Ju Mei,†,‡,∥ Nelson L. C. Leung,†,‡,∥ Ryan T. K. Kwok,†,‡ Jacky W. Y. Lam,†,‡ and Ben Zhong Tang*,†,‡,§ †HKUST-Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518057, China ‡Department of Chemistry, HKUST Jockey Club Institute for Advanced Study, Institute of Molecular Functional Materials, Division of Biomedical Engineering, State Key Laboratory of Molecular Neuroscience, Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Guangdong Innovative Research Team, SCUT-HKUST Joint Research Laboratory, State Key Laboratory of Luminescent Materials and Devices, South China University of Technology, Guangzhou 510640, China

Aggregation-Induced Emission: Together We Shine, United We Soar!

If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.

Why do cancers have high aerobic glycolysis

Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

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Regulation of cancer cell metabolism

Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis

Warburg's observation that cancer cells exhibit a high rate of glycolysis even in the presence of oxygen (aerobic glycolysis) sparked debate over the role of glycolysis in normal and cancer cells. Although it has been established that defects in mitochondrial respiration are not the cause of cancer or aerobic glycolysis, the advantages of enhanced glycolysis in cancer remain controversial. Many cells ranging from microbes to lymphocytes use aerobic glycolysis during rapid proliferation, which suggests it may play a fundamental role in supporting cell growth. Here, we review how glycolysis contributes to the metabolic processes of dividing cells. We provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass. We argue that the major function of aerobic glycolysis is to maintain high levels of glycolytic intermediates to support anabolic reactions in cells, thus providing an explanation for why in...

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Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

Proliferating embryonic and cancer cells preferentially use aerobic glycolysis to support growth, a metabolic alteration commonly referred to as the “Warburg effect.” Here, we show that the glycolytic enzyme hexokinase 2 (HK2) is crucial for the Warburg effect in human glioblastoma multiforme (GBM), the most common malignant brain tumor. In contrast to normal brain and low-grade gliomas, which express predominantly HK1, GBMs show increased HK2 expression. HK2 expression correlates with worse overall survival of GBM patients. Depletion of HK2, but neither HK1 nor pyruvate kinase M2, in GBM cells restored oxidative glucose metabolism and increased sensitivity to cell death inducers such as radiation and temozolomide. Intracranial xenografts of HK2-depleted GBM cells showed decreased proliferation and angiogenesis, but increased invasion, as well as diminished expression of hypoxia inducible factor 1α and vascular endothelial growth factor. In contrast, exogenous HK2 expression in GBM cells led to increased proliferation, therapeutic resistance, and intracranial growth. Growth was dependent on both glucose phosphorylation and mitochondrial translocation mediated by AKT signaling, which is often aberrantly activated in GBMs. Collectively, these findings suggest that therapeutic strategies to modulate the Warburg effect, such as targeting of HK2, may interfere with growth and therapeutic sensitivity of some GBMs.

https://rupress.org/jem/article-pdf/208/2/313/1205652/jem_20101470.pdf

Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme

Hypoxia exists in most human and rodent solid tumors and has been shown to correlate with poor survival in carcinoma of the cervix, carcinoma of the head and neck, and soft tissue sarcoma. It exists both chronically, due to the poorly organized vasculature of solid tumors, and acutely, due to fluctuations in blood flow. It has been found that tumors that are more hypoxic are more likely to metastasize in humans and in rodent models, and it has been demonstrated that exposure of tumor cells to hypoxia in vitro can transiently enhance their metastatic potential when they are reinjected i.v. into mice. The purpose of the present study was to determine whether experimentally imposed hypoxic stress in vivo , either chronic or acute, affects the process of spontaneous metastasis in tumor-bearing mice. We exposed mice bearing KHT tumors to low oxygen conditions (5–7% O2 breathing) daily during tumor growth in an attempt to induce additional chronic (2 h/day) and acute (12 × 10 min/day) hypoxia in their tumors. By monitoring tumor pO2 levels over the course of treatment, we demonstrated that these treatments produce acute and chronic hypoxia within the tumor tissue. The acute but not the chronic hypoxia treatment significantly increased the number of spontaneous microscopic lung metastases in the mice by a factor of about 2, and the results suggest that this effect was due to the changes induced in the primary tumor. This study describes a novel method for studying the effects of hypoxia in solid tumors and demonstrates that acute and chronic hypoxia can have different effects on tumor cell behavior in vivo .

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Acute (Cyclic) Hypoxia Enhances Spontaneous Metastasis of KHT Murine Tumors

As tumors progress to increased malignancy, cells within them develop the ability to invade into surrounding normal tissues and through tissue boundaries to form new growths (metastases) at sites distinct from the primary tumor. The molecular mechanisms involved in this process are incompletely understood but those associated with cell-cell and cell-matrix adhesion, with the degradation of extracellular matrix, and with the initiation and maintenance of early growth at the new site are generally accepted to be critical. This article discusses current knowledge of molecular events involved in these various processes. The potential role of adhesion molecules (eg. integrins and cadherins) has undergone a major transition over the last ten years, as it has become apparent that such molecules play a major role in signaling from outside to inside a cell, thereby controlling how a cell is able (or not) to sense and interact with its local environment. Similarly the roles of proteolytic enzymes and their inhibitors (eg. matrix metalloproteinases and TIMPs) have also expanded as it has become apparent that they not only have the abilities to break down the components of the extracellular matrix but also are involved in the release of factors which can affect the growth of the tumor cells positively or negatively. Recent work has highlighted the importance of the later, post-extravasational stages of metastasis, where adhesion and proteolysis are now known to play a role along with other processes such as apoptosis, dormancy, growth factor-receptor interactions and signal transduction. Recent work has also demonstrated that not only the immediate cellular microenvironment, in terms of specific cell-cell and cell-matrix interactions, but also the extended cellular microenvironment, in terms of vascular insufficiency and hypoxia in the primary tumor, can modify cellular gene expression and enhance metastasis. Mechanisms of metastasis appear to involve a complex array of genetic and epigenetic changes many of which appear to be specific both for different types of tumors and for different sites of metastasis. Our improved understanding of the expanded roles of the individual molecules involved has resulted in a mechanistic blurring of the previously described discrete stages of the metastatic process.

Molecular mechanisms of tumor invasion and metastasis: an integrated view.

An orthotopic mouse model of cervical carcinoma has been used to investigate the relationship between acute (cyclic) hypoxia and spontaneous lymph node metastasis in vivo. The human cervical carcinoma cell line ME-180 was stably transfected to express the fluorescent protein DsRed2, which allowed the in vivo optical monitoring of tumor growth and metastasis by fluorescent microscopy. The surgically implanted primary tumors metastasize initially to local lymph nodes and later to lung, a pattern consistent with the clinical course of the disease. The effect of acute hypoxia on the growth and spread of these tumors was examined by exposing tumor-bearing mice to treatment consisting of exposure to 12 cycles of 10 min 7% O(2) followed by 10 min air (total 4 h) daily during tumor growth. After 21 days, the tumors were excised, lymph node and lung metastases were quantified, and the hypoxic fraction and relative vascular area of the primary tumors were assessed by immunohistochemical staining for the hypoxic marker drug EF5 [2-(2-nitro-1H-imidazole-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] and the vascular marker CD31, respectively. In untreated mice, the primary tumor size was directly correlated with lymph node metastatic burden. The acute hypoxia treatment resulted in a significant decrease in the size of the primary tumors at the time of excision. However, the mice in the acute hypoxia group had an increased number of positive lymph nodes (2-4) as compared with control mice (1-3). Lung metastasis was not affected. The acute hypoxia treatment also decreased the relative vascular area in the primary tumors but did not affect the hypoxic fraction. These results suggest that fluctuating oxygenation in cervical carcinoma tumors may reduce tumor growth rate, but it may also enhance the ability of tumor cells to metastasize to local lymph nodes.

https://cancerres.aacrjournals.org/content/canres/64/6/2054.full.pdf

Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma.

The vascular supply to tumours is often poorly formed and irregular with the result that tumours may contain regions of poor nutritional supply with hypoxia and acidic pH. Clinical studies have demonstrated substantial heterogeneity in oxygenation in human tumours. In some studies tumours with poorer oxygenation were more likely to have metastasized. In our studies of carcinoma of the cervix, nodal metastases were 1.5 times more likely at diagnosis in patients with more hypoxic tumours relative to those with less hypoxic tumours. Transplanted rodent KHT fibrosarcomas and SCC-VII squamous cell tumours also have variability in levels of oxygenation; again, the more hypoxic tumours are found to be more metastatic. Furthermore, deliberate exposure of KHT tumours to cyclic hypoxia (12 cycles of 5% oxygen breathing for 10 min interspersed with 10 min air breathing) every day during their growth, doubled the level of micrometastases that were detected in the lungs of the mice. These findings are consistent with in vitro studies demonstrating that KHT and SCC-VII cells and B-16 melanoma cells exposed to hypoxia or low pH have increased propensity to form metastases following injection into-mice. This effect is transient and is lost within about 48 h of removal of exposure to hypoxia or low pH, suggesting that the effect may be due to changes in gene expression associated with that stress. Recent studies have implicated a number of genes, such as vascular endothelial growth factor and interleukin 8, in the effect of hypoxic and acid pH on metastasis.

Rob A. Cairns

Papers

Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme

Acute (Cyclic) Hypoxia Enhances Spontaneous Metastasis of KHT Murine Tumors

Molecular mechanisms of tumor invasion and metastasis: an integrated view.

Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma.

pH, hypoxia and metastasis.