Inhibition of mTOR reduces anal carcinogenesis in transgenic mouse model

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The molecular mechanisms underlying human anal squamous cell carcinoma (ASCC) remain largely unknown.
• Evidence suggests a link between ASCC development and the activation of the Akt/mammalian target of rapamycin (mTOR) pathway.

Purpose of the Study:

• To establish and characterize a novel mouse model for spontaneous ASCC.
• To investigate the role of the Akt/mTOR pathway in ASCC development.
• To evaluate the efficacy of mTOR inhibitors as a chemopreventive strategy for ASCC.

Main Methods:

• A conditional knockout mouse model was generated by inducing combined deletion of Tgfbr1 and Pten in stratified squamous epithelia using inducible K14-Cre.
• Histopathological analyses were performed to assess tumor development and precancerous lesions.
• Biomarker analyses, including assessment of Akt pathway activation, were conducted.
• Chemoprevention experiments involved treating mice with the mTOR inhibitor rapamycin.

Main Results:

• The Tgfbr1 and Pten double knockout (2cKO) mouse model exhibited a 33.3% susceptibility to ASCC and precancerous lesions.
• Akt pathway activation in the ASCC of 2cKO mice mirrored that observed in human ASCC.
• Rapamycin treatment significantly delayed ASCC onset and reduced tumor burden by inhibiting Akt and S6 phosphorylation.

Conclusions:

• This study presents the first conditional knockout mouse model for spontaneous ASCC, crucial for studying carcinogenesis without carcinogen induction.
• The model mimics key molecular features of human ASCC, particularly Akt pathway activation.
• The findings support the therapeutic potential of mTOR inhibitors for ASCC prevention and treatment, offering a platform for further drug development.