12 research outputs found
Clinically aggressive “low-grade” uterine carcinosarcoma: A case report
• We present a case of uterine carcinoma with low-grade carcinomatous and sarcomatous components. • The tumor is likely a rare biphasic form of carcinosarcoma. • Molecular profiling suggests that it is a Type I endometrial cancer. • The tumor was extremely chemotherapy-resistant
The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten.
Mutation of the tumor suppressor Pten often leads to tumorigenesis in various organs including the uterus. We previously showed that Pten deletion in the mouse uterus using a Pgr-Cre driver (Ptenf/fPgrCre/+) results in rapid development of endometrial carcinoma (EMC) with full penetration. We also reported that Pten deletion in the stroma and myometrium using Amhr2-Cre failed to initiate EMC. Since the Ptenf/fPgrCre/+ uterine epithelium was primarily affected by tumorigenesis despite its loss in both the epithelium and stroma, we wanted to know if Pten deletion in epithelia alone will induce tumorigenesis. We found that mice with uterine epithelial loss of Pten under a Ltf-iCre driver (Ptenf/f/LtfCre/+) develop uterine complex atypical hyperplasia (CAH), but rarely EMC even at 6 months of age. We observed that Ptenf/fPgrCre/+ uteri exhibit a unique population of cytokeratin 5 (CK5) and transformation related protein 63 (p63)-positive epithelial cells; these cells mark stratified epithelia and squamous differentiation. In contrast, Ptenf/fLtfCre/+ hyperplastic epithelia do not undergo stratification, but extensive epithelial cell apoptosis. This increased apoptosis is associated with elevation of TGFβ levels and activation of downstream effectors, SMAD2/3 in the uterine stroma. Our results suggest that stromal PTEN via TGFβ signaling restrains epithelial cell transformation from hyperplasia to carcinoma. In conclusion, this study, using tissue-specific deletion of Pten, highlights the epithelial-mesenchymal cross-talk in the genesis of endometrial carcinoma
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Reduced progression of endometrial hyperplasia with oral mTOR inhibition in the Pten heterozygote murine model
Phosphatase and tensin homolog (
PTEN) mutations are associated with human endometrial cancers, and
PTEN heterozygote
(±) mice have a high rate of endometrial neoplasia. The objective of this study was to evaluate an oral mTOR inhibitor (mTOR-I) on the reduction of endometrial hyperplasia in an animal model.
Three groups of 10 female mice were treated from age 20-26 weeks: group A,
Pten wild type with mTOR-I; group B,
Pten
± with placebo; and group C,
Pten ± with mTOR-I. Rates of hyperplasia and markers of proliferation and apoptosis were evaluated.
Higher grade hyperplasia occurred in a significantly greater percentage of the untreated
Pten
± group B (80%; 8/10) compared with groups A (0%; 0/10) and C (20%; 2/10;
P < .02). The treated
Pten
± mTOR-I group C also demonstrated significantly increased apoptosis (
P < .002) and decreased proliferation index (
P < .02) compared with the untreated group B.
Oral mTOR inhibition decreases the progression of endometrial hyperplasia in the
Pten heterozygote murine model through decreased cell proliferation and increased apoptosis