Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment
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REVIEW
Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment Julia López de Andrés1,2,3, Carmen Griñán‑Lisón1,2,3, Gema Jiménez1,2,3,4* and Juan Antonio Marchal1,2,3,5*
Abstract Cancer stem cells (CSCs) represent a tumor subpopulation responsible for tumor metastasis and resistance to chemoand radiotherapy, ultimately leading to tumor relapse. As a consequence, the detection and eradication of this cell subpopulation represent a current challenge in oncology medicine. CSC phenotype is dependent on the tumor microenvironment (TME), which involves stem and differentiated tumor cells, as well as different cell types, such as mesenchymal stem cells, endothelial cells, fibroblasts and cells of the immune system, in addition to the extracellular matrix (ECM), different in composition to the ECM in healthy tissues. CSCs regulate multiple cancer hallmarks through the interaction with cells and ECM in their environment by secreting extracellular vesicles including exosomes, and soluble factors such as interleukins, cytokines, growth factors and other metabolites to the TME. Through these fac‑ tors, CSCs generate and activate their own tumor niche by recruiting stromal cells and modulate angiogenesis, metas‑ tasis, resistance to antitumor treatments and their own maintenance by the secretion of different factors such as IL-6, VEGF and TGF-ß. Due to the strong influence of the CSC secretome on disease development, the new antitumor therapies focus on targeting these communication networks to eradicate the tumor and prevent metastasis, tumor relapse and drug resistance. This review summarizes for the first time the main components of the CSC secretome and how they mediate different tumor processes. Lastly, the relevance of the CSC secretome in the development of more precise and personalized antitumor therapies is discussed. Keywords: Cancer stem cells, Tumor microenvironment, Secretome, Growth factors, Interleukins, miRNAs, Exosomes Introduction The cancer stem cell (CSC) model is based on the identification of tumor cells in different stages of differentiation in a wide variety of tumors, including ovarian [1], breast [2, 3], brain [4], lung cancer [5], melanoma [6], prostate [7], colorectal [8] and liver cancer [9]. All of them are composed by a small subpopulation of cells with stem cell-like characteristics such as quiescence, slow cell *Correspondence: [email protected]; [email protected] 2 Instituto de Investigación Biosanitaria Ibs.GRANADA, University Hospitals of Granada-University of Granada, 18100 Granada, Spain 5 Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, 18016 Granada, Spain Full list of author information is available at the end of the article
cycle, expression of embryonic SC transcription factors and epigenomic regulation driven by micro-RNAs (miRNAs) [10]. Like normal SCs, CSCs can self-renew and divide asymmetrically to give rise to daughter cells, which constitute the bulk of the tumor, and this
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