Molecular profiling of ALDH1+ colorectal cancer stem cells reveals preferential activation of MAPK, FAK, and oxidative stress pro-survival signalling pathways
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Radhakrishnan Vishnubalaji1,2, Muthurangan Manikandan1, Mohamed Fahad1, Rimi Hamam1,3, Musaad Alfayez1, Moustapha Kassem1,2,4, Abdullah Aldahmash1,5 and Nehad M. Alajez1
1Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia
2Molecular Endocrinology Unit (KMEB), Department of Endocrinology, University Hospital of Odense and University of Southern Denmark, Odense, Denmark
3Departement de Medecine, Universite de Montreal, Montreal, Canada
4Department of Cellular and Molecular Medicine, Danish Stem Cell Center (DanStem), University of Copenhagen, Copenhagen, Denmark
5Prince Naif Health Research Center, King Saud University, Riyadh, Saudi Arabia
Nehad M. Alajez, email: [email protected]
Keywords: colorectal cancer; cancer stem cells; ALDH; microarray; resistance
Received: August 02, 2017 Accepted: February 01, 2018 Published: February 05, 2018
Tumour heterogeneity leads to variable clinical response and inaccurate diagnostic and prognostic assessment. Cancer stem cells (CSCs) represent a subpopulation responsible for invasion, metastasis, therapeutic resistance, and recurrence in many human cancer types. However, the true identity of colorectal cancer (CRC) SCs remains elusive. Here, we aimed to characterize and define the gene expression portrait of CSCs in CRC-model SW403 cells. We found that ALDH+ positive cells are clonogenic and highly proliferative; their global gene expression profiling-based molecular signature revealed gene enrichment related to DNA damage, MAPK, FAK, oxidative stress response, and Wnt signalling. ALDH+ cells showed enhanced ROS stress resistance, whereas MAPK/FAK pathway pharmacologic inhibition limited their survival. Conversely, 5-fluorouracil increased the ALDH+ cell fraction among the SW403, HCT116 and SW620 CRC models. Notably, analysis of ALDH1A1 and POU5F1 expression levels in cohorts of 462 or 420 patients for overall (OS) or disease-free (DFS) survival, respectively, obtained from the Cancer Genome Atlas CRC dataset, revealed strong association between elevated expression and poor OS (p = 0.006) and poor DFS (p = 0.05), thus implicating ALDH1A1 and POU5F1 in CRC prognosis. Our data reveal distinct molecular signature of ALDH+ CSCs in CRC and suggest pathways relevant for successful targeted therapies and management of CRC.
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