Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment

(2020) 13:136 López de Andrés et al. J Hematol Oncol https://doi.org/10.1186/s13045-020-00966-3 Open Access 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: ; 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 makes CSCs are responsible for the maintenance and proliferation of the tumor, as observed in healthy tissues [11]. However, identification of these subpopulations has not been easy, and although several markers have been described, tumor heterogeneity and inter-patient variations make it difficult to define robust markers [12]. In general terms, the most commonly used indicators to identify CSCs are surface markers such as CD133 and CD44 [13, 14], increased activity of aldehyde © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. López de Andrés et al. J Hematol Oncol (2020) 13:136 dehydrogenase (ALDH) [14, 15] and their ability to exclude Hoechst 33342 (side population) [16], and to form spheres in vitro [17]. In addition, CSCs drive tumor drug resistance due to their ability to enter a quiescent state, activate DNA repair mechanisms, reactivate drug efflux system and protect against ROS [12], ultimately being responsible for disease relapse. Therefore, the CSC model explains the poor prognosis of the disease and indicates that identifying and attacking CSCs are currently a major challenge in cancer research. As the importance of CSCs in tumor development has been elucidated, special attention has also been paid to their environment, since the tumor niche has a strong influence on the tumor behavior. The tumor microenvironment (TME) includes stem and differentiated cancer cells, the extracellular matrix (ECM), mesenchymal stem cells (MSCs), cancer-associated fibroblasts (CAFs), endothelial cells (ECs), immune system cells, and a complex network of cytokines and growth factors [18]. All these components orchestrate tumor processes in different ways. Non-tumor and differentiated tumor cells interact closely with CSCs by modulating their activity and contributing to key tumor processes such as tumor growth, metastasis, angiogenesis and immune system evasion [18]. Indeed, TME cells also promote resistance to antitumor therapies, since the secretion of soluble factors such as interleukin-6 (IL-6), hepatocyte growth factor (HGF), fibroblast growth factor (FGF), or transforming growth factor ß (TGF-ß) and ECM adhesion proteins such as integrins leads to the activation of several tumor survival pathways [19]. Additionally, the ECM has a different composition, organization and posttranscriptional modification in the TME than the surrounding normal tissue [20] and largely influences the intratumor signaling, transport mechanism, cell motility, metastasis and immune response [21, 22]. Moreover, tumor ECM shows higher density and stiffness, which can interfere on nutrient, oxygen and metabolite diffusion which in turn lead to tumor hypoxia. This stiff ECM also acts as a physical barrier to the action of chemoand radiotherapy agents. Tumor hypoxia and the barrier capacity are rela (...truncated)