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Additional file 1: Figure S1. Immunohistochemical distribution of CLIC1 in GBM. Figure S2. A) CLIC1 expression in GSCs isolated from 14 human GBMs, evaluated by RNA-seq, and expressed as counts per million reads mapped (CPM). Only GBM 39 (arrow) displayed low CLIC1 mRNA content. The Table reports the corresponding codes of the GSC cultures used in this study and the RNA-seq data deposited at NCBI Geo data set. B) Upper panel: CLIC1 expression evaluated by WB, in total cell lysates from selected GSC cultures. Membranes were re-probed with ��-tubulin antibody after stripping and used as a reference for protein loading. Lower panel: Histograms report CLIC1/��-tubulin ratio of densitometric values and expressed in arbitrary units (A.U.) as mean �� S.D. Figure S3. Dose-response curves of novel biguanide derivatives and metformin on individual GSC cultures. The average response is reported in the Fig. 1A of the manuscript. Figure S4. Dose-response curves of novel biguanide derivatives and metformin on individual non-stem differentiated GBM cell cultures (GBM D). The average response is reported in the Fig. 1B of the manuscript. Figure S5. Dose-response curves of metformin and novel biguanide derivatives on individual ucMSC cultures. The average response is reported in the Fig. 1C of the manuscript. Figure S6. Kaplan-Mayer curves of Q48, Q54, and metformin (MET) depicting the effect of supramaximal concentration of these compounds on zebrafish embryos survival. Limited toxicity, not different from controls, was observed for all the compounds up to 5 days of treatment. Experiments were repeated twice, n = 20 per experimental group. Q48: log rank test for trend p = 0.62; Q54: log rank test for trend p = 0.64; metformin: log rank test for trend p = 0.38. Figure S7. Effect of different doses of metformin and Q54 on chick embryo survival after 10 days of incubation. Experiments were performed by Inovotion (La Tronche, France). No toxicity was observed for these compounds up to 3 mM. Experiments were repeated twice, n = 18 per experimental group. Figure S8. A. Dose-response curves of Q46, Q48, Q54 and metformin on rat astrocyte cultures. Limited toxicity is observed for all the novel compounds. Only metformin reduced astrocyte viability (��� 50%) at the highest concentration tested (30 mM). Data are expressed as average of experiments preformed in quadruplicate and repeated twice. B. Table reports IC50 values in non-malignant rat astrocytes and GSCs and the calculated selectivity indices for each compound. According to the ���selectivity criteria��� all biguanides are considered selective compounds against GSCs (selectivity index > 10) (see reference [62]). Figure S9. A. CLIC1 expression in GBM19 GSCs carrying siRNA for both Luciferase (siLuc, silencing control) and CLIC1 (siCLIC1). B. Cell proliferation of GBM19 siLuc and GBM19 siCLIC1, treated with Q48 and Q54 (100 ��M) for 48 h and evaluated by counting live cells. Data represent the mean �� S.E.M. ***p

Peptide receptors involved in pathophysiological processes represent promising therapeutic targets. Neuropeptide somatostatin (SST) is produced by specialized cells in a large number of human organs and tissues. SST primarily acts as inhibitor of endocrine and exocrine secretion via the activation of five G-protein-coupled receptors, named sst1–5, while in central nervous system, SST acts as a neurotransmitter/neuromodulator, regulating locomotory and cognitive functions. Critical points of SST/SST receptor biology, such as signaling pathways of individual receptor subtypes, homo- and heterodimerization, trafficking, and cross-talk with growth factor receptors, have been extensively studied, although functions associated with several pathological conditions, including cancer, are still not completely unraveled. Importantly, SST exerts antiproliferative and antiangiogenic effects on cancer cells in vitro, and on experimental tumors in vivo. Moreover, SST agonists are clinically effective as antitumor agents for pituitary adenomas and gastro-pancreatic neuroendocrine tumors. However, SST receptors being expressed by tumor cells of various tumor histotypes, their pharmacological use is potentially extendible to other cancer types, although to date no significant results have been obtained. In this paper the most recent findings on the expression and functional roles of SST and SST receptors in tumor cells are discussed.

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Ovarian cancer is the most common type of gynecologic malignancy. Despite advances in surgery and chemotherapy, the survival rate is still low since most ovarian cancers relapse and become drug-resistant. Chemokines are small chemoattractant peptides mainly involved in the immune responses. More recently, chemokines were also demonstrated to regulate extra-immunological functions. It was shown that the chemokine network plays crucial functions in the tumorigenesis in several tissues. In particular the imbalanced or aberrant expression of CXCL12 and its receptor CXCR4 strongly affects cancer cell proliferation, recruitment of immunosuppressive cells, neovascularization, and metastasization. In the last years, several molecules able to target CXCR4 or CXCL12 have been developed to interfere with tumor growth, including pharmacological inhibitors, antagonists, and specific antibodies. This chemokine ligand/receptor pair was also proposed to represent an innovative therapeutic target for the treatment of ovarian cancer. Thus, a thorough understanding of ovarian cancer biology, and how chemokines may control these different biological activities might lead to the development of more effective therapies. This paper will focus on the current biology of CXCL12/CXCR4 axis in the context of understanding their potential role in ovarian cancer development.