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Home All Specialties Oncology

Rapamycin inhibits intestinal tumor formation and growth [PreClinical]

byElizabeth CramerandSarah Stapleton
November 11, 2014
in Oncology, Preclinical
Reading Time: 3 mins read
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1. Rapamycin (rapa) inhibited tumor initiation in Adenomatous polyposis coli gene (Apc)-deficient mouse intestinal epithelial cells, and enhanced survival in a mouse intestinal tumorigenesis model.

2. Translational elongation through the mTORC1 signaling pathway in Apc-deficient cells was identified as the mechanism targeted by such rapa treatment.

Evidence Rating Level: 1 (Excellent)

Study Rundown: APC, encoded by the Apc gene, is a tumor suppressor commonly inactivated in colorectal cancer, resulting in uncontrolled proliferation of the intestinal epithelium. The protein complex mechanistic target of rapamycin (mTORC1) is also involved in cell growth and proliferation, and is inhibited by the drug, rapa. This study investigated the efficiency and mechanism of Apc-deficient tumor growth inhibition by rapa treatment.

Following a wound to the mouse epithelium, rapa inhibited abnormal tissue proliferation without affecting healthy surrounding intestinal tissues. When researchers targeted Apc deletion to specific intestinal cells, they were able to drive Apc-deficient intestinal tumor initiation and growth. Treatment with rapa inhibited tumor growth in these mice, resulting in 100% survival of the treatment group. In a separate study, researchers implanted adenoma tumors into mice, and subsequently began treatment with rapa. They found the majority of the treatment group survived, while all control animals perished within five days of tumor implantation. When analyzed, the tumors in the treatment group were significantly reduced in size. Interestingly, when rapa treatment was halted, tumors appeared to return, suggesting tumor-initiating cells remained despite treatment. Researchers went on to establish that this inhibition of mTORC1 with rapa, was effectively inhibiting translational elongation through the mTORC1–S6K–eEF2K–eEF2 axis.

This work identified one cell-cycle regulating protein (Cyclin D3) affected by the increased translational elongation resulting from Apc deletion. Identification of other affected proteins and their contribution to proliferation may provide insight into further therapeutic targets. This study’s exciting findings suggest clinically approved drugs, such as rapa, may be useful for treatment of early colorectal cancer or at-risk patients.

Click to read the study in Nature

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Relevant Reading: Targeted inhibition of mammalian target of rapa signaling inhibits tumorigenesis of colorectal cancer

In-Depth [animal study]: Researchers separately used Apc-deletion or an intestinal challenge model in mice to investigate the role of mTORC1 in abnormal intestinal proliferation. In a challenge model, mice were exposed to damaging gamma-irradiation, which drives subsequent intestinal Wnt-dependent regeneration. Following irradiation, regeneration was evaluated by counting the size and number of viable intestinal crypts. The number of regenerating crypts was reduced in rapa-treated mice or raptor (Rptor, a component of mTORC1) conditional knockout (CKO) mice compared to wild type mice (p < 0.02). Abnormal cell proliferation in Apc-deficient mice also appeared decreased by rapa treatment or Rptor deletion.

The effect of rapa on tumor initiation and growth was assessed with a murine model for intestinal tumorigenesis using Apc-deficient stem cells. Forty days after treatment with rapa, mice with targeted Apc-deletion remained tumor free and exhibited 100% survival. Researchers implanted established Apc-deficient adenomas in mice, and subsequently treated with rapa. Sixty percent of the treatment group survived at 30 days compared to none of the control group (p < 0.001). When rapa treatment was removed, signs of intestinal neoplasia were observed.

The effect of mTROC1 loss on protein translation was assessed. Polysomes were decreased in Apc-deficient cells compared to wild type and Apc/Rptor-deficient intestinal epithelial cells. In vitro intestinal crypt cultures labeled with radioactive methionine/cysteine, and the harringtonine run-off assay identified higher levels of protein synthesis and translational elongation in Apc-deficient cells compared to wild type cells. Using numerous knockout or mutant mice strains, inhibition of eEF2K was identified as the key component downstream of mTROC1 responsible for intestinal proliferation after Apc loss.

Image: PD

©2012-2014 2minutemedicine.com. All rights reserved. No works may be reproduced without expressed written consent from 2minutemedicine.com. Disclaimer: We present factual information directly from peer reviewed medical journals. No post should be construed as medical advice and is not intended as such by the authors, editors, staff or by 2minutemedicine.com. PLEASE SEE A HEALTHCARE PROVIDER IN YOUR AREA IF YOU SEEK MEDICAL ADVICE OF ANY SORT. 

Tags: Sirolimus (rapamycin)tumor
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