Abstract
Genetic mouse models of soft tissue sarcoma provide critical insights into disease pathophysiology, which are oftentimes unable to be extracted from human tumor samples or xenograft models. In this study we describe a mouse model of soft tissue sarcoma mediated by adenoviral-Cre recombinase injection into Trp53fl/fl/Ptenfl/fl lox-stop-lox luciferase mice. Injection of adenovirus expressing Cre recombinase, either subcutaneously or intramuscularly in two experimental groups, results in viral infection and gene recombination with 100% penetrance within the first 24 hours following injection. Luciferase expression measured by real-time bioluminescence imaging increases over time, with an initial robust increase following viral injection, followed by a steady rise over the next several weeks as primary tumors develop and grow. Intramuscular injections were more commonly associated with evidence of systemic viral distribution than subcutaneous injections. All mice developed soft tissue sarcomas at the primary injection site, with histological examination identifying 93% of tumors as invasive pleomorphic sarcomas based on microscopic morphology and immunohistochemical expression of sarcoma markers. A lymphocytic infiltrate was present in 64% of the sarcomas in this immunocompetent model and 71% of tumors expressed PD-L1. This is the first report of a viral-Cre mediated Trp53/Pten mouse model of undifferentiated pleomorphic sarcoma. The bioluminescence imaging feature, along with high penetrance of the model and its immunological characteristics, makes it suited for pre-clinical studies of soft tissue sarcoma.
Highlights
Soft tissue sarcomas pose a significant clinical challenge, with approximately 12,000 new diagnoses and an estimated 4,700 sarcoma-related deaths per year [1]
We describe a viralmediated inducible mouse model of soft tissue sarcoma based on somatic induction and tissue-specific homozygous loss of Trp53 and Pten
In this study we examined the consequence of temporally and spatially controlled Trp53 and Pten deletion by somatic Cre recombinase expression on sarcoma formation
Summary
Soft tissue sarcomas pose a significant clinical challenge, with approximately 12,000 new diagnoses and an estimated 4,700 sarcoma-related deaths per year [1]. Soft tissue sarcoma is a malignant mesenchymal neoplasm that is able to arise from many different tissue types and may occur in nearly any location in the body. Sarcoma may develop from muscle, fat, cartilage, connective tissue, nerves, blood vessels, and bone, and there is considerable heterogeneity between tumor types. The most frequently diagnosed soft tissue sarcoma in adults is undifferentiated pleomorphic sarcoma (UPS), with the most common locations being the extremities and trunk. The tumor initiating cell of UPS is not currently known; it is considered by pathologists and clinicians to be a diagnosis of exclusion [3]. UPS demonstrates spindle cell morphology, mitotic activity, nuclear pleomorphism, and areas of tumor necrosis; immunoreactivity for myogenic markers such as smooth muscle actin (SMA), and desmin may be present in UPS, but they do not fully exhibit skeletal muscle or smooth muscle differentiation [4]
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