The role of stem cells in glioma progression and therapy

Izvor tumorjev in stohastično naravo procesa karcinogeneze najbolje opisuje hierarhični model, ki predvideva obstoj tumorskih matičnih celic (TMC). Slednje predstavljajo populacijo celic z neomejenim samoobnovitvenim potencialom, ki so se sposobne diferencirati v vrste celic vseh treh zarodnih linij in so manj občutljive na večino protirakavih učinkovin. Zato predstavljajo glavni vir za razvoj in rast tumorja, zaradi svoje odpornosti na kemoterapijo pa so vzrok za ponovitev bolezni. Za uspešno zdravljenje možganskega tumorja glioma in njegove najbolj maligne oblike, glioblastoma multiformae (GBM), bi zato bilo potrebno odstraniti prav vse TMC. Žal slednjega zaradi prehitre infiltrativne vrasti subpopulacije GBM celic z visoko izraženimi geni za gibljivost (migratom) v okolno zdravo možgansko tkivo, ni možno doseči s trenutno uporabljanimi načini zdravljenja (npr. kirurškim izrezom) Poleg TMC, ki so ključne za razvoj in razrast tumorja, tkivo tumorja vsebuje še hematopoetske matične celice, endotelne predniške celice in mezenhimske matične celice (MMC). Delovanje teh drugih vrst matičnih celic, kjer je bila celicam MMC že dokazana protitumorska aktivnost v GBM, pa je odvisno od tumorskega mikrookolja. Žal mehanizmi in delovanje MMC med modulacijo rasti tumorja preko parakrinih in neposrednih interakcij z GBM (matičnimi) celicami še niso znani. Kljub temu pa matične celice, s poudarkom na MMC, predstavljajo nove nosilce npr. za ciljni vnos terapevtske učinkovine v tumor, ki bi lahko izboljšali učinkovitost trenutnih protitumorskih terapij. Razvoj celičnih zdravil veliko obeta, saj so MMC, poleg svojih imunomodulacijskih lastnosti, sposobne tudi usmerjenega gibanja v GBM in tam učinkovati, o čemer razpravlja ta prispevek.The concepts of tumour origin and stochastic nature of carcinogenesis are being challenged today by hierarchical models that predict the existence of cancer stem cells (CSCs), which are postulated as unique cell population capable of infinite self renewal, multilineage differentiation and having a higher resistance to conventional cancer therapy–thus facilitating malignant growth and therapy resistance. Accordingly, successful treatment of adult brain tumour–glioma and its most malignant stage–glioblastoma multiforme (GBM), would require the elimination of CSCs to avoid tumour relapse. Yet, with available therapy (i.e. surgery) in GBMs this cannot be achieved, due to infiltrative growth of a subpopluation of GBM cells with highly expressed migratory genes (migratome) into the normal brain tissue

The role of stem cells in glioma progression and therapy

The concepts of tumour origin and stochastic nature of carcinogenesis are being challenged today by hierarchical models that predict the existence of cancer stem cells (CSCs), which are postulated as unique cell population capable of infinite self renewal, multilineage differentiation and having a higher resistance to conventional cancer therapy thus facilitating malignant growth and therapy resistance. Accordingly, successful treatment of adult brain tumourglioma and its most malignant stageglioblastoma multiforme (GBM), would require the elimination of CSCs to avoid tumour relapse. Yet, with available therapy (i.e. surgery) in GBMs this cannot be achieved, due to infiltrative growth of a subpopluation of GBM cells with highly expressed migratory genes (migratome) into the normal brain tissue. Besides CSCs a proven prerequisite for tumour development and progression, tumour bulk mass also comprises haematopoietic stem cells, endothelial progenitor cells and mesenchymal stem cells (MSCs). The role of these other types of stem cell was shown to largely depend on the tumour microenvironment, where their contradictory anti-tumour action was evidenced. Yet, the exact mechanisms and MSCs role in cell-mediated modulation of tumour behaviour via paracrine and direct interactions with GBM (stem) cells still remain unknown. Nevertheless these stem cells, particularly MSCs, may represent novel therapeutic vectors for enhanced target-site delivery of chemotherapeutics, which are urgently needed to improve efficiency of current glioma treatment. So far, cell therapy using MSCs appears promising, due to MSCs selective tumour tropism and their immuno-modulatory potential regarding treatment of GBM, which will be discussed in this review

Complexity of cancer protease biology: Cathepsin K expression and function in cancer progression

Proteases, including lysosomal cathepsins, are functionally involved in many processes in cancer progression from its initiation to invasion and metastatic spread. Only recently, cathepsin K (CatK), the cysteine protease originally reported as a collagenolytic protease produced by osteoclasts, appeared to be overexpressed as well in various types of cancers. In this review, the physiological functions of CatK are presented and compared to its potential role in pathobiolology of processes associated with tumour growth, invasion and metastasis of cancer cells and their interactions with the tumour microenvironment. CatK activity is either indirectly affecting signalling pathways, or directly degrading extracellular matrix (ECM) proteins, for example in bone metastases. Recently, CatK was also found in glioma, possibly regulating cancer stem-like cell mobilisation and modulating recently found physiological CatK substrates, including chemokines and growth factors. Moreover, CatK may be useful in differential diagnosis and may have prognostic value. Finally, the application of CatK inhibitors, which are already in clinical trials for treatment of osteoporosis, has a potential to attenuate cancer aggressivenes

Transmembrane protein CD9 is glioblastoma biomarker, relevant for maintenance of glioblastoma stem cells

The cancer stem cell model suggests that glioblastomas contain a subpopulation of stem-like tumor cells that reproduce themselves to sustain tumor growth. Targeting these cells thus represents a novel treatment strategy and therefore more specific markers that characterize glioblastoma stem cells need to be identified. In the present study, we performed transcriptomic analysis of glioblastoma tissues compared to normal brain tissues revealing sensible up-regulation of CD9 gene. CD9 encodes the transmembrane protein tetraspanin which is involved in tumor cell invasion, apoptosis and resistance to chemotherapy. Using the public REMBRANDT database for brain tumors, we confirmed the prognostic value of CD9, whereby a more than two fold up-regulation correlates with shorter patient survival. We validated CD9 gene and protein expression showing selective up-regulation in glioblastoma stem cells isolated from primary biopsies and in primary organotypic glioblastoma spheroids as well as in U87-MG and U373 glioblastoma cell lines. In contrast, no or low CD9 gene expression was observed in normal human astrocytes, normal brain tissue and neural stem cells. CD9 silencing in three CD133+ glioblastoma cell lines (NCH644, NCH421k and NCH660h) led to decreased cell proliferation, survival, invasion, and self-renewal ability, and altered expression of the stem-cell markers CD133, nestin and SOX2. Moreover, CD9-silenced glioblastoma stem cells showed altered activation patterns of the Akt, MapK and Stat3 signaling transducers. Orthotopic xenotransplantation of CD9-silenced glioblastoma stem cells into nude rats promoted prolonged survival. Therefore, CD9 should be further evaluated as a target for glioblastoma treatment

La Vigie marocaine

08 avril 19361936/04/08 (A27,N8879)-1936/04/08

Identification of plasma biomarker candidates in glioblastoma using an antibody-array-based proteomic approach

Background. Glioblastoma multiforme (GBM) is a brain tumour with a very high patient mortality rate, with a median survival of 47 weeks. This might be improved by the identification of novel diagnostic, prognostic and predictive therapy-response biomarkers, preferentially through the monitoring of the patient blood. The aim of this study was to define the impact of GBM in terms of alterations of the plasma protein levels in these patients. Materials and methods. We used a commercially available antibody array that includes 656 antibodies to analyse blood plasma samples from 17 healthy volunteers in comparison with 17 blood plasma samples from patients with GBM. Results. We identified 11 plasma proteins that are statistically most strongly associated with the presence of GBM. These proteins belong to three functional signalling pathways: T-cell signalling and immune responsescell adhesion and migrationand cell-cycle control and apoptosis. Thus, we can consider this identified set of proteins as potential diagnostic biomarker candidates for GBM. In addition, a set of 16 plasma proteins were significantly associated with the overall survival of these patients with GBM. Guanine nucleotide binding protein alpha (GNAO1) was associated with both GBM presence and survival of patients with GBM. Conclusions. Antibody array analysis represents a useful tool for the screening of plasma samples for potential cancer biomarker candidates in small-scale exploratory experimentshowever, clinical validation of these candidates requires their further evaluation in a larger study on an independent cohort of patients

Scheme of cellular processes and activities involving overexpressed protease and protease inhibitor genes in GBM.

<p>The overexpressed protease and inhibitor genes in GBM tissues and cells were queried by the Biomine search engine which identified processes and activities ascribed with KEGG and GO identifiers (in circles) in which selected genes (in bold caption) are involved.</p

Signaling pathways in which the candidate genes are involved.

<p>An extensive literature search revealed that the candidate genes are cross-linked to 3 signaling pathways: NF-κB, Akt and MAPK, which all play a role in cancer. NF-κB signaling pathway has a crucial role in regulating immune responses, whereas Akt signaling has been shown to inhibit the growth of GBM cells and GBM stem-like cells that may also be impaired by MAPK signaling disruption. Because of the RT-qPCR results, <i>CTSK</i>'s role has been examined and it was found via cross linking to other candidate genes obtained via osteopontin (<i>OPN</i>) gene functions.</p