Roles of hypoxia in tumor progression and novel strategies for cancer treatment (original) (raw)
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The Role of Hypoxia-Induced Factors in Tumor Progression
The Oncologist, 2004
Hypoxia is a common characteristic of locally advanced solid tumors that has been associated with diminished therapeutic response and, more recently, with malignant progression, that is, an increasing probability of recurrence, locoregional spread, and distant metastasis. Emerging evidence indicates that the effect of hypoxia on malignant progression is mediated by a series of hypoxiainduced proteomic and genomic changes activating angiogenesis, anaerobic metabolism, and other processes that enable tumor cells to survive or escape their oxygen-deficient environment. The transcription factor hypoxiainducible factor 1 (HIF-1) is a major regulator of tumor cell adaptation to hypoxic stress. Tumor cells with proteomic and genomic changes favoring survival under hypoxic conditions will proliferate, thereby further aggravating the hypoxia. The selection and expansion of new (and more aggressive) clones, which eventually become the dominant tumor cell type, lead to the establishment of a vicious circle of hypoxia and malignant progression.
The American Journal of Pathology, 2008
Hypoxia and the acquisition of a glycolytic phenotype are intrinsic features of the tumor microenvironment. The hypoxia inducible factor-1␣ (HIF-1␣) pathway is activated under hypoxic conditions and orchestrates a complex transcriptional program that enhances cell survival. Although the consequences of HIF-1␣ inactivation in cancer cells have been widely investigated, only a few studies have addressed the role of HIF-1␣ in the survival of cancer cells endowed with different glycolytic capacities. In this study, we investigated this aspect in ovarian cancer cells. Hypoxia-induced toxicity was increased in highly glycolytic cells compared with poorly glycolytic cells; it was also associated with a sharp decrease in intracellular ATP levels and was prevented by glucose supplementation. Stable HIF-1␣ silencing enhanced hypoxia-induced cell death in vitro due to a lack of cell cycle arrest. Tumors bearing attenuated HIF-1␣ levels had similar growth rates and vascularization as did controls, but tumors showed higher proliferation levels and increased necrosis. Moreover, tumors formed by HIF-1␣ deficient cells had higher levels of lactate and lower ATP concentrations than controls as shown by metabolic imaging. The findings that such metabolic properties can affect the survival of cancer cells under hypoxic conditions and that these properties con-
Overexpression of hypoxia-inducible factor and metabolic pathways: possible targets of cancer
Cell & bioscience, 2017
Cancer, the main cause of human deaths in the modern world is a group of diseases. Anticancer drug discovery is a challenge for scientists because of involvement of multiple survival pathways of cancer cells. An extensive study on the regulation of each step of these pathways may help find a potential cancer target. Up-regulated HIF-1 expression and altered metabolic pathways are two classical characteristics of cancer. Oxygen-dependent (through pVHL, PHDs, calcium-mediated) and independent (through growth factor signaling pathway, mdm2 pathway, HSP90) regulation of HIF-1α leads to angiogenesis, metastasis, and cell survival. The two subunits of HIF-1 regulates in the same fashion through different mechanisms. HIF-1α translation upregulates via mammalian target of rapamycin and mitogen-activated protein kinase signaling pathways, whereas HIF-1β through calmodulin kinase. Further, the stabilized interactions of these two subunits are important for proper functioning. Also, metabolic ...
Hypoxia signalling in cancer and approaches to enforce tumour regression
Nature, 2006
We have learned, over the past two decades, how mammalian cells perceive signals to induce cell-cycle progression, proliferation and survival. Two major pathways that are frequently mutated in human cancer, the Ras-extracellular signal-regulated kinase (ERK) 1-3 and the phosphatidylinositol-3-OH kinase (PI(3)K)-AKT 4 (see the review in this issue by Shaw and Cantley, page 424) signalling cascades, are activated by a vast array of growth factor polypeptides, hormones and extracellular matrix proteins 5. Activation of these two pathways is sufficient to trigger multiple cycles of division and survival of normal cells under the 'rich' conditions of tissue culture. In vivo, however, growing cells must constantly instruct the microenvironment to maintain a supply of essential nutrients. It is remarkable that the Ras-ERK and PI(3)K-AKT pathways also control the expression of the ubiquitous vascular endothelial growth factor-A (VEGF-A), which is a key factor in vascularization/angiogenesis 6,7. During embryonic development or in the context of tumour expansion, growing cells rapidly outstrip the supply of nutrients. Although cells sense and respond to variations in concentrations of all nutrients, oxygen sensing has emerged as a central control mechanism of vasculogenesis 8,9. At the heart of this regulatory system is HIF 10,11 , which controls, among other gene products, the expression of two key angiogenic factors: VEGF-A 12 and angiopoietin-2 (Ang-2) 13. This finding has placed the hypoxia-signalling pathway at the forefront of nutritional control-a notion reinforced by the fact that growth factors enhance HIF expression and converge with hypoxia in inducing maximal expression of VEGF-A. HIF can induce a vast array of gene products controlling energy metabolism, neovascularization, survival, pH i and cell migration, and has become recognized as a strong promoter of tumour growth 14. This pro-oncogenic feature is only one facet of the dual action of HIF. Besides being a 'guardian' of oxygen homeostasis, HIF is capable of inducing pro-apoptotic genes 14 leading to autophagy and cell death, which can be features of hypoxic tissues. In this regard, HIF can be likened to p53, which has dual roles as a guardian of genome integrity and a promoter of apoptosis. In this review we highlight the most recently revealed features of hypoxia signalling, and the role of hif as a master gene controlling nutritional stress, angiogenesis, tumour metabolism, invasion and autophagy/ cell death. Finally, we discuss potential new and exciting approaches to
Cancer and Metastasis Reviews, 2007
A major feature of solid tumours is hypoxia, decreased availability of oxygen, which increases patient treatment resistance and favours tumour progression. How hypoxic conditions are generated in tumour tissues and how cells respond to hypoxia are essential questions in understanding tumour progression and metastasis. Massive tumour-cell proliferation distances cells from the vasculature, leading to a deficiency in the local environment of blood carrying oxygen and nutrients. Such hypoxic conditions induce a molecular response, in both normal and neoplastic cells, that drives the activation of a key transcription factor; the hypoxia-inducible factor. This transcription factor regulates a large panel of genes that are exploited by tumour cells for survival, resistance to treatment and escape from a nutrient-deprived environment. Although now recognized as a major contributor to cancer progression and to treatment failure, the precise role of hypoxia signalling in cancer and in prognosis still needs to be further defined. It is hoped that a better understanding of the mechanisms implicated will lead to alternative and more efficient therapeutic approaches.
Anatomy and Cell Biology 2012; 45:73 - 78, 2012
Hypoxia, defined as a decrease of tissue oxygen levels, represents a fundamental pathophysiological condition in the microenvironment of solid tumors. Tumor hypoxia is known to be associated with radio/chemo-resistance and metastasis that eventually lead to cancer progression contributing to poor prognosis in cancer patients. Among transcription factors that accumulated under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1) is a master transcription factor that has received the most intense attention in this field of research due to its capacity to modulate several hundred genes. With a clearer understanding of the HIF-1 pathway, eff orts are directed at manipulation of this complex genetic process in order to ultimately decrease cellular HIF-1 levels. Some novel agents have been shown to have HIF-1 inhibition activity through a variety of molecular mechanisms and have provided promising results in the preclinical setting.
Targeting hypoxia cell signaling for cancer therapy
Cancer and Metastasis Reviews, 2007
Hypoxia, a decrease in oxygen levels, is a hallmark of solid tumors. Hypoxic cells are more resistant to killing by ionizing radiation and chemotherapy, are more invasive and metastatic, resistant to apoptosis, and genetically unstable. Over the last two decades, the discovery of Hypoxia Inducible Factors, a family of transcription factors crucially involved in the response of mammalian cells to oxygen deprivation, has led to the identification of a molecular target associated with hypoxia suitable for the development of cancer therapeutics. These features of solid tumors may offer a unique opportunity for selective therapeutic approaches. A number of strategies targeting hypoxia and/or Hypoxia Inducible Factors (HIF) have been developed over the last several years and will be described. The exponentially growing interest in therapeutic strategies targeting hypoxia/HIF will undoubtedly generate more active compounds for preclinical and clinical development. A rational development plan aimed to validate target inhibition in preclinical models and early clinical trials is essential for a rapid translation of these agents to the treatment of human cancers.
International Journal of Advanced Research, 2020
Oxygen and nutrients are delivered to the cells with the help of the vascular networking system, which makes availability of oxygen as primary regulator for many processes. Low oxygen availability condition activates the Hypoxia Inducible Factors (HIF), which are transcription regulators helping in the expression of genes related to cell cycle regulation and angiogenesis. HIF is hence regarded as the master regulator of angiogenesis. The oxygen deprival is due to the increased consumption of oxygen in the tumor microenvironment and in turn leads to hypoxia. A thorough understanding of how hypoxia influences angiogenesis mediated by several pathways has become essential for identifying novel strategies targeting HIF thereby blocking angiogenesis. In this review we would discuss about the HIF signaling pathways and altered functions of immune cells due to hypoxia by considering that reducing or targeting hypoxia may in turn prevent the suppression of anti-tumor immune response.
Frontiers in Genetics
Metabolic alterations are one of the hallmarks of cancer, which has recently gained great attention. Increased glucose absorption and lactate secretion in cancer cells are characterized by the Warburg effect, which is caused by the metabolic changes in the tumor tissue. Cancer cells switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis due to changes in glucose degradation mechanisms, a process known as “metabolic reprogramming”. As a result, proteins involved in mediating the altered metabolic pathways identified in cancer cells pose novel therapeutic targets. Hypoxic tumor microenvironment (HTM) is anticipated to trigger and promote metabolic alterations, oncogene activation, epithelial-mesenchymal transition, and drug resistance, all of which are hallmarks of aggressive cancer behaviour. Angiogenesis, erythropoiesis, glycolysis regulation, glucose transport, acidosis regulators have all been orchestrated through the activation and stability of a transcription facto...