An immunocompetent rectal cancer model to study radiation therapy.
An immunocompetent rectal cancer model to study radiation therapy.
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DOI：
10.1016/j.crmeth.2022.100353
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发表时间：
2022-12-19
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我们描述了一种小鼠直肠癌（RC）模型，在免疫功能强的环境下通过原位移植快速植入肿瘤类器官。这种方法使用简单的机械破坏来允许植入，避免使用葡聚糖硫酸钠。由此产生的RC肿瘤从粘膜表面侵入并转移到远处器官。在组织学上，肿瘤与人类RC非常相似，肿瘤微环境在辐射反应中发生了镜像重塑。因此，这种小鼠RC模型概括了人类RC发病机制的关键方面，并为生理学上更准确的临床前疗效研究提供了一种可行的方法。肿瘤概述了解剖起源、组织学和对辐射的反应。易用性和生理学相关性可以改善临床前治疗模型。直肠癌（RC）的发病率在全球范围内呈上升趋势，尤其是在50岁及以下的年轻人中。治疗的复杂性突出表明需要开发快速模型，以便更好地了解RC的生物学并进行可靠的临床前研究。目前，方法利用葡聚糖硫酸钠（DSS）诱导，其改变微环境的免疫生理，或肿瘤起源于粘膜下层的模型，而粘膜下层不是典型的疾病起源部位。这些局限性尤其重要，因为最近的报道表明，炎症相关结直肠肿瘤的潜在生物学和遗传学与非炎症性肿瘤不同。DSS治疗如何或在多大程度上影响这一点尚不清楚，但系统性副作用是一个值得关注的问题，开发一种更简单、更快速、无DSS的模型将有助于解开这些因素。因此，我们试图开发一个更解剖学和生理学相关的RC小鼠模型，这是直接和快速的。这里描述的模型依赖于简单的机械破坏靶组织，而不是DSS治疗，并且将植入定位于粘膜组织，这更好地反映了这种肿瘤类型的解剖学起源。Kim等人展示了一种避免使用葡聚糖硫酸钠的具有免疫功能的直肠癌植入模型。使用这种方法，原位移植肿瘤可以用于放射增敏剂、免疫调节剂和其他癌症治疗和研究中出现的疗法的快速临床前筛选。
We describe a mouse model of rectal cancer (RC) involving rapid tumor organoid engraftment via orthotopic transplantation in an immunocompetent setting. This approach uses simple mechanical disruption to allow engraftment, avoiding the use of dextran sulfate sodium. The resulting RC tumors invaded from the mucosal surface and metastasized to distant organs. Histologically, the tumors closely resemble human RC and mirror remodeling of the tumor microenvironment in response to radiation. This murine RC model thus recapitulates key aspects of human RC pathogenesis and presents an accessible approach for more physiologically accurate, preclinical efficacy studies. An immunocompetent endoluminal rectal cancer murine model Engraftment is based on mechanical disruption Tumors recapitulate anatomical origin, histology, and response to radiation Ease of use and physiological relevance can improve preclinical therapy modeling Rectal cancer (RC) incidence is increasing worldwide, especially among young adults 50 years of age and younger. The complexity of treatment highlights the need for the development of rapid models that can be used to better understand the biology of RC and to conduct robust preclinical studies. Current, approaches utilize induction by dextran sulfate sodium (DSS), which alters the immune physiology of the microenvironment, or models in which tumor origin occurs from the submucosa, which is not the typical site of disease origin. These limitations are particularly important as recent reports suggest that the underlying biology and genetics of inflammatory-associated colorectal tumors are distinct from non-inflammatory tumors. How or to what extent DSS treatment influences this is unknown, but the systemic side effects are a concern, and development of a simpler and faster, DSS-free model would be helpful to disentangle these factors. We therefore sought to develop a more anatomically and physiologically relevant RC murine model that is straightforward and rapid. The model described here relies on simple mechanical disruption of the target tissue, rather than DSS treatment, and localizes engraftment to the mucosal tissue, which better reflects the anatomical origin of this tumor type. Kim et al. demonstrate an immunocompetent rectal cancer implantation model that avoids the use of dextran sulfate sodium. Using this approach, orthotopically transplanted tumors can be used for rapid preclinical screening of radiosensitizers, immunomodulators, and other therapies emerging in cancer treatment and research.