Rwandamuriye Francois X, Weston Breana J, Johns Terrance G, Lesterhuis W Joost, Zemek Rachael M
School of Biomedical Sciences, University of Western Australia; Telethon Kids Institute, University of Western Australia.
Telethon Kids Institute, University of Western Australia; College of Science, Health, Engineering and Education, Murdoch University.
J Vis Exp. 2020 Jul 28(161). doi: 10.3791/60882.
Surgery is often the first treatment for many solid tumors. However, local relapses frequently occur following primary tumor resection, despite adjuvant or neo-adjuvant therapies. This occurs when surgical margins are insufficiently tumor-free, resulting in residual cancer cells. From a biological and immunological perspective, surgery is not a null event; the wound healing environment is known to induce both pro- and anti-tumorigenic pathways. As a consequence, preclinical models for drug development aimed at preventing local relapse should incorporate surgical resection when testing new (neo)adjuvant therapies, to model the clinical settings in patients treated with surgery. Here, we describe a mouse model of incomplete surgical resection of WEHI 164 soft tissue sarcoma that allows testing of (neo)adjuvant therapies in the setting of a wound healing response. In this model, 50% or 75% of the tumor is removed, leaving behind some cancer tissue in situ to model gross residual disease after surgery in the clinical setting. This model allows testing therapies in the context of surgery while also considering the wound healing response, which may affect the efficacy of (neo)adjuvant treatments. The incomplete surgical resection results in reproducible regrowth of the tumor in all mice in the absence of adjuvant therapy. Adjuvant treatment with checkpoint blockade results in reduced tumor regrowth. This model is thus appropriate for testing therapies in the context of debulking surgery and its associated wound healing response and can be extended to other types of solid cancer.
手术通常是许多实体瘤的首选治疗方法。然而，尽管进行了辅助或新辅助治疗，原发性肿瘤切除后局部复发仍经常发生。当手术切缘无肿瘤组织不足，导致残留癌细胞时，就会出现这种情况。从生物学和免疫学角度来看，手术并非无影响的事件；已知伤口愈合环境会诱导促肿瘤和抗肿瘤途径。因此，旨在预防局部复发的药物开发临床前模型在测试新的（新）辅助治疗时应纳入手术切除，以模拟接受手术治疗患者的临床情况。在此，我们描述了一种WEHI 164软组织肉瘤不完全手术切除的小鼠模型，该模型允许在伤口愈合反应的背景下测试（新）辅助治疗。在这个模型中，切除50%或75%的肿瘤，在原位留下一些癌组织，以模拟临床环境中手术后的大体残留疾病。该模型允许在手术背景下测试治疗方法，同时考虑伤口愈合反应，这可能会影响（新）辅助治疗的疗效。在没有辅助治疗的情况下，不完全手术切除会导致所有小鼠的肿瘤可重复生长。使用检查点阻断进行辅助治疗可减少肿瘤再生长。因此，该模型适用于在减瘤手术及其相关伤口愈合反应的背景下测试治疗方法，并且可以扩展到其他类型的实体癌。
