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Glioblastoma (GBM) is one of the most aggressive forms of cancer. It has been proposed that the presence within these tumors of a population of cells with stem-like features termed Glioma Initiating Cells (GICs) is responsible for the relapses that take place in the patients with this disease. Targeting this cell population is therefore an issue of great therapeutic interest in neuro-oncology. We had previously found that the neurotrophic factor MIDKINE (MDK) promotes resistance to glioma cell death. The main objective of this work is therefore investigating the role of MDK in the regulation of GICs. Methods : Assays of gene and protein expression, self-renewal capacity, autophagy and apoptosis in cultures of GICs derived from GBM samples subjected to different treatments. Analysis of the growth of GICs-derived xenografts generated in mice upon blockade of the MDK and its receptor the ALK receptor tyrosine kinase (ALK) upon exposure to different treatments. Results : Genetic or pharmacological inhibition of MDK or ALK decreases the self-renewal and tumorigenic capacity of GICs via the autophagic degradation of the transcription factor SOX9. Blockade of the MDK/ALK axis in combination with temozolomide depletes the population of GICs in vitro and has a potent anticancer activity in xenografts derived from GICs. Conclusions : The MDK/ALK axis regulates the self-renewal capacity of GICs by controlling the autophagic degradation of the transcription factor SOX9. Inhibition of the MDK/ALK axis may be a therapeutic strategy to target GICs in GBM patients., Competing Interests: Competing Interests: Research in G Velasco's group was partially funded by LYRAMID. J Sepúlveda received a grant from Pfizer that provided pure substance for the study., (© The author(s).)

Metformin, a drug widely used in the treatment of type II diabetes mellitus (T2DM), has been the focus of interest as a potential therapeutic agent for certain types of malignancies, including gynaecological cancers [i.e. endometrial cancer (EC)]. Although the exact mechanism behind the potential anticancer activity of metformin is still not completely understood, certain studies have suggested that different effects on cell functions, such as inhibition of cell migration, apoptosis and tumor cell proliferation, are involved in its preventive and therapeutic effects in certain types of malignancies, including EC. In contrast, midkine (MK), a heparin-binding growth factor and cytokine, which induces carcinogenesis and chemoresistance, promotes the development and progression of many malignant tumours by increasing diverse cell functions such as cell proliferation, cell survival and antiapoptotic activities via mainly the activation of phosphatidyl inositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. The same pathways are also subject to certain therapeutic effects of metformin, although this cytokine and this drug have some different mechanism of action pathways as well. Taken together, MK and metformin appear to have opposite effects in various biological processes such as apoptosis, cell proliferation, cell survival, cell migration, and angiogenesis. On the other hand, MK activates PI3K and MAPK cell signal pathways, whereas metformin inhibits these two pathways. It seems likely that almost all the pathways and cell functions, which play important roles in malignancies, are inhibited by metformin and activated by MK. Given the opposite relationship between the actions of metformin and MK, we hypothesize that metformin may act like a novel MK inhibitor in some malignancies. We also discuss the possible relationship between metformin and MK in the context of EC, the most common gynecological cancer worldwide, which incidence is rising rapidly, in parallel with the increase in obesity, T2DM and insulin resistance. In this respect, the therapeutic use of metformin may improve the survival of EC or other cancers, via inhibiting or overcoming the unwanted effects of MK in carcinogenesis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Midkine (MK) is a heparin-binding anti-apoptotic growth factor or cytokine also known as neurite growth-promoting factor 2 (NEGF2). It is developmentally an important retinoic acid-responsive gene product strongly induced during the mid-gestation stage. Midkine promotes different cellular events such as cell growth, differentiation, survival, gene expression, and drug resistence. Midkine, the phosphatidylinositol 3-kinases (PI3-kinase, PI3K) and glycogen synthase kinase-3 beta (GSK-3β) inhibitors together with lithium chloride may be a very effective treatment modality, especially in tumors with high expression of these two molecules. PI3 kinase and GSK-3β, both serine threonine kinases located in the center of the signaling network, are very important regulator molecules for cell survival or death. Lithium chloride (LiCl), with its newly discovered antineoplastic effect and cytotoxicity potentiation, has become a promising agent in the application of new combination treatments. Although the LiCl mechanism of action is still not fully understood, previous studies have shown that LiCl is an inhibitör of the inositol monophosphatase (IMPase) and GSK-3β. GSK-3β, is a serine-threonine protein kinase involved in cell proliferation, differentiation, survival, apotosis, and tumorogenesis. The role of GSK-3β in tumorigenesis and cancer remains controversial. It may have a function as a tumor suppressor for certain types of tumors, but it promotes cell growth and development in other tumor types.