Glioblastoma stem cells: a new target for metformin and arsenic trioxide.

The high malignancy of glioblastoma has been recently attributed to the presence, within the tumor, of glioblastoma stem cells (GSC) poorly responsive to chemo- and radiotherapy. Here, the potential employment of metformin and arsenic trioxide (ATO) in glioblastoma therapy is discussed focusing on their effects on GSC. Metformin exerts anticancer effects by primarily blocking the pivotal LKB1/AMPK/mTOR/S6K1 pathway-dependent cell growth, induces selective lethal effects on GSC by impairing the GSC-initiating spherogenesis and inhibits the proliferation of CD133+ cells, while having a low or null effect on differentiated glioblastoma cells and normal human stem cells. Metformin and ATO induce autophagy and apoptosis in glioma cells by inhibiting and stimulating the PI3K/Akt and the mitogen-activated protein kinase pathways, respectively. Both drugs promote differentiation of GSC into non-tumorigenic cells. In this regard, metformin acts via activation of the AMPK-FOXO3 axis, whereas ATO blocks the interleukin 6-induced promotion of STAT3 phosphorylation. Blood-brain barrier, easily crossed by metformin but not by ATO, undergoes important glioblastoma-induced alterations that increase its permeability, thus allowing ATO to distribute more into the glioblastoma bulk than in the normal brain parenchyma. A prompt clinical assessment of metformin and ATO in glioblastoma patients would represent a valid attempt to improve their survival.

Paraneoplastic syndromes with connective tissue involvement. "It's not always lupus!".

Paraneoplastic syndromes (PNS) are remote effects of cancer that are, by definition, caused neither by invasion of the tumor or its metastases nor by infection, ischemia, metabolic and nutritional deficits, surgery or other forms of tumor treatment. The purpose of the current review was to present the challenging elements of differential diagnosis in oncology, as they may represent the main clinical problem in a patient diagnosed with cancer, even though the complete knowledge of both their clinical aspects and pathogenesis remain quite poor. This review focuses on the paraneoplastic syndromes related to dermatology and rheumatology, as the most frequent manifestations come from connective tissues that might determine a patient to ask for consultation by a general practitioner.

Antidiabetic pharmacology: a link between metabolic syndrome and neuro-oncology?

One of the main topics of the annual meeting of the American Society for Clinical Oncology in 2011 were the results presented on breast cancer chemotherapy and concomitant administration of the oral antidiabetic metformin. The overall agreement was that current evidence is just enough to dramatically change the clinical practice of oncology, and in our case, brain cancer treatment, and that further research is needed to address the relationship between diabetes, metabolism, insulin analogues and neoplasia. Still, it is very interesting to explore the potentially beneficial effects of metformin in glioma chemo/immunotherapy and wait for results in the clinic. In the current paper we present the cell and molecular aspects of the metabolic syndrome, metformin administration and cancer chemotherapy, with a special emphasis in neuro-oncology, since brain tumors are usually devastating diseases with an extremely high mortality within two years of diagnosis even when surgical, radiotherapeutic and chemotherapeutic interventions are applied.

Metformin plus temozolomide-based chemotherapy as adjuvant treatment for WHO grade III and IV malignant gliomas.

PURPOSE: Glioblastoma multiforme (GBM) remains one of the most devastating diseases known to man and affects more than 17,000 patients in the United States alone every year. This malignancy infiltrates the brain early in its course and makes complete neurosurgical resection almost impossible. Recent years have brought significant advances in tumor biology, including the discovery that many cancers, including gliomas, appear to be supported by cells with stem-like properties. In the current study we have investigated the effects of combining metformin with the standard treatment-of-care, as this drug, already used in the treatment of diabetes mellitus, has shown surprising results in the treatment of breast cancer, being also associated with lower mortality in several other malignancies. METHODS: The subjects of the current study were 8 patients with newly diagnosed high-grade gliomas, operated at the Department of Neurosurgery - Clinical University Emergency Hospital, Cluj Napoca. Tumor tissue cultures were established and characterized using immunofluorescence microscopy and PCR analysis and the sensitivity to metformin, epidermal growth factor (EGF) and temozolomide (TMZ) was tested. Microvascular density (MVD) assay was performed on the tumor samples. RESULTS: Seven of the 8 cases had a positive correlation between the number of endothelial cells, the phenotype of isolated tumor cells and the response to adjuvant chemoradiotherapy. The isolated tumor cells had a stem-like behavior, being resistant to conventional drugs. In most cases there was no statistical significant difference between TMZ alone and TMZ plus EGF arms, but there was a important difference between TMZ alone and TMZ plus metformin arms in 6 of the cases. CONCLUSION: New drugs and targeted molecular therapies are important for future therapeutics, but sometimes we must not exclude drugs already used in the clinic that might have remarkable results. Such is the case of metformin, a drug used for decades in the treatment of type 2 diabetes mellitus that has proven to enhance the effect of TMZ in the treatment of breast cancer and, starting with this paper, of brain cancer.

HLA Genotyping using Next Generation Sequencing.

From an oncological perspective, the second most common malignancies in children are brain tumors. Despite the recent therapeutic breakthroughs in this field, concerning surgery, radiotherapy and chemotherapy alike, some cases still have poor outcomes in curability. This is especially the case in patients with high-risk histological types of tumors, and those suffering from residual, remitting and disseminated diseases. Due to the unique neuroanatomical emplacement of brain tumors and their aggressive infiltrative behavior, their total removal remains a demanding task. This can be perceived in the high rates of failure treatment and disease recurrence. Furthermore, the adjacent healthy brain tissue is inevitably damaged in the surgical process of effectively removing these tumors. Thus, stem cell transplantation may be a viable solution for the clinical management of these malignancies, as proven by various recent breakthroughs. In the current concise review, we present the role of next generation sequencing in HLA typing for stem cell transplantation in primary CNS pediatric malignancies.

Metformin plus PIAF combination chemotherapy for hepatocellular carcinoma.

OBJECTIVES: Metformin, the most used oral antidiabetic drug for the treatment of type 2 diabetus mellitus, has proved encouraging results when used in the treatment of various types of cancer such as triple-negative breast cancer. Despite compelling evidence of a role of metformin as an anticancer drug, the mechanisms by which metformin exerts its oncostatic actions are not fully understood yet. Therefore, we tried to bring new insights by analyzing the anti-neoplastic effect of metformin for hepatocellular carcinoma-derived stem-like cells treated with conventional combination chemotherapy. METHODS: Cancer stem-like cells previusly isolated from a hepatocellular carcinoma biopsy were treated with metformin, PIAF chemotherapy regimen and the combination of these two protocols. Measurements of lipid peroxidation, reduced glutathione, fluorescein diacetate and proliferation rates were determined, apart from the autophagy assay and apoptosis determination by chip flow cytometry. RESULTS: Metformin alone and especially metformin in association with PIAF increases oxidative stress within the cells by increasing the levels of lipid peroxids as well as decreasing the levels of reduced glutathione. The MTT cell proliferation assay showed decreased prolife-ration rates for the arm treated with metformin and with the combination of drugs in comparison with the control arm, proving high correlation with the oxidative stress results. The autophagy assay and determination of apoptosis by chip flow cytometry confirmed the results obtained in the previous assays. CONCLUSION: Metformin could be used in chemotherapy treatments to induce reactive oxygen species and increase the cytostatics effects within the tumor cell. Still, further experiments must be carried out on murine models before we can move on and use this drugs in the adjuvant setting for unresectable primary liver cancer.

The axis of evil in the fight against cancer.

Over the past years medicine has undergone intensive changes, evolving from classical semiology and internal medicine to individualized treatments, based on recent breakthroughs in immunology and genetics. This concept has had a profound impact in all medical specialties and as a consequence pharmacology and various treatment plans will be based on monoclonal antibodies and targeted cell therapies. One such target is the SDF-1-CXCR4 axis bacause it plays a critical role in many physiological processes that involve cell migration and cell fate decisions, ranging from stem cell homing, angiogenesis and neuronal development to immune cell trafficking. The chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha are also implicated in various pathological conditions, including metastatic spread and HIV infection. In this review, we present the concept that the SDF-1-CXCR4 axis is a master regulator of trafficking of both normal and cancer stem cells, based on the growing evidence that it plays a pivotal role in the regulation of trafficking of normal hematopoietic stem cells and their homing to the bone marrow. Because most malignancies originate in the progenitor cell compartment, cancer stem cells also express CXCR4 on their surface and migrate to organs that highly express SDF-1. Hence, we postulate that the metastasis of cancer stem cells and trafficking of normal stem cells involve similar mechanisms, which may be regulated by several small molecules related to inflammation. Consequently, strategies aimed at modulating the SDF-1-CXCR4 axis could have important clinical applications in both tissue engineering and in clinical hematology and oncology to inhibit metastasis of cancer stem cells.

Stem-like cells in colorectal oncology.

Although the treatment for colorectal cancer has seen considerable progress during the past few years, the mortality associated with this type of tumor remains high. This article presents the existing methods of treatment, focusing on the new treatments made possible by the advances in the field of normal and tumor stem cells. Starting from the normal architecture of the colon and the properties of the cells identified in it, we sought to present a few notions concerning these cells which have a direct relevance for both pathology and treatment. The manner in which they divide (symmetrically or asymmetrically) as well as the molecules which control their circulation through the body are just a few examples which are likely to influence the treatment of colorectal cancer in the future.