Angiogenesis-independent tumor growth mediated by stem-like cancer cells.

In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers, showed a migratory behavior similar to normal human neural stem cells, and gave rise to tumors in vivo after regrafting. Serial passages in animals gradually transformed the tumors into an angiogenesis-dependent phenotype. This process was characterized by a reduction in stem cells markers. Gene expression profiling combined with high throughput immunoblotting analyses of the angiogenic and nonangiogenic tumors identified distinct signaling networks in the two phenotypes. Furthermore, proinvasive genes were up-regulated and angiogenesis signaling genes were down-regulated in the stem-like tumors. In contrast, proinvasive genes were down-regulated in the angiogenesis-dependent tumors derived from the stem-like tumors. The described angiogenesis-independent tumor growth and the uncoupling of invasion and angiogenesis, represented by the stem-like cancer cells and the cells derived from them, respectively, point at two completely independent mechanisms that drive tumor progression. This article underlines the need for developing therapies that specifically target the stem-like cell pools in tumors.

Cell therapies for glioblastoma.

Malignant gliomas, including the most devastating type, glioblastoma multiforme (GBM), are characterised by their local growth and aggressive infiltration of the normal brain. GBMs result in a profound disability, leading to death in almost all cases. There has been little improvement in outcome despite intensive clinical and laboratory research during recent decades. Interestingly, many researchers have been successful in treating GBM models in animals, but the success has been limited when new treatment principles have been translated into the clinic. One reason for this failure is the lack of appropriate animal models that reflect the behaviour of human GBMs. Therapeutic progress has also been hindered by the limited delivery of effective therapeutic compounds to an extremely heterogenic tumour cell population. This article discusses the present use and limitations of preclinical animal models to study glioma growth and progression. In addition, it focuses on the potential use of cell-based therapies for the treatment of GBMs. This includes aspects of gene therapy, stem cell therapy and immunotherapy. Several of these treatment modalities use the principle of transplanting cells or compounds that either directly or indirectly show therapeutic efficacy. Many of these principles depend on an increased biological knowledge of gliomas. The development of new therapeutic principles based on such knowledge may finally provide glioma patients with an improved survival.

Distribution patterns of the anti-angiogenic protein ADAMTS-1 during rat development.

A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-1) belongs to the large ADAM family of proteins. ADAMTS-1 contains a metalloproteinase domain, a disintegrin domain and three thrombospondin-like repeats but unlike ADAMs lacks a transmembrane domain. For the elucidation of the biological functions of ADAMTS-1, we raised new antibodies against ADAMTS-1. We show an accumulation of ADAMTS-1 protein at the basal lamina of rat embryonal epithelia of intestines, nasal cavity, choroid plexus, skin and in intracellular storage vesicles of epithelial cells. ADAMTS-1 protein seems to play a role in the development of the neuronal system, adipose tissue, muscle, heart, liver and adrenal glands. At the time of birth its presence is reduced in most organs. However, in the developing bone as well as in the skin, labelling increased towards late embryonal development. Immunoblots revealed a strong presence of a 62 kDa ADAMTS-1 fragment in kidneys, adrenal glands, lungs, intestines and heart. ADAMTS-1 was also present in the corresponding adult rat organs, but in more restricted distribution patterns. It was typically found in principal cells of collecting ducts, of the renal medulla, in ependymal cells of the ventricles and in some neurons. The results were confirmed by real-time PCR. The specific distribution pattern of ADAMTS-1 in a variety of organs during embryogenesis suggests a role of the molecule in tissue remodelling, vasculogenesis and angiogenesis.

Migration, proliferation, and invasion of human glioma cells following treatment with simvastatin.

This study describes the migration, proliferation, and invasion behaviour of two human glioma cell lines, GaMg and U-87 Mg, grown as multicellular tumour spheroids after 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitor (simvastatin) therapy. Migration and proliferation studies were performed using simvastatin in concentrations of 0.2-30 microg/ml(-1). A coculture system in which tumour spheroids were confronted with foetal rat brain aggregates was used for invasion studies. A dose-dependent growth and migratory inhibitory response to simvastatin treatment was observed. Marked invasion of the glioma spheroids into the brain aggregates could be seen in both treated and nontreated groups. Simvastatin therapy inhibits tumour cell growth and migration, but the invasiveness of the remaining tumour cells seems to be unaffected.

Proliferation, migration, and invasion of human glioma cells exposed to fractionated radiotherapy in vitro.

Radiotherapy is a well established treatment for malignant gliomas. This study describes the migration, proliferation, and invasion behaviour of two human glioma cell lines (GaMg and U-87 Mg) grown as multicellular tumour spheroids after radiotherapy. Migration and proliferation studies were performed using conventional and accelerated fractionation up to 60 Gy and 59.4 Gy, respectively. A dose-dependent growth and migratory response to irradiation independent of the type of fractionation was observed. A coculture system in which tumour spheroids were confronted with foetal rat brain aggregates was used for invasion studies. Marked invasion of the glioma spheroids into the brain aggregates occurred with or without radiotherapy. For the GaMg cells, flow cytometric DNA histograms after treatment with 10 Gy and 40 Gy showed an accumulation of cells in the G2/M phase of the cell cycle. Radiotherapy inhibits tumour cell growth and migration, but the invasiveness of the remaining tumour cells seems to be unaffected.