/pdf/cancer-stem-cells-and-drug-resistance-the-potential-of-2yhm8xdpth.pdf

Cancer stem cells and drug resistance: the potential of nanomedicine.

Hypoxia is a microenvironmental factor which plays a critical role in development and tumor progression. The hypoxic response is mainly mediated by hypoxia inducible factor-1 (HIF-1) composed of HIF-1alpha and HIF-1beta, which becomes active under low oxygen condition. HIF-1 activates the transcription of hypoxia inducible genes which regulate diverse cellular functions including metabolism, angiogenesis and invasion. In cancer metastasis, HIF-1-regulated genes promote angiogenesis, invasion and epithelial-mesenchymal transition (EMT), a critical step of metastasis. TWIST is a master regulator of gastrulation and mesoderm specification and is recently implicated to be essential to mediate cancer metastasis. We recently showed that HIF-1 promotes EMT through direct regulation of TWIST expression. TWIST is critical for hypoxia mediated EMT and metastasis. TWIST plays a non-redundant role in relation to other EMT regulators (e.g., Snail) under hypoxia. Co-expression of HIF-1alpha, TWIST and Snail could be used as a prognostic marker in cancer patients. These findings suggest that hypoxia and/or HIF-1 orchestrates EMT and metastasis through the coordinated regulation of different EMT regulators. Our results provide the important link between hypoxia and developmental processes regulated by TWIST. The implications of the roles of hypoxia and TWIST in early embryonic development are discussed.

TWIST activation by hypoxia inducible factor-1 (HIF-1) : Implications in metastasis and development

Normal cells produce adenosine 5′-triphosphate (ATP) mainly through mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is available. Most cancer cells, on the other hand, are known to produce energy predominantly through accelerated glycolysis, followed by lactic acid fermentation even under normoxic conditions. This metabolic phenomenon, known as aerobic glycolysis or the Warburg effect, is less efficient compared with OXPHOS, from the viewpoint of the amount of ATP produced from one molecule of glucose. However, it and its accompanying pathway, the pentose phosphate pathway (PPP), have been reported to provide advantages for cancer cells by producing various metabolites essential for proliferation, malignant progression, and chemo/radioresistance. Here, focusing on a master transcriptional regulator of adaptive responses to hypoxia, the hypoxia-inducible factor 1 (HIF-1), we review the accumulated knowledge on the molecular basis and functions of the Warburg effect and its accompanying pathways. In addition, we summarize our own findings revealing that a novel HIF-1-activating factor enhances the antioxidant capacity and resultant radioresistance of cancer cells though reprogramming of the glucose metabolic pathway.

HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance

Radioresistance is a major factor leading to the failure of radiotherapy and poor prognosis in tumor patients. Following the application of radiotherapy, the activity of various metabolic pathways considerably changes, which may result in the development of resistance to radiation. Here, we discussed the relationships between radioresistance and mitochondrial and glucose metabolic pathways, aiming to elucidate the interplay between the tumor cell metabolism and radiotherapy resistance. In this review, we additionally summarized the potential therapeutic targets in the metabolic pathways. The aim of this review was to provide a theoretical basis and relevant references, which may lead to the improvement of the sensitivity of radiotherapy and prolong the survival of cancer patients.

/pdf/role-of-metabolism-in-cancer-cell-radioresistance-and-4s49140xzk.pdf

Role of metabolism in cancer cell radioresistance and radiosensitization methods.

A tumor-specific microenvironment is characterized by hypoxia, in which oxygen tension is considerably lower than in normal tissues. The hypoxic status of various solid tumors has been attributed as an indicator of adverse prognosis due to tumor progression toward a more malignant phenotype with increased metastatic potential and resistance to treatment. Various exogenous and endogenous markers for hypoxia are currently available and studied in relation to each other, tumor architecture, and tumor microenvironment. Over the last few decades, various methods have been suggested to assess the level of oxygenation in solid tumors. Among them, nitroimidazole compounds have provided promising information on tumor hypoxia. To quantify the extent of hypoxia requires that nitroimidazole binding be primarily dependent on oxygen concentration as well as nitroreductase levels in the tumor cells. Furthermore, recent progress in molecular biology has highlighted a transcription factor, hypoxia-inducible factor (HIF)-1, whose activity is induced by hypoxia. HIF-1 plays a central role in malignant progression by inducing the expression of various genes, whose functions are strongly associated with malignant alteration of the entire tumor. The cellular changes induced by HIF-1 are extremely important therapeutic targets of cancer therapy, particularly in the therapy against refractory cancers. In this review, we will discuss the significance of pimonidazole and HIF-1 as exogenous and endogenous hypoxia markers, respectively, as well as their evaluation and imaging of tumor hypoxia.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.2009.01195.x

Significance of nitroimidazole compounds and hypoxia-inducible factor-1 for imaging tumor hypoxia

Human solid tumors contain hypoxic regions that have considerably lower oxygen tension than the normal tissues. Hypoxia offers resistance to radiotherapy and anticancer chemotherapy, as well as predispose to increased tumor metastases. Furthermore, hypoxia induces hypoxia-inducible factor-1 (HIF-1), which in turn increases tumor angiogenesis. Thus, eradication of HIF-1-active/hypoxic tumor cells is very important for cancer therapy. We have previously reported that procaspase-3 fused with a von Hippel–Lindau (VHL)-mediated protein destruction motif of alpha subunit of HIF-1 (HIF-1α) containing Pro564, named TAT-ODD-procaspase-3 (TOP3), specifically induced cell death to hypoxic cells in vivo as well as in vitro. We now report that TOP3 also eradicates the radiation-induced HIF-1-active tumor cells. HIF-1 activity in the xenografts of human tumor cells, which express luciferase under the transcriptional control of HIF-1, were monitored and quantified daily with an in vivo bioluminescence photon-counting device. HIF-1 activity in tumors was more rapidly increased by ionizing radiation (IR) compared to untreated tumors. TOP3 efficiently decreased the HIF-1-activity in irradiated tumors as well as unirradiated ones, indicating TOP3 eradicated tumor cells with HIF-1-activity induced by IR as well as hypoxia. Eradication of HIF-1-active/hypoxic cells in the xenografts during irradiation exhibited significant suppression in angiogenesis and strong enhancement in a long-term growth suppression of tumor xenografts. These results further strengthen the argument that HIF-1-active/hypoxic cells play crucial roles in angiogenesis and radioresistance.

G Li

Papers

Significance of HIF-1-active cells in angiogenesis and radioresistance.