤的患者(尤其是转移性疾病患者)的效果。模型的少量反映了这些肿瘤的罕见性、缓慢生长和遗传复杂性。虽然没有真正复制这些肿瘤基因型或表型的人类细胞系或异种移植模型,但过去十年在动物模型的开发和利用方面取得了进展,包括用于SDH缺陷型嗜铬细胞瘤和与种系Sdhb突变相关的大鼠和小鼠模型。此外,还有创新方法用于人类肿瘤原代培养物的药物临床前测试。这些原代培养物的挑战包括如何考虑异质细胞群体(会因最初的肿瘤解离而异)以及如何区分药物对肿瘤细胞与正常细胞的影响。维持培养的可行时间也必须与可靠评估药效所需的时间取得平衡。所有体外研究都可能涉及的重要因素包括物种差异、表型漂移、从组织到细胞培养的转化所发生的变化以及培养物维持的氧浓度。
Experimental models for pheochromocytoma and paraganglioma are needed for basic pathobiology research and for pre-clinical 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 pre-clinical 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 versus 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 transition from tissue to cell culture and the O2 concentration in which cultures are maintained.