Metabolic regulation of the tumour and its microenvironment: The role of Epstein-Barr virus.

The Epstein-Barr virus (EBV), the first identified human tumour virus, infects over 95% of the individuals globally and has the potential to induce different types of cancers. It is increasingly recognised that EBV infection not only alters cellular metabolism, contributing to neoplastic transformation, but also utilises several non-cell autonomous mechanisms to shape the metabolic milieu in the tumour microenvironment (TME) and its constituent stromal and immune cells. In this review, we explore how EBV modulates metabolism to shape the interactions between cancer cells, stromal cells, and immune cells within a hypoxic and acidic TME. We highlight how metabolites resulting from EBV infection act as paracrine factors to regulate the TME, and how targeting them can disrupt barriers to immunotherapy.

Evolution of transoral endoscopic thyroidectomy vestibular approach according to the IDEAL framework.

BACKGROUND: The IDEAL Framework is a scheme for safe implementation and assessment of surgical innovation. The transoral endoscopic thyroidectomy vestibular approach (TOETVA) is a new innovation in thyroid surgery that eliminates the need for a cervical incision. Despite considerable interest and adoption worldwide, significant scepticism remains regarding the outcomes and cost-effectiveness for healthcare systems. The aim of this narrative review was to appraise the available literature and examine whether TOETVA has progressed in line with the IDEAL Framework. METHODS: A literature review of PubMed with a focus on historical and landmark studies was undertaken to classify the evidence according to the different stages of the IDEAL Framework. RESULTS: Several different transoral approaches were developed by a small of number of surgeon-innovators on animals and cadavers, and subsequently in first-in-human studies. The trivestibular approach emerged as the safest technique, with further refinements of this technique culminating in TOETVA. The basic steps and indications for this technique have been standardized and it is now being replicated by early adopters in many centres worldwide. The development of TOETVA has closely aligned with the IDEAL Framework, and is currently at stage 2B (Exploration). CONCLUSION: There is need for multi-institutional collaborations and international registry studies to plan high-quality randomized trials comparing TOETVA with other remote-access approaches and collect long-term follow-up data. In countries where TOETVA has yet to be adopted, the IDEAL Framework will be a useful roadmap for government regulators and professional societies to evaluate, regulate, and provide best practice recommendations for the adoption of this technique.

Negative Index Metamaterial-Based Frequency-Reconfigurable Textile CPW Antenna for Microwave Imaging of Breast Cancer.

In this paper, we report the design and development of a metamaterial (MTM)-based directional coplanar waveguide (CPW)-fed reconfigurable textile antenna using radiofrequency (RF) varactor diodes for microwave breast imaging. Both simulation and measurement results of the proposed MTM-based CPW-fed reconfigurable textile antenna revealed a continuous frequency reconfiguration to a distinct frequency band between 2.42 GHz and 3.2 GHz with a frequency ratio of 2.33:1, and with a static bandwidth at 4-15 GHz. The results also indicated that directional radiation pattern could be produced at the frequency reconfigurable region and the antenna had a peak gain of 7.56 dBi with an average efficiency of more than 67%. The MTM-based reconfigurable antenna was also tested under the deformed condition and analysed in the vicinity of the breast phantom. This microwave imaging system was used to perform simulation and measurement experiments on a custom-fabricated realistic breast phantom with heterogeneous tissue composition with image reconstruction using delay-and-sum (DAS) and delay-multiply-and-sum (DMAS) algorithms. Given that the MWI system was capable of detecting a cancer as small as 10 mm in the breast phantom, we propose that this technique may be used clinically for the detection of breast cancer.

HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells.

In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1ß rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1ß for activation. However, HIF-1ß is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.

How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH.

The acidic tumour microenvironment is now recognized as a tumour phenotype that drives cancer somatic evolution and disease progression, causing cancer cells to become more invasive and to metastasise. This property of solid tumours reflects a complex interplay between cellular carbon metabolism and acid removal that is mediated by cell membrane carbonic anhydrases and various transport proteins, interstitial fluid buffering, and abnormal tumour-associated vessels. In the past two decades, a convergence of advances in the experimental and mathematical modelling of human cancers, as well as non-invasive pH-imaging techniques, has yielded new insights into the physiological mechanisms that govern tumour extracellular pH (pHe). In this review, we examine the mechanisms by which solid tumours maintain a low pHe, with a focus on carbonic anhydrase IX (CAIX), a cancer-associated cell surface enzyme. We also review the accumulating evidence that suggest a role for CAIX as a biological pH-stat by which solid tumours stabilize their pHe. Finally, we highlight the prospects for the clinical translation of CAIX-targeted therapies in oncology.

Comparing the Utility and Surgical Outcomes of Harmonic Focus Ultrasonic Scalpel with Ligasure Small Jaw Bipolar Device in Thyroidectomies: A Prospective Randomized Controlled Trial.

BACKGROUND: Ultrasonic or bipolar radiofrequency energy devices are routinely used for dissection and hemostasis during thyroidectomy. We report a single-center, prospective, randomized controlled trial comparing the utility and outcomes of Harmonic Focus, an ultrasonic coagulating shear device (UCSD), versus Ligasure Small Jaw, an electrothermal bipolar vessel sealer (EBVS) in thyroidectomy (NCT01765686). METHODS: Between December 2012 to January 2016, eligible patients were randomized to undergo hemithyroidectomy using either a UCSD or an EBVS. The primary outcome was duration of surgery. Secondary outcomes included blood loss, postoperative complications, ease of device use, ease of device set-up, vocal cord function, postoperative wound drainage, pain score, and adverse events. RESULTS: Of 110 patients assessed for eligibility, 100 were randomly allocated (UCSD: 49 patients; EBVS: 51 patients) and analyzed by intention-to-treat. There were no differences in specimen delivery time, total duration of surgery, wound drainage, and adverse events between the two groups. The UCSD group had a greater proportion of patients with higher postoperative pain scores in the first 72 h (8.1% vs. 2.0%, p = 0.043). Surgeons reported greater ease of use for the UCSD (49% vs. 27%; p = 0.005), while operating room staff favored the EBVS (60% vs. 33%, p = 0.005). CONCLUSIONS: Energy devices are equally effective in reducing thyroidectomy operative times, with no differences in the duration of surgery, drainage, or adverse events. Use of the UCSD was associated with higher postoperative pain scores, but was favored by the surgeons, likely due to the ability to perform fine dissection with the device itself.

Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo.

BACKGROUND: Tumour carbonic anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, is thought to acidify the tumour microenvironment by hydrating CO2 to form protons and bicarbonate, but there is no definitive evidence for this in solid tumours in vivo. METHODS: We used 1H magnetic resonance spectroscopic imaging (MRSI) of the extracellular pH probe imidazolyl succinic acid (ISUCA) to measure and spatially map extracellular pH in HCT116 tumours transfected to express CAIX and empty vector controls in SCID mice. We also measured intracellular pH in situ with 31P MRS and measured lactate in freeze-clamped tumours. RESULTS: CAIX-expressing tumours had 0.15 pH-unit lower median extracellular pH than control tumours (pH 6.71 tumour vs pH 6.86 control, P = 0.01). Importantly, CAIX expression imposed an upper limit for tumour extracellular pH at 6.93. Despite the increased lactate concentration in CAIX-expressing tumours, 31P MRS showed no difference in intracellular pH, suggesting that CAIX acidifies only the tumour extracellular space. CONCLUSIONS: CAIX acidifies the tumour microenvironment, and also provides an extracellular pH control mechanism. We propose that CAIX thus acts as an extracellular pH-stat, maintaining an acidic tumour extracellular pH that is tolerated by cancer cells and favours invasion and metastasis.

Carbonic Anhydrase Activity Monitored In Vivo by Hyperpolarized 13C-Magnetic Resonance Spectroscopy Demonstrates Its Importance for pH Regulation in Tumors.

Carbonic anhydrase buffers tissue pH by catalyzing the rapid interconversion of carbon dioxide (CO2) and bicarbonate (HCO3 (-)). We assessed the functional activity of CAIX in two colorectal tumor models, expressing different levels of the enzyme, by measuring the rate of exchange of hyperpolarized (13)C label between bicarbonate (H(13)CO3(-)) and carbon dioxide ((13)CO2), following injection of hyperpolarized H(13)CO3(-), using (13)C-magnetic resonance spectroscopy ((13)C-MRS) magnetization transfer measurements. (31)P-MRS measurements of the chemical shift of the pH probe, 3-aminopropylphosphonate, and (13)C-MRS measurements of the H(13)CO3(-)/(13)CO2 peak intensity ratio showed that CAIX overexpression lowered extracellular pH in these tumors. However, the (13)C measurements overestimated pH due to incomplete equilibration of the hyperpolarized (13)C label between the H(13)CO3(-) and (13)CO2 pools. Paradoxically, tumors overexpressing CAIX showed lower enzyme activity using magnetization transfer measurements, which can be explained by the more acidic extracellular pH in these tumors and the decreased activity of the enzyme at low pH. This explanation was confirmed by administration of bicarbonate in the drinking water, which elevated tumor extracellular pH and restored enzyme activity to control levels. These results suggest that CAIX expression is increased in hypoxia to compensate for the decrease in its activity produced by a low extracellular pH and supports the hypothesis that a major function of CAIX is to lower the extracellular pH.

Magnetic resonance spectroscopy of cancer metabolism and response to therapy.

Magnetic resonance spectroscopy allows noninvasive in vivo measurements of biochemical information from living systems, ranging from cultured cells through experimental animals to humans. Studies of biopsies or extracts offer deeper insights by detecting more metabolites and resolving metabolites that cannot be distinguished in vivo. The pharmacokinetics of certain drugs, especially fluorinated drugs, can be directly measured in vivo. This review briefly describes these methods and their applications to cancer metabolism, including glycolysis, hypoxia, bioenergetics, tumor pH, and tumor responses to radiotherapy and chemotherapy.

MRI & MRS assessment of the role of the tumour microenvironment in response to therapy.

MRI and MRS techniques are being applied to the characterisation of various aspects of the tumour microenvironment and to the assessment of tumour response to therapy. For example, kinetic parameters describing tumour blood vessel flow and permeability can be derived from dynamic contrast-enhanced MRI data and have been correlated with a positive tumour response to antivascular therapies. The ongoing development and validation of noninvasive, high-resolution anatomical/molecular MR techniques will equip us with the means to detect specific tumour biomarkers early on, and then to monitor the efficacy of cancer treatments efficiently and reliably, all within a clinically relevant time frame. Reliable tumour microenvironment imaging biomarkers will provide obvious advantages by enabling tumour-specific treatment tailoring and potentially improving patient outcome. However, for routine clinical application across many disease types, such imaging biomarkers must be quantitative, robust, reproducible, sufficiently sensitive and cost-effective. These characteristics are all difficult to achieve in practice, but image biomarker development and validation have been greatly facilitated by an increasing number of pertinent preclinical in vivo cancer models. Emphasis must now be placed on discovering whether the preclinical results translate into an improvement in patient care and, therefore, overall survival.