Introduction

Pleomorphic liposarcoma is a rare and aggressive subset of soft-tissue sarcomas with a high mortality burden. Local treatment largely consists of radiation therapy and wide surgical resection, but options for systemic therapy in the setting of metastatic disease are limited and largely ineffective, prompting exploration of novel therapeutic strategies and experimental models. As with other cancers, sarcoma cell lines and patient-derived xenograft models have been developed and used to characterize these tumors and identify therapeutic targets, but these models have inherent limitations. The establishment of genetically engineered mouse models represents a more realistic framework for reproducing clinically relevant conditions for studying pleomorphic liposarcoma.

Methods

Trp53^fl/fl/Rb1^fl/fl/Pten^fl/fl (RPP) mice were used to reliably generate an immunocompetent model of mouse pleomorphic liposarcoma through Cre-mediated conditional silencing of the Trp53, Rb1, and Pten tumor suppressor genes. Evaluation of tumor-infiltrating lymphocytes was assessed with immunostaining for CD4, CD8, and PD-L1, and flow cytometry with analysis of CD45, CD3, CD4, CD8, CD19, F4/80, CD11b, and NKp46 sub-populations.

Results

Mice reliably produced noticeable soft-tissue tumors in approximately 6 weeks with rapid tumor growth between 100 and 150 days of life, after which mice reached euthanasia criteria. Histologic features were consistent with pleomorphic liposarcoma, including widespread pleomorphic lipoblasts. Immunoprofiling and assessment of tumor-infiltrating lymphocytes was consistent with other soft-tissue sarcomas.

Conclusion

Genetically engineered RPP mice reliably produced soft-tissue tumors consistent with pleomorphic liposarcoma, which immunological findings similar to other soft-tissue sarcomas. This model may demonstrate utility in testing treatments for this rare disease, including immunomodulatory therapies.

中文翻译：

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多形性脂肪肉瘤基因工程小鼠模型：免疫表型和组织学特征

介绍

多形性脂肪肉瘤是一种罕见且具有侵袭性的软组织肉瘤亚型，具有很高的死亡率。局部治疗主要包括放射治疗和广泛的手术切除，但转移性疾病的全身治疗选择有限且基本上无效，这促使人们探索新的治疗策略和实验模型。与其他癌症一样，肉瘤细胞系和患者来源的异种移植模型已被开发并用于表征这些肿瘤并确定治疗靶点，但这些模型具有固有的局限性。基因工程小鼠模型的建立代表了一个更现实的框架，可以重现研究多形性脂肪肉瘤的临床相关条件。

方法

Trp53 ^fl/fl / Rb1 ^fl/fl / Pten ^fl/fl (RPP) 小鼠用于通过 Cre 介导的Trp53、Rb1和Pten肿瘤抑制基因的条件沉默可靠地生成小鼠多形性脂肪肉瘤的免疫活性模型。通过 CD4、CD8 和 PD-L1 免疫染色以及流式细胞术分析 CD45、CD3、CD4、CD8、CD19、F4/80、CD11b 和 NKp46 亚群来评估肿瘤浸润淋巴细胞。

结果

小鼠在大约 6 周内可靠地产生了明显的软组织肿瘤，并且在生命的 100 至 150 天之间肿瘤快速生长，此后小鼠达到了安乐死标准。组织学特征与多形性脂肪肉瘤一致，包括广泛的多形性脂肪母细胞。肿瘤浸润淋巴细胞的免疫分析和评估与其他软组织肉瘤一致。

结论

基因工程 RPP 小鼠可靠地产生了与多形性脂肪肉瘤一致的软组织肿瘤，其免疫学结果与其他软组织肉瘤相似。该模型可能在测试这种罕见疾病的治疗方法（包括免疫调节疗法）方面具有实用性。