Likely Common Role of Hypoxia in Driving 18 F-FDG Uptake in Cancer,Myocardial Ischemia,Inflammation and Infection

Abstract

First introduced in 1976, ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) has become an indispensable tool for diagnosis and prognostic evaluation of tumors, heart disease, as well as other conditions, including inflammation and infection. Because ¹⁸F-FDG can accurately reflect the glucose metabolism level of organs and tissues, it is known as a “century molecule” and is currently the main agent for PET imaging. The degree of ¹⁸F-FDG uptake by cells is related to both the rate of glucose metabolism and glucose transporter expression. These, in turn, are strongly influenced by hypoxia, in which cells meet their energy needs through glycolysis, and ¹⁸F-FDG uptake increased due to hypoxia. ¹⁸F-FDG uptake is a complex process, and hypoxia may be one of the fundamental driving forces. The correct interpretation of ¹⁸F-FDG uptake in PET imaging can help clinics make treatment decisions more accurately and effectively. In this article, we review the application of ¹⁸F-FDG PET in tumors, myocardium, and inflammation. We discuss the relationship between ¹⁸F-FDG uptake and hypoxia, the possible mechanism of ¹⁸F-FDG uptake caused by hypoxia, and the associated clinical implications.

Introduction

¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) imaging is being increasingly utilized in the clinic to follow the metabolic changes in tumor tissue at the molecular level, yielding information on tumor diagnosis and staging and monitoring for recurrence, including metastatic spread and response to therapy.^1,2 In cardiology, ¹⁸F-FDG PET myocardial metabolism imaging is considered the gold standard for detecting the myocardial viability. Furthermore, direct myocardial ischemia imaging can overcome some limitations of stress-rest perfusion imaging.³ Finally, due to the high sensitivity and spatial resolution, ¹⁸F-FDG PET is becoming more common in the imaging of inflammation and infectious lesions.

However, some exceptions may occur with clinical imaging; some malignant tumors may have low ¹⁸F-FDG uptake and benign lesions with high uptake.^4
–6 In severe multivessel coronary artery disease, myocardial perfusion imaging and resting metabolic imaging may be “normal”. However, direct imaging of exercise-induced myocardial ischemia imaging may reveal the presence of myocardial ischemia.⁷ In clinical practice, it is observed that ¹⁸F-FDG uptake is low in the acute and high chronic phase of inflammation.^8,9 Plausible explanations to these seemingly contradictory problems are still pending.

Studies have demonstrated that ¹⁸F-FDG uptake is not intrinsic to cancer, ischemic myocardium, or inflammation, but hypoxia may be related to it, resulting in altered energy metabolism by increased anaerobic glycolysis.^3,9,10 In 1861, Louis Pasteur found that while yeast cells cultured in anaerobic conditions had reduced growth, their glucose consumption significantly increased, the so-called Pasteur Effect. So, what is the relationship between ¹⁸F-FDG uptake and hypoxia and its specific mechanism? Those answers will aid in a correct interpretation of ¹⁸F-FDG lesion-uptake in PET imaging, resulting in more accurate and useful clinical treatment decisions.

In this article, we review the application of ¹⁸F-FDG PET in cancer, heart, and inflammation and discuss the relationship between ¹⁸F-FDG uptake and hypoxia, the possible mechanism of ¹⁸F-FDG uptake caused by hypoxia, and their clinical implications.

¹⁸F-FDG PET Use in the Imaging of Tumors, Myocardial Ischemia and Inflammation

¹⁸F-FDG is the essential imaging agent for PET imaging at present. Like glucose, deoxyglucose and fluorodeoxyglucose are imported into the cell by glucose transporters and phosphorylated by hexokinase. However, in its phosphorylated form, it is not a substrate for the next enzyme in the glycolytic pathway (phosphoglucose isomerase) and thus is not further metabolized. Because of phosphorylation, fluorodeoxyglucose-6-phosphate is membrane-impermeable and thus trapped intracellularly.¹¹ The accumulation of ¹⁸F-FDG allows a PET image to report on the local glucose metabolism in vivo.

The uncontrolled proliferation of tumor cells leads to high glucose consumption, and consequently, intravenous injection of ¹⁸F-FDG results in most tumor lesions showing high ¹⁸F-FDG uptake. Therefore, ¹⁸F-FDG PET imaging is used to detect primary and metastatic lesions at an early stage. Also, ¹⁸F-FDG is a promising direct imaging agent for exercise-induced myocardial ischemia. The difference in glucose uptake between normal and ischemic myocardium allows ¹⁸F-FDG as a “hot spot” imaging agent for myocardial ischemia imaging in patients with known or suspected coronary artery disease.^3,12
–14 Furthermore, inflammatory lesion glucose metabolism measured by ¹⁸F-FDG uptake may result in early diagnosis of the disease, prevention of related complications, and early treatment.

¹⁸F-FDG PET Cancer Imaging and Hypoxia

Increased glucose demand regarded as one of the fundamental characteristics of tumors, and this is the rationale for the use of ¹⁸F-FDG PET in oncology. However, not all malignant tumors show high levels of ¹⁸F-FDG uptake, and conversely, some benign lesions show significant tracer uptake. More and more evidence shows that the accumulation of ¹⁸F-FDG in tumors depends on the microenvironment.^15,16 ¹⁸F-FDG accumulates preferentially in tumor cells with low proliferation and hypoxia, but less so in well perfused, and thus highly proliferative, areas of the tumor.^10,17,18

Hypoxia is a common feature of solid tumors, closely related to radiotherapy and chemotherapy resistance, tumor metastasis, and prognosis.^19,20 Hypoxia arises through the rate of oxygen consumption by cancer exceeding the oxygen delivery rate by the vasculature, which is often irregular, with chaotic blood flow. The unchecked proliferation of tumor cells leads to elevated oxygen demand, as tumor tissue outgrows the existing vasculature.^21,22 Studies have shown that hypoxic conditions play a crucial role in inducing high ¹⁸F-FDG accumulation, resulting in anaerobic glycolysis.^23
–25 It is relatively inefficient as a pathway of energy generation, which requires significantly more glucose substrate for equivalent ATP production.¹⁸F-FDG uptake is lower in viable and well-perfused tumor areas and therefore fails to map oxygenated tumor cells.

Our previous research proved that ¹⁸F-FDG uptake occurred significantly higher in severely hypoxic ascites carcinomas and the hypoxic portion of larger tumors.¹⁰ As in Figure 1, the spatial distribution of ¹⁸F-FDG in the A549 peritoneal tumor model precisely matched with tumor hypoxia, visualized by the hypoxia-specific probe pimonidazole. Besides, the clinical data from lung cancers provide indirect evidence that ¹⁸F-FDG PET reports on tumor hypoxia (Fig. 2).²⁶ The tracer signal in the early phase of the ¹⁸F-FDG imaging, primarily defined by blood delivery or supply, may assess the tumor perfusion. However, by 60-min after ¹⁸F-FDG injection, activity has accumulated in cells via the GLUT-1/hexokinase pathway, which reveals that the tumor volumes associated with low blood perfusion display the greatest concentration of ¹⁸F-FDG uptake.

FIG. 1.

Comparison of ¹⁸F-FDG uptake with tumor hypoxia. (A) ¹⁸F-FDG uptake and tumor hypoxia in A549 ascites tumors: ascites tumors have high ¹⁸F-FDG uptake and high pimonidazole binding and GLUT-1 expression. Scale bar, 500 μm. GLUT-1 imaging was obtained from the adjacent section and all others from the same section. (B) ¹⁸F-FDG uptake and tumor hypoxia in A549 serosa tumors: increased ¹⁸F-FDG uptake is coincident with high pimonidazole binding (hypoxia, as indicated by an arrow). Regions of the tumor lacking pimonidazole are well perfused, as indicated by the blood flow marker, Hoechst 33342. (A normoxic tumor region is marked by an asterisk.) Oxygenate tumor tissue, as well as normal liver, tumor stroma, and necrosis are all associated with low ¹⁸F-FDG uptake. T, tumor tissue; scale bar, 2 mm. (C) ¹⁸F-FDG uptake and tumor hypoxia in HT29 subcutaneous xenograft. High ¹⁸F-FDG uptake is coincident with high pimonidazole binding as indicated by a white arrow. Normoxic (red arrow) and necrotic (N) regions are associated with low ¹⁸F-FDG uptake; scale bar, 1 mm. Hematoxylin and eosin stain from the same section is provided for reference. (D) Quantitative ¹⁸F-FDG uptake based on a collection of intraperitoneal tumors. ¹⁸F-FDG uptake is significantly higher in hypoxia regions than nonhypoxic (normoxic) tumor tissue, stroma, necrosis, and normal liver (p < 0.001 to all). Low ¹⁸F-FDG uptake in nonhypoxic tumor tissue is not significantly different from stroma, necrosis, and normal liver. This research was originally published in Li et al.¹⁰ Color images are available online.

FIG. 2.

Mismatched intratumoral distribution between early phase perfusion imaging versus 60-min metabolism imaging. A 52-year-old male with pathologically confirmed adenocarcinoma in the right lung, received 6 mCi (222MBq) ¹⁸F-FDG bolus injection. (A) CT image with the tumor mass circled; (B) PET/CT image obtained over the first 5 min (C) PET/CT image obtained 60 min after injection. Comparison of (B) and (C) reveals an apparent mismatch between perfusion and metabolism. The region indicated by red arrows has high blood perfusion over the first 5 min, but associate with low ¹⁸F-FDG accumulation at 60 min PET imaging. This research was originally published in Shen et al.²⁶ Color images are available online.

Other studies have reported similar results. Kaira et al. also found a significant correlation between ¹⁸F-FDG uptake and hypoxia.²⁷ In a clinical study of primary and metastatic non-small cell lung cancers, it was reported that low ¹⁸F-FDG uptake was associated with well oxygenated tumor regions' high levels of angiogenesis.¹⁷ These findings demonstrated that viable and well-perfused cancer regions in patients were associated with low ¹⁸F-FDG uptake, while areas with high ¹⁸F-FDG accumulation had low to absent blood perfusion. Therefore, the Pasteur Effect may explain the nature of the ¹⁸F-FDG uptake in cancer.

Cell proliferation and hypoxia are usually mutually exclusive. However, the presence of tumor hypoxia results from the extensive increase of tumor cells surpassing angiogenesis.²⁸ The tumor cells close to the functional vessels should have a higher proliferation rate, while the hypoxic tumor cells located far from the active vessels will propagate slowly. Interestingly, the ¹⁸F-FDG uptake of cells with less proliferation in the hypoxic area of the tumor was higher than that in the normoxic tumor zone.^10,29,30 Other studies verified such observations. In a well-differentiated occult sphenoclival tumor, immunohistochemistry showed low tumor cell proliferation but intense focal ¹⁸F-FDG uptake, which explained the paradox between tumor differentiation and PET results.³¹ In well-differentiated neuroendocrine tumors, ¹⁸F-FDG PET uptake correlates with both tumor size and proliferation.³²

A possible explanation is that proliferating tumor cells generate ATP from glucose at least to some extent through efficient oxidative phosphorylation, so less glucose is needed, thus resulting in with low accumulation of ¹⁸F-FDG. Also, the necrotic tumor zones were associated with lower ¹⁸F-FDG activity.¹⁸ However, there are also different opinions. For example, Türkcan et al. reported that in mouse tumor grafts, the uptake of ¹⁸F-FDG in the tumor's core was usually lower than the periphery. Since the tumor core is likely to be highly hypoxic, they conclude that severe hypoxia is not associated with elevated ¹⁸F-FDG uptake.³³ We thought a more plausible explanation might be that the tumor center is hypoxic since it is dominated by necrotic tissue, which has no glucose metabolism and no ¹⁸F-FDG uptake; The ¹⁸F-FDG activity is lower than the periphery of the lesion.

The high accumulation of ¹⁸F-FDG does not indicate areas of tumor cells with increased proliferation but tumor cells with a low proliferation rate. Also, the lack of ¹⁸F-FDG does not necessarily mean the absence of viable tumor cells.

¹⁸F-FDG PET Myocardial Ischemia Imaging and Hypoxia

Direct myocardial ischemia imaging can overcome some of the limitations of stress-rest perfusion imaging currently used and provide a unique opportunity to detect and image an episode of ischemia in the preceding hours, even in the absence of other markers of ongoing myocardial ischemia.³⁴ Sometimes, even in the presence of severe multivessel coronary artery disease, myocardial perfusion imaging and resting ¹⁸F-FDG metabolic imaging may appear normal. However, ¹⁸F-FDG can successfully image the exercise-induced direct myocardial ischemia because of the vital link between the tissue ¹⁸F-FDG uptake and hypoxia, which has a greater significance for the diagnosis, management of heart disease. The profound metabolic differential between the normal and the ischemic myocardium on exercise permits the use of ¹⁸F-FDG for myocardial ischemia imaging.

Several unique characteristics of myocardial metabolism and its myocardial ischemia changes explain why ¹⁸F-FDG uptake would respond strongly to exercise-induced myocardial ischemia. Under fasting conditions, the level of free fatty acids is higher. The levels of glucose and insulin are lower, so free fatty acid is the primary source of energy production, and glucose uptake is relatively low. After a carbohydrate-rich meal, both blood sugar and insulin levels are high, so myocardial glucose uptake increases, and glucose accounts for a higher percentage of energy production.

With the occurrence of myocardial ischemia, myocardial cells have undergone profound changes in substrate utilization and metabolism due to hypoxia. Glycolysis becomes the main source of energy production for the sustenance of the ischemic myocardium. However, glycolysis is an inefficient form of energy production. Therefore, myocardial ischemia results in a dramatic and sustained increase in glucose uptake compared with the normal myocardium. However, the normal myocardium would have much lower glucose extraction on exercise under fasting conditions because free fatty acid would be its primary energy production source. Thus, a profound metabolic difference exists between normal and ischemic myocardium on exercise, allowing ¹⁸F-FDG to accumulate in ischemic tissue allowing “hot-spot” imaging.^13,14

For example, He et al. found that the areas diagnosed as myocardial ischemia during stress-rest perfusion imaging showed intense ¹⁸F-FDG uptake in exercise ¹⁸F-FDG ischemia imaging.³ However, for patients with coronary artery disease who received revascularization of the abnormal myocardium, postexercise ¹⁸F-FDG images show no excessive ¹⁸F-FDG uptake, in agreement with the notion that the recovery of blood flow providing normal oxygenation will also normalize the¹⁸F-FDG PET images.³⁵

Interestingly, not infrequently, nuclear cardiologists have observed cases with minimal perfusion abnormalities in patients with severe multivessel coronary artery disease, in whom their postexercise myocardial ischemia imaging is showing intense global ¹⁸F-FDG uptake.⁷ For severe multivessel coronary heart disease, direct myocardial ischemia imaging can show ischemic myocardium more accurately than perfusion imaging. The principal reason of which is the high uptake of ¹⁸F-FDG in hypoxic cardiac myocytes with low perfusion. Exercise-induced regional myocardial ¹⁸F-FDG uptake is highly specific and sensitive for myocardial ischemia, which may persist 24 h after an episode of myocardial ischemia in some patients.³⁶

¹⁸F-FDG PET Inflammation Imaging and Hypoxia

¹⁸F-FDG PET imaging has a high sensitivity for the detection of inflamed or infected tissues, lesions. The ¹⁸F-FDG PET imaging may enable us to localize and diagnose inflammatory lesions and estimate the degree of infection to guide clinical treatment decision-making.³⁷ Specifically, ¹⁸F-FDG PET has significant clinical diagnostic value for bacterial or viral pneumonia, endocarditis, arteritis, rheumatoid arthritis, atherosclerosis, tuberculosis, and fever of unknown origin.^38
–40 In the clinical application of ¹⁸F-FDG PET imaging, ¹⁸F-FDG uptake is usually low in acute inflammation and high in the chronic phase,^8,9 which might be confusing.

The increased uptake of ¹⁸F-FDG in inflammatory lesions is due to increased metabolism of inflammatory cells such as macrophages, increased expression of cell-membrane glucose transporter, and increased glucose uptake.^41,42 Of the acute and chronic phase of the inflammation, the vascular reactions dominate the acute phase, and the cellular hyperplasia and necrosis dominate the chronic stage. As the disease progresses, due to increased catabolism at the lesion site, oxygen consumption also increases. Also, disordered local blood circulation and impaired enzyme activity intensify tissue hypoxia. Eventually, tissue metabolism switches to anaerobic glycolysis, with a concomitant increase in ¹⁸F-FDG uptake.

Although hypoxia is not apparent in the acute phase of inflammation, it is severe in the chronic phase, so that ¹⁸F-FDG uptake could be low in the acute phase of inflammation and high in the chronic phase. In rheumatoid arthritis, Matsui et al. reported tissue hypoxia leading to enhanced ¹⁸F-FDG uptake by macrophages and fibroblasts via the glycolytic pathway.⁹ Further, studies have shown that intraplaque hypoxia, but not proinflammatory cytokines, potently stimulated glucose uptake in human macrophages and foam cells in atheroma plaques.⁴³ Future preclinical and clinical studies may need to explore ¹⁸F-FDG uptake in inflammation and infection.

Possible Mechanism of Hypoxia-Induced ¹⁸F-FDG Uptake

In the tumor, myocardial ischemia, and inflammation imaging, ¹⁸F-FDG uptake is positively associated with the degree of hypoxia. The specific mechanism of hypoxia-induced ¹⁸F-FDG uptake is still unclear. Nevertheless, a large number of studies have shown that it may be related to metabolic changes, macrophage activation, and alterations in glycolysis-related enzyme activity caused by hypoxia (Fig. 3).

FIG. 3.

Possible mechanism of hypoxia-induced ¹⁸F-FDG uptake. Color images are available online.

Significant consequences of hypoxia are that cells activate an angiogenic program to increase oxygen delivery and adjust their cellular fuel metabolism from mitochondrial respiration to glycolysis.⁴⁴ Another result of reduced oxygen availability is the induction of hypoxia-inducible factor (HIF). When activated, HIF enhances glucose uptake and glycolysis by directly inducing the GLUT1 and glycolytic genes transcription.⁴⁵ Also, hypoxia leads to the upregulation of hexokinase protein, an essential promoter of glucose uptake and metabolism.⁴⁶ Cells must then rely on glycolysis so that their bioenergetics demands are met. Anaerobic glycolysis is an inefficient energy production way, and thus, hypoxic tissue cells need to take up a higher amount of ¹⁸F-FDG. Cellular uptake of ¹⁸F-FDG is proportional to glycolytic activity and promoted by upregulation of GLUT, increased hexokinase activity, and reduced glucose-6-phosphatase activity.

Malignant tumors may have insufficient angiogenesis resulting in severe hypoxia, making cells switch from aerobic metabolism to anaerobic metabolism. This adaptive response involves the coordinated expression of many HIF regulatory proteins, such as GLUT-1 and various glycolytic enzymes. The overexpression of GLUT-1on the surface of tumor cells helps to transport more glucose into tumor cells to meet the needs of high metabolism and rapid growth.⁴⁷ High ¹⁸F-FDG uptake and tumor-associated macrophages (TAM) positively correlated with each other in patients with nonsmall cell lung cancer. TAM can significantly enhance tumor hypoxia by increasing peroxisome proliferator-activated receptor gamma coactivator 1-alpha.⁴⁸

Also, the ischemic myocardium requires a large amount of glucose to maintain its nutrition, caused by a rapid translocation of specialized glucose transporters, such as GLUT-4 and GLUT-1 from the cytosol to the sarcolemma.^3,12 Lee and his colleagues demonstrated that depletion of macrophages could lead to a significant decrease of ¹⁸F-FDG uptake in the heart after acute myocardial infarction in mice.⁴⁹

The chronic phase of inflammation is marked by infiltration of inflammatory cells such as macrophages, which can phagocytize pathogens and remove tissue disintegration products. In inflammation, ¹⁸F-FDG accumulates mostly in macrophages due to their high glycolytic activity and increased density in inflamed areas.⁵⁰ Clinical and preclinical studies have positively associated increased ¹⁸F-FDG uptake in atherosclerotic arteries with high macrophage density.^51,52 Hypoxia may affect the metabolic system by increasing activity in the glycolytic and pentose phosphate pathways of infiltrating macrophages in atherosclerotic arteries. Hypoxia is a potent stimulus for increased glucose uptake of macrophages.^53,54

The Correct Interpretation of ¹⁸F-FDG PET Imaging and Its Enlightenment to Clinical Practice

Despite that hypoxia may be an essential driving force of ¹⁸F-FDG uptake, as a PET imaging agent, uptake of ¹⁸F-FDG is not specific to the tumor, ischemic myocardium, or inflammation. In ¹⁸F-FDG PET tumor imaging, low or absence of ¹⁸F-FDG uptake does not mean that the lesion is a benign tumor and the prognosis is well. Similarly, the high ¹⁸F-FDG uptake does not mean that the lesion is a malignant tumor with a poor prognosis.

As mentioned earlier in this text, ¹⁸F-FDG tissue uptake is affected positively by the degree of cell hypoxia to some extent, but ¹⁸F-FDG is not a specific cancer-avid PET tracer. The reason why PET imaging can successfully use ¹⁸F-FDG in cancer detection is that 95% of solid malignant tumors have some degree of hypoxia. ¹⁸F-FDG accumulated heavily in anoxic tumor cells with poor proliferation and low blood flow but low uptake in oxygen-rich tumor cells with intense proliferation and high perfusion.¹⁰ Consequently, some untreated malignant lesions may have little or no ¹⁸F-FDG uptake. Also, low ¹⁸F-FDG accumulation after anticancer therapy does not necessarily mean the total elimination of all viable cancer cells since well-oxygenated or necrotic cancer cells also have low ¹⁸F-FDG uptake.

As with ¹⁸F-FDG tumor imaging, hypoxic cardiac myocytes with low perfusion showed high ¹⁸F-FDG uptake in exercise-induced myocardial ischemia imaging. Direct myocardial ischemia imaging can show ischemic myocardium more accurately than perfusion imaging. Especially in severe multivessel coronary heart disease, direct myocardial ischemia imaging can accurately show the lesions, which provides more accurate imaging evidence for clinical diagnosis and treatment. If there is ¹⁸F-FDG uptake in the perfusion defect area, it indicates the existence of viable myocardium. However, ¹⁸F-FDG uptake not only indicates myocardial viability but also proves that cardiac myocytes are in a state of ischemia and hypoxia or even on the verge of death, giving the clinic a hint of an urgent need for intervention and treatment.

In ¹⁸F-FDG PET inflammation imaging, low ¹⁸F-FDG uptake does not necessarily indicate the absence of inflammation, but may imply an acute phase of inflammation known to have no prominent hypoxia. On the contrary, a high degree of ¹⁸F-FDG uptake does not indicate the severity or intensity of the inflammation; it merely may imply a chronic phase of inflammation known to be associated with severe hypoxia. The correct interpretation of ¹⁸F-FDG uptake help clinicians make accurate and useful treatment decisions resulting in improved patient prognosis outcomes.

Non-¹⁸F-FDG PET Hypoxia Imaging Agents

Several specific hypoxia avid PET tracers other than the ¹⁸F-FDG metabolic imaging agent, with its tissue uptake enhanced by hypoxia, are available. ¹⁸F-Fluoromisonidazole (¹⁸F-FMISO) is the most widely used radiolabeled hypoxia imaging tracer. ¹⁸F-FMISO is a nitroimidazole compound that enters cells through, and proportional, the blood flow. Redox reactions can occur under the action of xanthine oxidase. In hypoxic cells, the nonoxidized reduced nitro group will permanently firmly combine with some cell components. It is the first hypoxia PET tracer used clinically. It has good reproducibility and can comprehensively evaluate hypoxia, guide treatment, and predict the therapy's efficacy.

More current, PET tracers include, for example, ¹⁸F-Fluoroerythronitroimidazole (¹⁸F-FETNIM), a novel imaging agent currently under investigation for the in vivo detection of tumor hypoxia, has a lower peripheral metabolic rate, has higher hydrophilicity, and lower neurotoxicity.⁵⁵ It is easier to prepare and less costly than ¹⁸F-FMISO. The hypoxic PET tracer ¹⁸F-FAZA (¹⁸F-Fluoroazomycinarabinoside) has a stronger affinity for hypoxic tumor areas and has a faster clearance rate from human tissues.⁵⁶ ¹⁸F-flortanidazole (¹⁸F-HX4) is a next-generation 2-nitroimidazole tumor hypoxia imaging tracer, specifically designed to maximize pharmacokinetic and clearance properties. It has the potential to aid hypoxia-targeted treatments.⁵⁷ Also, a nitroimidazole group compound, ¹⁸F-nitroimidazolpentafluoropropylacetamide (¹⁸F-EF5), has considerable membrane permeability and the capability to accumulate in viable hypoxic, although not in apoptotic or necrotic cells. It has more specificity and lower toxicity when taken up by hypoxic cells.⁵⁸

Conclusions

¹⁸F-FDG is not a specific PET tracer, and its uptake is increased due to hypoxia. In PET imaging of tumors, myocardium, and inflammation, hypoxia may be one of the fundamental driving forces. The possible mechanism of ¹⁸F-FDG uptake caused by hypoxia may be related to metabolic changes, macrophage activation, and alterations in glycolysis-related enzyme activity.

Footnotes

Acknowledgment

The authors thank Dr. James Russell, PhD from Memorial Sloan-Kettering Cancer Center (New York, NY) for critically reading the article.

Authors' Contributions

Y.Y. drafted and revised the article. Y.-M.L., Z.-X.H., and A.C.C. reviewed and modified all versions of the article. X.-F.L. supervised, wrote, and modified the article. All coauthors have reviewed and approved the article before submission.

Disclosure Statement

All authors declare that they have no conflict of interest.

Funding Information

The authors' current research is partially supported by an internal grant from Shenzhen People's Hospital (X.-F.L.), Shenzhen Science Technology Project (JCYJ20190806151003583) (X.-F.L.), and grant from China Postdoctoral Science Foundation (2020M673079) (Y.Y.).

References

Grootjans

, de Geus-Oei

, Troost

, et al. PET in the management of locally advanced and metastatic NSCLC. Nat Rev Clin Oncol, 2015; 12:395.

Civelek

, Piotrowski

, Osman

, et al. Cutaneous metastatic lung cancer detected with 18F-FDG PET. Ann Nucl Med, 2006; 20:147.

Jain

, He

. Direct imaging of myocardial ischemia: A potential new paradigm in nuclear cardiovascular imaging. J Nucl Cardiol, 2008; 15:617.

Christlieb

, Strandholdt

, Olsen

, et al. Dual time-point FDG PET/CT and FDG uptake and related enzymes in lymphadenopathies: Preliminary results. Eur J Nucl Med Mol Imaging, 2016; 43:1824.

van Elmpt

, Zegers

CML

, Reymen

, et al. Multiparametric imaging of patient and tumour heterogeneity in non-small-cell lung cancer: Quantification of tumour hypoxia, metabolism and perfusion. Eur J Nucl Med Mol Imaging, 2016; 43:240.

Iwano

, Ito

, Tsuchiya

, et al. What causes false-negative PET findings for solid-type lung cancer?. Lung Cancer, 2013; 79:132.

, Shi

, Wu

, et al. Direct imaging of exercise-induced myocardial ischemia with fluorine-18-labeled deoxyglucose and Tc-99m-sestamibi in coronary artery disease. Circulation, 2003; 108:1208.

Maftei

, Shi

, Bayer

, et al. Comparison of (immuno-)fluorescence data with serial [¹⁸F]Fmiso PET/CT imaging for assessment of chronic and acute hypoxia in head and neck cancers. Radiother Oncol, 2011; 99:412.

Matsui

, Nakata

, Nagai

, et al. Inflammatory cytokines and hypoxia contribute to 18F-FDG uptake by cells involved in pannus formation in rheumatoid arthritis. J Nucl Med, 2009; 50:920.

10.

, Du

, Ma

, et al. (18)F-fluorodeoxyglucose uptake and tumor hypoxia: Revisit (18)f-fluorodeoxyglucose in oncology application. Transl Oncol, 2014; 7:240.

11.

Pauwels

, Ribeiro

, Stoot

, et al. FDG accumulation and tumor biology. Nucl Med Biol, 1998; 25:317.

12.

Jain

, He

, Ghanbarinia

. Exercise (18)FDG imaging for the detection of CAD: What are the clinical hurdles?. Curr Cardiol Rep, 2010; 12:170.

13.

Jain

, He

. Direct myocardial ischemia imaging with exercise ¹⁸FDG. J Nucl Cardiol, 2015; 22:111.

14.

Jain

, He

, Lele

. Cardiac Hot Spot Imaging With (18)FDG. Semin Nucl Med, 2014; 44(5):375.

15.

Garrigue

, Bodin-Hullin

, Balasse

, et al. The Evolving Role of Succinate in Tumor Metabolism: An (18)F-FDG-Based Study. J Nucl Med, 2017; 58:1749.

16.

Yamamoto

, Brender

, Seki

, et al. Molecular imaging of the tumor microenvironment reveals the relationship between tumor oxygenation, glucose uptake, and glycolysis in pancreatic ductal adenocarcinoma. Cancer Res, 2020; 80:2087.

17.

Beer

, Lorenzen

, Metz

, et al. Comparison of integrin alphaVbeta3 expression and glucose metabolism in primary and metastatic lesions in cancer patients: A PET study using 18F-galacto-RGD and 18F-FDG. J Nucl Med, 2008; 49:22.

18.

Huang

, Civelek

, Li

, et al. Tumor microenvironment-dependent 18F-FDG, 18F-fluorothymidine, and 18F-misonidazole uptake: A pilot study in mouse models of human non-small cell lung cancer. J Nucl Med, 2012; 53:1262.

19.

Moulder

, Rockwell

. Hypoxic fractions of solid tumors: Experimental techniques, methods of analysis, and a survey of existing data. Int J Radiat Oncol Biol Phys, 1984; 10:695.

20.

Graeber

, Osmanian

, Jacks

, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature, 1996; 379:88.

21.

Dunn

Oxygen and cancer. N C Med J, 1997; 58:140.

22.

, Carlin

, Urano

, et al. Visualization of hypoxia in microscopic tumors by immunofluorescent microscopy. Cancer Res, 2007; 67:7646.

23.

Clavo

, Brown

, Wahl

. Fluorodeoxyglucose uptake in human cancer cell lines is increased by hypoxia. J Nucl Med, 1995; 36:1625.

24.

Burgman

, Odonoghue

, Humm

, et al. Hypoxia-Induced increase in FDG uptake in MCF7 cells. J Nucl Med, 2001; 42:170.

25.

Dirckx

, Tower

, Mercken

, et al. Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism. J Clin Invest, 2018; 128:1087.

26.

Shen

, Huang

, Sun

, et al. Revisit 18F-fluorodeoxyglucose oncology positron emission tomography: “systems molecular imaging” of glucose metabolism. Oncotarget, 2017; 8:43536.

27.

Kaira

, Shimizu

, Kitahara

, et al. 2-Deoxy-2-[fluorine-18] fluoro-d-glucose uptake on positron emission tomography is associated with programmed death ligand-1 expression in patients with pulmonary adenocarcinoma. Eur J Cancer, 2018; 101:181.

28.

Fox

, Gatter

, Bicknell

, et al. Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res, 1993; 53:4161.

29.

Zhang

, Li

, Wang

, et al. The reverse Warburg effect and 18F-FDG uptake in non-small cell lung cancer A549 in mice: A pilot study. J Nucl Med, 2015; 56:607.

30.

, Sun

, Ma

, et al. Detection of hypoxia in microscopic tumors using 131I-labeled iodo-azomycin galactopyranoside (131I-IAZGP) digital autoradiography. Eur J Nucl Med Mol Imaging, 2010; 37:339.

31.

Jannin

, Turpin

, Baillet

, et al. High 18F-FDG Avidity of Low-Grade Esthesioneuroblastoma. Clin Nucl Med, 2018; 43:e101.

32.

Bucau

, Laurent-Bellue

, Poté

, et al. 18F-FDG Uptake in Well-Differentiated Neuroendocrine Tumors Correlates with Both Ki-67 and VHL Pathway Inactivation. Neuroendocrinology, 2018; 106:274.

33.

Türkcan

, Kiru

, Naczynski

, et al. Lactic Acid Accumulation in the Tumor Microenvironment Suppresses (18)F-FDG Uptake. Cancer Res, 2019; 79:410.

34.

Jain

, He

, Lele

, et al. Direct myocardial ischemia imaging: A new cardiovascular nuclear imaging paradigm. Clin Cardiol, 2015; 38:124.

35.

Gould

, Taegtmeyer

Myocardial ischemia, fluorodeoxyglucose, and severity of coronary artery stenosis: The complexities of metabolic remodeling in hibernating myocardium. Circulation, 2004; 109:e167; author reply e167.

36.

Dou

, Gao

, Xie

, et al. Dual-time-point myocardial (18)F-FDG imaging in the detection of coronary artery disease. BMC Cardiovasc Disord, 2017; 17:120.

37.

, Wang

, et al. Expert Consensus on clinical application of FDG PET/CT in infection and inflammation. Ann Nucl Med, 2020; 34:369.

38.

Blokhuis

, Bleeker-Rovers

, Diender

, et al. Diagnostic value of FDG-PET/(CT) in children with fever of unknown origin and unexplained fever during immune suppression. Eur J Nucl Med Mol Imaging, 2014; 41:1916.

39.

Thackeray

, Bengel

. Molecular Imaging of Myocardial Inflammation With Positron Emission Tomography Post-Ischemia: A Determinant of Subsequent Remodeling or Recovery. JACC Cardiovasc Imaging, 2018; 11:1340.

40.

Pelletier-Galarneau

, Ruddy

. Molecular imaging of coronary inflammation. Trends Cardiovasc Med, 2019; 29:191.

41.

Jiemy

, Heeringa

, Kamps

, et al. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of macrophages in large vessel vasculitis: Current status and future prospects. Autoimmun Rev, 2018; 17:715.

42.

Yamashita

, Zhao

, Matsuura

, et al. Increased metabolite levels of glycolysis and pentose phosphate pathway in rabbit atherosclerotic arteries and hypoxic macrophage. PLoS One, 2014; 9:e86426.

43.

Folco

, Sheikine

, Rocha

, et al. Hypoxia but not inflammation augments glucose uptake in human macrophages: Implications for imaging atherosclerosis with 18fluorine-labeled 2-deoxy-D-glucose positron emission tomography. J Am Coll Cardiol, 2011; 58:603.

44.

Shweiki

, Itin

, Soffer

, et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature, 1992; 359:843.

45.

Ouiddir

, Planès

, Fernandes

, et al. Hypoxia upregulates activity and expression of the glucose transporter GLUT1 in alveolar epithelial cells. Am J Respir Cell Mol Biol, 1999; 21:710.

46.

Wyatt

, Wu

, Rabeh

, et al. Regulation and cytoprotective role of hexokinase III. PLoS One, 2010; 5:e13823.

47.

, Ma

, Sun

, et al. High 18F-FDG uptake in microscopic peritoneal tumors requires physiologic hypoxia. J Nucl Med, 2010; 51:632.

48.

Jeong

, Kim

, Hong

, et al. Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis. Cancer Res, 2019; 79:795.

49.

Lee

, Marinelli

, van der Laan

, et al. PET/MRI of inflammation in myocardial infarction. J Am Coll Cardiol, 2012; 59:153.

50.

, Li

, Niu

, et al. PET imaging of inflammation biomarkers. Theranostics, 2013; 3:448.

51.

Ogawa

, Ishino

, Mukai

, et al. (18)F-FDG accumulation in atherosclerotic plaques: Immunohistochemical and PET imaging study. J Nucl Med, 2004; 45:1245.

52.

Yun

, Yeh

, Araujo

, et al. F-18 FDG uptake in the large arteries: A new observation. Clin Nucl Med, 2001; 26:314.

53.

Sluimer

, Daemen

. Novel concepts in atherogenesis: Angiogenesis and hypoxia in atherosclerosis. J Pathol, 2009; 218:7.

54.

Abdelbaky

, Tawakol

. Noninvasive Positron Emission Tomography Imaging of Coronary Arterial Inflammation. Curr Cardiovasc Imaging Rep, 2011; 4:41.

55.

Grönroos

, Eskola

, Lehtiö

, et al. Pharmacokinetics of [18F]FETNIM: A potential marker for PET. J Nucl Med, 2001; 42:1397.

56.

Piert

, Machulla

, Picchio

, et al. Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside. J Nucl Med, 2005; 46:106.

57.

Carlin

, Humm

. PET of hypoxia: Current and future perspectives. J Nucl Med, 2012; 53:1171.

58.

Laasik

, Hynninen

, Forsback

, et al. The feasibility of [(18)F]EF5-PET/CT to image hypoxia in ovarian tumors: A clinical study. EJNMMI Res, 2020; 10:103.

Likely Common Role of Hypoxia in Driving 18 F-FDG Uptake in Cancer,Myocardial Ischemia,Inflammation and Infection

Abstract

Introduction

18F-FDG PET Use in the Imaging of Tumors, Myocardial Ischemia and Inflammation

18F-FDG PET Cancer Imaging and Hypoxia

18F-FDG PET Myocardial Ischemia Imaging and Hypoxia

18F-FDG PET Inflammation Imaging and Hypoxia

Possible Mechanism of Hypoxia-Induced 18F-FDG Uptake

The Correct Interpretation of 18F-FDG PET Imaging and Its Enlightenment to Clinical Practice

Non-18F-FDG PET Hypoxia Imaging Agents

Conclusions

Footnotes

Acknowledgment

Authors' Contributions

Disclosure Statement

Funding Information

References

¹⁸F-FDG PET Use in the Imaging of Tumors, Myocardial Ischemia and Inflammation

¹⁸F-FDG PET Cancer Imaging and Hypoxia

¹⁸F-FDG PET Myocardial Ischemia Imaging and Hypoxia

¹⁸F-FDG PET Inflammation Imaging and Hypoxia

Possible Mechanism of Hypoxia-Induced ¹⁸F-FDG Uptake

The Correct Interpretation of ¹⁸F-FDG PET Imaging and Its Enlightenment to Clinical Practice

Non-¹⁸F-FDG PET Hypoxia Imaging Agents