In Vivo Intra‐Uterine Delivery of TAT‐Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53‐Deficient Endometrial Cancers

Abstract

Phosphatase and TENsin homolog (Pten) and p53 are two of the most frequently mutated tumor suppressor genes in endometrial cancer. However, the functional consequences and histopathological manifestation of concomitant p53 and Pten loss of function alterations in the development of endometrial cancer is still controversial. Here, it is demonstrated that simultaneous Pten and p53 deletion is sufficient to cause epithelial to mesenchymal transition phenotype in endometrial organoids. By a novel intravaginal delivery method using HIV1 trans‐activator of transcription cell penetrating peptide fused with a Cre recombinase protein (TAT‐Cre), local ablation of both p53 and Pten is achieved specifically in the uterus. These mice developed high‐grade endometrial carcinomas and a high percentage of uterine carcinosarcomas resembling those found in humans. To further demonstrate that carcinosarcomas arise from epithelium, double Pten/p53 deficient epithelial cells are mixed with wild type stromal and myometrial cells and subcutaneously transplanted to Scid mice. All xenotransplants resulted in the development of uterine carcinosarcomas displaying high nuclear pleomorphism and metastatic potential. Accordingly, in vivo CRISPR/Cas9 disruption of Pten and p53 also triggered the development of metastatic carcinosarcomas. The results unfadingly demonstrate that simultaneous deletion of p53 and Pten in endometrial epithelial cells is enough to trigger epithelial to mesenchymal transition that is consistently translated to the formation of uterine carcinosarcomas in vivo.

Construction and Evaluation of BAL-PTX Co-Loaded Lipid Nanosystem for Promoting the Anti-Lung Cancer Efficacy of Paclitaxel and Reducing the Toxicity of Chemotherapeutic Drugs

“…A subcutaneously implanted tumor model was constructed to further study the pharmacodynamics of combination treatment. 51 , 52 The body weight of nude mice from all groups (except those in the BAL-PTX-LN preparation group) decreased in in vivo pharmacodynamic trials compared with their body weight at the start of treatment. Furthermore, the control group exhibited the largest decrease ( P < 0.05).…”

Bioengineering approaches for the endometrial research and application

“…This discovery has provided new insights into the mechanisms underlying the initial stages of endometrial tumorigenesis. Further studies have suggested that the concurrent deletion of PTEN, forkhead box protein A2, and p53 in endometrial epithelial cells plays a key role in triggering mesenchymal transition [ 39 , 124 , 125 ]. Aberrations in the phosphatidylinositol 3-kinase pathway and Kirsten rat sarcoma viral oncogene mutations may exert synergistic effects [ 126 ].…”