Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 1/2014

01-01-2014 | Colorectal Cancer

Significance of mTOR Signaling and Its Inhibitor Against Cancer Stem-Like Cells in Colorectal Cancer

Authors: Zerong Cai, MD, Jia Ke, MD, Xiaosheng He, MD, Ruixue Yuan, PhD, Yufeng Chen, MD, Xianrui Wu, MD, Lei Wang, MD, PhD, Jianping Wang, MD, PhD, Ping Lan, MD, PhD, Xiaojian Wu, MD, PhD

Published in: Annals of Surgical Oncology | Issue 1/2014

Login to get access

Abstract

Purpose

To determine the role of the mammalian target of rapamycin (mTOR) signaling in sustaining cancer stem-like cells and its clinical values in colorectal cancer (CRC).

Methods

mTOR expression in CRC patients was analyzed by immunohistochemistry and survival analysis was used to confirm the clinical value of mTOR. Colorectal cell lines were treated by mTOR inhibitors rapamycin and PP242, and sphere formation assay and aldehyde dehydrogenase (ALDH) assay were utilized to determine the impact of mTOR inhibition in CRC stem-like cells, combined or not combined with chemotherapeutic drug (fluorouracil and oxaliplatin).

Results

mTOR expression was associated with outcomes of CRC patients and predicted poor prognosis in stage II CRC patients. mTOR signaling was activated in stem-like colorectal cancer cells, and mTOR inhibitors (rapamycin and PP242) decreased the capacity of sphere formation as well as ALDH activity. Furthermore, mTOR inhibitors also were demonstrated to suppress the stimulation of stem-like cells by chemotherapy.

Conclusions

mTOR shared predictive significance in stage II CRC patients’ outcomes and played a vital role in the maintenance of colorectal cancer stem-like cells. mTOR inhibitors might hold the potential to become a therapeutic target against CRC stem cells.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward W, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.PubMedCrossRef
2.
Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3(12):895–902.PubMedCrossRef
3.
Todaro M, Francipane MG, Medema JP, Stassi G. Colon cancer stem cells: promise of targeted therapy. Gastroenterology. 2010;138(6):2151–62.PubMedCrossRef
4.
Sanders MA, Majumdar AP. Colon cancer stem cells: implications in carcinogenesis. Front Biosci. 2011;16:1651–62.CrossRef
5.
Li F, Tiede B, Massague J, Kang Y. Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res. 2007;17(1):3–14.PubMedCrossRef
6.
Lou H, Dean M. Targeted therapy for cancer stem cells: the patched pathway and ABC transporters. Oncogene. 2007;26(9):1357–60.PubMedCrossRef
7.
8.
Frogne T, Jepsen JS, Larsen SS, Fog CK, Brockdorff BL, Lykkesfeldt AE. Antiestrogen-resistant human breast cancer cells require activated protein kinase B/Akt for growth. Endocr Relat Cancer. 2005;12(3):599–614.PubMedCrossRef
9.
Vanderweele DJ, Rudin CM. Mammalian target of rapamycin promotes vincristine resistance through multiple mechanisms independent of maintained glycolytic rate. Mol Cancer Res. 2005;3(11):635–44.PubMedCrossRef
10.
Panner A, James CD, Berger MS, Pieper RO. mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme cells. Mol Cell Biol. 2005;25(20):8809–23.PubMedCentralPubMedCrossRef
11.
Yu HG, Ai YW, Yu LL, et al. Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. Int J Cancer. 2008;122(2):433–43.PubMedCrossRef
12.
Abraham RT, Gibbons JJ. The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res. 2007;13(11):3109–14.PubMedCrossRef
13.
Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006;22(2):159–68.PubMedCrossRef
14.
Gulhati P, Bowen KA, Liu J, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 2011;71(9):3246–56.PubMedCentralPubMedCrossRef
15.
Atreya CE, Ducker GS, Feldman ME, Bergsland EK, Warren RS, Shokat KM. Combination of ATP-competitive mammalian target of rapamycin inhibitors with standard chemotherapy for colorectal cancer. Invest New Drugs. 2012;30(6):2219–25.PubMedCrossRef
16.
Xue Q, Hopkins B, Perruzzi C, Udayakumar D, Sherris D, Benjamin LE. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Res. 2008;68(22):9551–7.PubMedCentralPubMedCrossRef
17.
Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.PubMedCrossRef
18.
19.
Wu XR, He XS, Chen YF, et al. High expression of CD73 as a poor prognostic biomarker in human colorectal cancer. J Surg Oncol. 2012;106(2):130–7.PubMedCrossRef
20.
21.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.PubMedCrossRef
22.
Douville J, Beaulieu R, Balicki D. ALDH1 as a functional marker of cancer stem and progenitor cells. Stem Cells Dev. 2009;18(1):17–25.PubMedCrossRef
23.
Huang EH, Hynes MJ, Zhang T, et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 2009;69(8):3382–9.PubMedCentralPubMedCrossRef
24.
Johnson SM, Gulhati P, Rampy BA, et al. Novel expression patterns of PI3 K/Akt/mTOR signaling pathway components in colorectal cancer. J Am Coll Surg. 2010;210(5):767–76, 776–8.
25.
Wolpin BM, Meyerhardt JA, Mamon HJ, Mayer RJ. Adjuvant treatment of colorectal cancer. CA Cancer J Clin. 2007;57(3):168–85.PubMedCrossRef
26.
Creighton CJ, Li X, Landis M, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA. 2009;106(33):13820–5.PubMedCrossRef
27.
Conley SJ, Gheordunescu E, Kakarala P, et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA. 2012;109(8):2784–9.PubMedCrossRef
28.
Gulhati P, Cai Q, Li J, et al. Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer. Clin Cancer Res. 2009;15(23):7207–16.PubMedCentralPubMedCrossRef
29.
Roulin D, Cerantola Y, Dormond-Meuwly A, Demartines N, Dormond O. Targeting mTORC2 inhibits colon cancer cell proliferation in vitro and tumor formation in vivo. Mol Cancer. 2010;9:57.PubMedCentralPubMedCrossRef
30.
Feldman ME, Apsel B, Uotila A, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009;7(2):e38.PubMedCrossRef
Metadata
Title
Significance of mTOR Signaling and Its Inhibitor Against Cancer Stem-Like Cells in Colorectal Cancer
Authors
Zerong Cai, MD
Jia Ke, MD
Xiaosheng He, MD
Ruixue Yuan, PhD
Yufeng Chen, MD
Xianrui Wu, MD
Lei Wang, MD, PhD
Jianping Wang, MD, PhD
Ping Lan, MD, PhD
Xiaojian Wu, MD, PhD
Publication date
01-01-2014
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue 1/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-013-3146-8

Other articles of this Issue 1/2014

Annals of Surgical Oncology 1/2014 Go to the issue

Thoracic Oncology

Proposed Modification of the Seventh American Joint Committee on Cancer Staging System for Esophageal Squamous Cell Carcinoma in Chinese Patients

SSO Special Article

Society of Surgical Oncology Distinguished Service Award: Honoring David P. Winchester, M.D.

Reconstructive Oncology

Immediate Breast Reconstruction Does Not Increase Postmastectomy Pain

Hepatobiliary Tumors

Reconsideration of the Indications for Adjuvant Chemotherapy for Liver Metastases from Colorectal Cancer After Initial Hepatectomy

Breast Oncology

Lymph Node Counts and Ratio in Axillary Dissections Following Neoadjuvant Chemotherapy for Breast Cancer: A Better Alternative to Traditional pN Staging

Breast Oncology

Axillary Dissection Can Be Avoided in the Majority of Clinically Node-Negative Patients Undergoing Breast-Conserving Therapy, by Dengel et al.