Tumour hypoxia: Impact on biology, prognosis and treatment of solid malignant tumours
ABSTRACT Tumour hypoxia is a major constraint for radiotherapy and many types of chemotherapy. A variety of different pathogenetic mechanisms contribute to the development of hypoxia in solid tumours. Hypoxia is associated with unfavourable prognosis, regardless of the treatment modality applied. Two different effects have been considered to explain the deleterious effects of hypoxia on the outcome of tumour patients. The first aspect encompasses the direct interference of hypoxia with antineoplastic treatment modalities. The efficacy of ionizing radiation, but also of a variety of cytotoxic drugs and cytokines rely directly on adequate oxygen tensions. The second aspect concerns the effects of hypoxia on the biology of tumour and stromal cells. Hypoxia is related to malignant progression, increased invasion, angiogenesis and an increased risk of metastasis formation. Possibly, hypoxia is furthermore a stressor which selects cells with increased resistance to apoptosis and thereby indirectly contributes to treatment resistance. This article reviews in brief the specific pathophysiology of tumour oxygenation and its implications for prognosis, tumour treatment and biology.
SourceAvailable from: Aleksandra M Kubiak[Show abstract] [Hide abstract]
ABSTRACT: Despite substantial investment in prevention, treatment and aftercare, cancer remains a leading cause of death worldwide. More effective and accessible therapies are required. A potential solution is the use of endospore forming Clostridium species, either on their own, or as a tumour delivery vehicle for anti-cancer drugs. This is because intravenously injected spores of these obligate anaerobes can exclusively germinate in the hypoxic/necrotic regions present in solid tumours and nowhere else in the body. Research aimed at exploiting this unique phenomenon in anti-tumour strategies has been ongoing since the early part of the 20th century. Only in the last decade, however, has there been significant progress in the development and refinement of strategies based on spore-mediated tumour colonisation using a range of clostridial species. Much of this progress has been due to advances in genomics and our ability to modify strains using more sophisticated gene tools.Research in Microbiology 01/2015; 166(4). DOI:10.1016/j.resmic.2014.12.006 · 2.83 Impact Factor
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ABSTRACT: Epithelial-mesenchymal transition (EMT) is regarded as the most important mechanism behind the initiation of cancer metastasis. Though there has been great interest in developing therapies aimed at impairing the process of EMT, only few molecules have been identified to orchestrate it so far. Here we report that the dual PI3K/mTOR inhibitor NVP-BEZ235 is capable of preventing human ovarian cancer cell line SKOV-3 and prostatic cancer cell line PC-3 from hypoxia- and TGF-β1-induced EMT. The addition of NVP-BEZ235 reverses the EMT-like morphologic changes, down-regulation of E-cadherin, and enhancement of cell migration induced by 1% O2 partially through interfering with the expression and transcriptional activity of Hif-1α via PI3K/mTOR pathway. In addition, NVP-BEZ235 inhibits TGF-β1-induced phosphorylation of Smad2/3 and Akt/GSK-3β, reduces the expression of Snail both in transcriptional and post-translational level, and consequently prevents the repression of E-cadherin expression as well as the increase of cell motility caused by TGF-β1. Moreover, in nude mice bearing SKOV-3 ovarian cancer xenografts, NVP-BEZ235 significantly increases the mRNA level of E-cadherin. Taken together, our study demonstrates, for the first time, NVP-BEZ235 can prevent microenvironment and growth factor induced EMT, which suggests this agent as a potential candidate for cancer metastasis treatment.European journal of pharmacology 04/2014; 729. DOI:10.1016/j.ejphar.2014.02.011 · 2.68 Impact Factor
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ABSTRACT: A microfluidic system for cell culture and drug response studies was developed to elucidate the effects of hypoxia on drug susceptibility. Drug response studies were performed in prostate cancer cells and Ramos B cells under normoxic and hypoxic conditions. A vacuum actuated microfluidic culture device was used for cell culture and PC3 cells were cultured in the chip up to 16 hours. Cells were treated with several concentrations of staurosporine and apoptosis was assayed using the fluorescent probes MitoTracker Deep Red and Annexin-V. For hypoxic samples, the chip was placed in a hypoxia chamber and pre-conditioned at <1% oxygen before inducing the cells with staurosporine. Cells exposed to 2 μM staurosporine were 32% ± 10% apoptotic under normoxic conditions but only 1.5% ± 12% apoptotic under hypoxic conditions. As little as 1 hour of hypoxic preconditioning increased drug resistance. Cell apoptosis correlated with drug dose, although in each case hypoxia reduced the apoptotic fraction significantly. Given the rapid nature of cell adaptation to hypoxia, this chip and analysis approach can be used to identify compounds that can induce cell death in hypoxic tumor cells rapidly.The Analyst 01/2014; 139(13). DOI:10.1039/c3an02324a · 3.91 Impact Factor