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.
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References
Jemal A, Bray F, Center MM, Ferlay J, Ward W, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.
Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3(12):895–902.
Todaro M, Francipane MG, Medema JP, Stassi G. Colon cancer stem cells: promise of targeted therapy. Gastroenterology. 2010;138(6):2151–62.
Sanders MA, Majumdar AP. Colon cancer stem cells: implications in carcinogenesis. Front Biosci. 2011;16:1651–62.
Li F, Tiede B, Massague J, Kang Y. Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res. 2007;17(1):3–14.
Lou H, Dean M. Targeted therapy for cancer stem cells: the patched pathway and ABC transporters. Oncogene. 2007;26(9):1357–60.
Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12(1):9–22.
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.
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.
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.
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.
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.
Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006;22(2):159–68.
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.
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.
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.
Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.
Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29(34):4741–51.
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.
Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal. 2009;2(67):pe24.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111–5.
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.
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.
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.
Wolpin BM, Meyerhardt JA, Mamon HJ, Mayer RJ. Adjuvant treatment of colorectal cancer. CA Cancer J Clin. 2007;57(3):168–85.
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.
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.
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.
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.
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.
Acknowledgment
The work was supported by the Natural Science Foundation of Guangdong Province, China (No. 10151008901000112), National Natural Science Foundation of China (No. 91029702) and International S&T Cooperation Program of China (No. 2013DFG32990). No potential conflict of interest with the research, authorship, and/or publication exists in this article.
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Zerong Cai and Jia Ke have contributed equally to this study.
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Cai, Z., Ke, J., He, X. et al. Significance of mTOR Signaling and Its Inhibitor Against Cancer Stem-Like Cells in Colorectal Cancer. Ann Surg Oncol 21, 179–188 (2014). https://doi.org/10.1245/s10434-013-3146-8
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DOI: https://doi.org/10.1245/s10434-013-3146-8