Spatially resolved metabolomics to discover tumorassociated. Evaluating acetate metabolism for imaging and targeting in. Imaging tumor metabolism is a subset of molecular imaging where biological processes are visualized and quantified at cellular and subcellular levels within an. Molecular imaging of tumor energy metabolism as an early. Hopkinton, ma and tumor size was quantified using living image software caliper life sciences. Magnetic resonance imaging mri was employed for noninvasively assessing tumor volumes and cell density in the tumor bearing animals. Ijms free fulltext slmp531 inhibits tumor cell growth through. Hereinweprovideproofofconceptevidencefor the use of 11cacetatepet metabolic imaging of multiple myeloma mm in preclinical models to assess tumor burden and early response to therapy.
Changes in tumor metabolism modify the microenvironment and lead to the evolution and progression of primary tumors, as well as the development of tumor metastases. We hypothesized that in multiple myeloma cells mmc, high membrane biosynthesis will induce acetate uptake in vitro and in vivo. Some of warburgs observations were in fact based on levels of oxygen consumption in tumor cells and lactate secretions in ascites fluid. Jan 02, 2019 tumor cells reprogram their metabolism to support cell growth, proliferation, and differentiation, thus driving cancer progression.
We describe how these imaging modalities can be combined with mass spectrometry and quantitative immunochemistry to obtain more complete picture of cancer metabolism. Jci insight tumor cell oxidative metabolism as a barrier to. Although methods to study tumor metabolism at the cellular level are emerging. Fluorescent imaging agent panel tumor metabolism perkinelmer. Metabolic imaging of tumors using intrinsic and extrinsic fluorescent markers. By profiling the metabolic processes of individual tumor cells on a chip. Jci insight tumor cell oxidative metabolism as a barrier.
In these types of cancer, overall robust clinical literature demonstrates that a therapyinduced decrease in tumor fdg avidity, as a biomarker of a decrease in tumor metabolism and tumor cell mass, correlates with histopathologic response and is often prognostically powerful, often when conventional changes in tumor volume e. Transcriptional reprogramming of cellular metabolism is a hallmark of cancer. All in vivo animal imaging studies were performed at the colorado animal imaging shared resource aisr. In vivo imaging of tumor metabolism and acidosis by combining. Ai12 metabolic competition in the microenvironment is a driver of cancer. Breast cancer metabolism in vitro uptake studies with 18 f fdg. This work is licensed under a creative commons attribution 4. The fact that tumor cells have altered metabolism compared to their tissues of origin has been known for more than 90 years. Mar 20, 2018 the unique ability of our imaging strategy to riskstratify women with clear cell rcc using a combination of visceral fat and tumor metabolism suggests a synergy between host and tumor metabolism that directly plays a role in outcomes independent of conventional assessments of prognosis eg, grade and stage.
However, published data have shown that pet sensitivity is high in other tumor models see,e. May 11, 2017 new insights into the tumor metabolism. Imaging metabolic heterogeneity in cancer molecular cancer. In vivo imaging of glucose uptake and metabolism in tumors. We are confident that data obtained from imaging tumor xenografts reflect tumorspecific metabolism for three reasons. Despite the importance of glutamine in cancer metabolism, the mitochondrial glutamine transporter has long been unknown. Bmp is a highly collaborative network with close connections to the broads metabolite profiling platform, as well as the genomics platform, the. Novel approaches to imaging tumor metabolism ncbi nih. As a consequence, much of the focus of cancer metabolism research in the past 15 years has been on cancer cell autonomous metabolic changes, explains anastasiou. Concurrent imaging of vascularization and metabolism in a. Pdf a nude mouse model of orthotopic liver transplantation. The techniques and concepts described in the current study, together with the accompanying manuscript in this issue of cell metabolism wang et al. Positron emission tomography pet is an extraordinarily sensitive clinical imaging modality for interrogating tumor metabolism. Feb 29, 2016 in particular, we emphasize the role of radiolabeled choline, acetate, and amino acid tracers for monitoring efficacy or predicting response to new therapies that directly or indirectly inhibit tumor cell metabolism.
This chapter examines how an understanding of the mathematics of the biodistribution of radiopharmaceuticals facilitates 1 the design of optimal study protocols, 2 image interpretation, and 3 quantitation of important functional parameters. Oct 31, 20 tumor angiogenesis is a vital process in the early phases of cancer progression. We believe that in vivo imaging of glucose uptake, mmp, and vascular features simultaneously in the same animal will prove useful as a complementary new technique for the study of tumor metabolism. Bitter melon juiceintake modulates glucose metabolism and. Ultimately, the goal of research in tumor metabolism is to exploit differences between tumors and normal tissue for diagnostic and therapeutic benefit. Metabolic profiling of cancer cells reveals genomewide crosstalk. For morphological analysis of blood vessels, confocal images of cd31.
Quantitative optical imaging of primary tumor organoid. Complex clinical decisions about treatment of oncologic patients are largely guided by imaging. Thus, tumor cells cannot adapt efficiently to metabolic stress and could be induced to. Supplemental information lkb1 inactivation dictates. Analysis of cancer metabolism by imaging hyperpolarized nuclei.
Myc regulates a transcriptional program that stimulates mitochondrial. Ijms free fulltext slmp531 inhibits tumor cell growth. Due to its versatile nature, bigluc could also be extended beyond cancer to image dysfunctional cells of many other important human pathologies in which changes in metabolism play a. Recently, cafs were shown to participate in tumor cell metabolism by providing metabolites used by cancer cells for energy production and biosynthetic processes through the tricarboxylic acid tca cycle, known as the reverse warburg effect pavlides et al. Jci insight tumor cell oxidative metabolism as a barrier to pd1. Of late, functional imaging using nearinfrared nir diffuse optical spectroscopy dos has been used to develop noninvasive measurements for detection of primary breast cancer 46. Boosting t cell mitochondrial metabolism through metabolic reprogramming, costimulatory immunotherapy, 15, or mitigation of tumor cell oxidative metabolism results in increased antitumor immunity and response to pd1 blockade immunotherapy, suggesting that the oxidative axis is also an important metabolic consideration in cancer immunity. With other biosensors it is often not clear whether measured changes take place. Imaging tumour cell heterogeneity following cell transplantation into optically clear immunedeficient zebrafish notescitation information published innature communications, v.
The goal of the broad metabolism program bmp is to pioneer new methods to systematically investigate metabolism and exploit the resulting discoveries to decipher the metabolic basis of human disease, leading to better treatments or interventions. In vitro methods have played a key role in our understanding of cancer cell metabolism. Signature genes involved in lipid metabolism, dendritic cell maturation, macrophage maturation, tumor. Tumor cell metabolism diagnostic could predict nsclc treatment. We describe several noninvasive imaging techniques that provide both anatomical and. In this report, we applied matrixassisted laser desorptionionization mass spectrometry imaging maldimsi to examine the spatial distribution of the drug irinotecan and its metabolites in ctos from two patients. To date, the main focus for innovations in imaging has been the achievement of excellence in anatomic resolution. Cancer associated fibroblast fak regulates malignant cell. The persistent activation of aerobic glycolysis in cancer cells.
Metabolic catastrophe as a means to cancer cell death journal of. Therefore, one would have predicted tumor cell metabolism imaging to provide an unspeci. After intravenous injection, 18 ffdg is transported across the cell membrane by sodiumindependent, facilitative glucose transporters gluts fig. Thompson, in the molecular basis of cancer third edition, 2008. Synergy of sex differences in visceral fat measured with ct.
Thus, 18ffdg6phosphate produced inside the tumour cells remains retained within the cell 15,36,37. Biomarkers of tumor metabolism offer not only opportunities to study tumor progression but also to specifically assess therapies that target critical pathways in tumor metabolism. Imaging tumor metabolism using positron emission tomography. Profiling of the metabolic signatures in heterogeneous tumors facilitates the understanding of tumor metabolism and introduces potential metabolic vulnerabilities that might be targeted therapeutically. In a biopsy sample, metabolites can be measured and quantified using imaging bioluminescence. Cancer associated fibroblasts cafs have been suggested. Automated image analysis software to streamline the cellularlevel processing of organoid.
Optical metabolic imaging quantifies the fluorescence intensity and lifetime of nadh and fad, coenzymes of metabolism. The antioxidant glutathione restricts serine metabolism in tregs to preserve their suppressive function such that glutathione depletion boosts anti tumor immunity. Here, we show that optical metabolic imaging of organoids derived from primary tumors can predict the therapeutic response of xenografts and measure antitumor drug responses in human tumorderived organoids. Tumors were located on the t2weighted fast spin echo images, and a single slice through the largest crosssection of the tumor was selected for the cest imaging measurements. Quantitative optical imaging of primary tumor organoid metabolism predicts drug response in breast cancer alex j.
Herein, we unveiled that p53 activation by stryptophanolderived oxazoloisoindolinone slmp531 mediated the reprograming of glucose metabolism in cancer cells and xenograft human tumor tissue, interfering with angiogenesis and migration. Imaging tumor metabolism is a subset of molecular imaging where biological processes are visualized and quantified at cellular and subcellular levels within an intact organism. The study of the tumor metabolism, also known as tumor metabolome describes the different characteristic metabolic changes in tumor cells. Results obtained with pet scanning are related to tumor metabolism and glucose uptake by the tumors. Imaging perspectives using mr imaging and spectroscopy. Imaging of tumor metabolism using positron emission. Keystone symposia scientific conferences on biomedical. Nanotechnology and early cancer detection and diagnosis. In vivo imaging data of tumor metabolism, anatomy and vascularization were acquired weekly in vehicle veh and sunitinib sunitreated mice.
Nov 14, 20 recent findings are starting to unravel the interplay between oncogenic signaling pathways and aberrant tumor metabolism, and this has renewed the interest in imaging tumor metabolism. Radiolabeled pet substrates can be traced at subphysiological concentrations, allowing noninvasive imaging of metabolism and intratumoral heterogeneity in systems ranging from advanced cancer models to patients in the clinic. The warburg effect is an emerging hallmark of cancer, which has the tumor suppressor p53 as its major regulator. We proposed a spatially resolved metabolomics method for high. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells. Recently, cafs were shown to participate in tumor cell metabolism by providing metabolites used by cancer cells for energy production and biosynthetic processes through the tricarboxylic acid tca cycle, known as the reverse warburg effect. An introduction to petct imaging1 vibhu kapoor, md barry m. The characteristic attributes of the tumor metabolome are high glycolytic enzyme activities, the expression of the pyruvate kinase isoenzyme type m2, increased channeling of glucose carbons into synthetic processes, such as nucleic acid, amino acid and. Interestingly, early experiments using this technique demonstrate much. Imaging endogenous macrophage iron deposits reveals a. Thus, we sought to use this tool to profile tumor cell metabolism. Positron emission tomography imaging of tumor cell metabolism and. While these newer in vivo techniques may greatly enhance our understanding of the whole tumor metabolism, there are additional challenges in accurately imaging tumor metabolic heterogeneity in that some of these techniques require more translational validation before being used regularly in the clinic. Tumors, inflammation and circulatory disorders locally disturb the bodys acidbase balance.
Radiotherapy rt is routinely used in cancer treatment, but expansion of its clinical indications remains challenging. Pet and ct images were analyzed using osirix imaging software version 3. Over the past decade there has been a revival of interest in developing new therapies that target metabolic vulnerabilities of tumor cells. The accumulation of hemosiderin iron in tumor associated macrophages enables the imaging of these cells in heterogeneous tumor microenvironments according to localized differences in iron metabolism. Glutathione restricts serine metabolism to preserve. These multimodality imaging approaches are now becoming the standard for staging and restaging of. Reprogramming of fatty acid metabolism in glioblastoma is a known phenomenon. Glutathione is thus a stress sensor in tregs whose manipulation holds promise for antiinflammatory and anti tumor therapies. Positron emission tomography 18 fdgpet and magnetic resonance imaging on tumor bearing animals. Cellular metabolic heterogeneity in vivo is recapitulated in tumor.
Molecular imaging of tumor metabolism has gained considerable interest, since preclinical studies have indicated a close relationship between the activation of various oncogenes and alterations of. Preclinical studies in mice using multimodality imaging of tumor metabolism to guide targeted therapies a overview of longitudinal 18 ffdg petct and bli imaging of genetically engineered mouse model of lung cancer at 2, 6, 8 and 10 weeks post tumor induction. Nevertheless, while useful in the context of glutamine uptake, 18 ffgln cannot be used to resolve the metabolic fates of glutamine, thus limiting its utility in cancers where glutamine anaplerosis has been linked to tumor cell metabolism such as the formation of the oncometabolite 2hydroxyglutarate 2hg in the setting of idh mutations. In this way, dysregulated tumor phe and upregulated glucose metabolism are linked tightly and their relative assessment may be useful to gain understanding of the underlying biology. Results for representative animals are shown in figure 2. Mar 25, 2020 ultrafast repeated staining and destaining of cell samples for tumor diagnostics. Understanding the metabolic differences between normal cells and cancer cells is a major. Cancer cell, volume 23 supplemental information lkb1 inactivation dictates therapeutic response of nonsmall cell lung cancer to the metabolism drug phenformin david b. We suggest that the ribe is predominantly mediated by irradiated tumor cellreleased microparticles rtmps, which induce broad antitumor effects and. A nude mouse model of orthotopic liver transplantation of human hepatocellular carcinoma hcclm3 cell xenografts and the use of imaging to evaluate tumor progression. Fibroblasts mobilize tumor cell glycogen to promote. Data are expressed as mean sd from two to four independent experiments. The optimal imaging time point, pertinent imaging variable, and criteria for response will require further interrogation. Nanotechnology provides new molecular contrast agents and materials to enable earlier and more accurate initial diagnosis as well as in continual monitoring of cancer patient treatment.
These changes in ph value could be used for example to verify the success of cancer treatments. May 17, 2017 mri offers new insights into tumor metabolism may 17, 2017 tumors, inflammation and circulatory disorders locally disturb the bodys acidbase balance. Mri offers new insights into tumor metabolism imaging. B representative histology performed on mice imaged with petct and bli. Positron emission tomography imaging of tumor cell metabolism. Cancer cell metabolism is characterized by an enhanced uptake and utilization of glucose, a phenomenon known as the warburg effect.
Removal of acbp from tumors leads to widespread tumor senescence and increased survival of experimental. Here, we studied acetate metabolism and targeting in mmc in vitro and tested the efficacy of 11 cacetatepositron emission tomography pet to detect and quantitatively image myeloma treatment response in vivo. Cancer is a genetic disease that is caused by mutations in oncogenes, tumor suppressor genes and stability genes. Imaging mass cytometry analysis sheds light on type 1 diabetes progression manuscript submitted to cell metabolism. The mechanism underlying the radiationinduced bystander effect ribe is not understood and not therapeutically exploited. Analysis of cancer metabolism by imaging hyperpolarized. Dec 07, 2017 preclinical studies in mice using multimodality imaging of tumor metabolism to guide targeted therapies a overview of longitudinal 18 ffdg petct and bli imaging of genetically engineered mouse model of lung cancer at 2, 6, 8 and 10 weeks post tumor induction. Molecular imaging of tumor energy metabolism as an early indicator of anticancer drug efficacy in small animal models introduction targeted cancer therapy aims to block key signaling pathways that are critical for tumor cell growth and survival. Shedding light on cancer metabolism in realtime with.
Metabolic imaging is a key tool in the diagnosis, management, and evaluation of treatment response in a variety of cancertypes. Jan 29, 2019 the accumulation of hemosiderin iron in tumor associated macrophages enables the imaging of these cells in heterogeneous tumor microenvironments according to localized differences in iron metabolism. Tumor cells reprogram their metabolism to support cell growth, proliferation, and differentiation, thus driving cancer progression. Tumors have a greater reliance on anaerobic glycolysis for energy production than normal tissues. Magnetic resonance spectroscopy mrs provides a noninvasive way to examine tumor metabolism in living systems, ranging from cultured cancer cells, to tumor models in experimental. For the analysis and quantification of the information, specific software. Ultrafast repeated staining and destaining of cell samples. However, it is also now becoming clear that there are metabolic changes at the level of the whole body that might be linked to the metabolism of tumors, and that these changes have. Irinotecan is a prodrug and is often prescribed as part of therapeutic regimes for patients with advanced colorectal cancer. The fact that the metabolism of tumor cells is altered has been known for many years. We used imaging mass cytometry to simultaneously image 37 biomarkers with single cell and spatial resolution in pancreas sections from 12 human donors at different stages of type 1 diabetes. After the discovery of based on the altered cancer cell metabolism in 1930, loads of studies have shed light on several aspects of cancer metabolism with a common goal to find new ways for effectively eliminating tumor cells by targeting their energy metabolism. Prospects for translation to clinical research article pdf available in neoplasia new york, n.
Mmi combines several in vivo techniques that can provide complementary information related to cancer metabolism. Several modalities can be used in humans for tumor cell metabolism imaging, including spect, pet, and magnetic resonance spectroscopy mrs. Cest data analysis postprocessing software was developed with idl exelis, boulder, co and was based on asymmetry analysis of the zspectrum as reported elsewhere 24, 25. Here, we show that optical metabolic imaging of organoids derived from primary tumors can predict the therapeutic response of xenografts and measure antitumor drug responses in human tumor derived organoids.
The first adaptive events in tumor metabolism to be identified are an exacerbated glucose uptake and glycolysis utilization leading to increased lactate production that is, the warburg effect 4. A comparison of imaging techniques to monitor tumor growth. The complex relaxation mechanisms of nuclear spins provide unique and convertible tissue contrasts, making magnetic resonance imaging mri and magnetic resonance spectroscopy mrs pertinent imaging tools in both clinics and research. Cancer cells reprogram their metabolism to maintain viability via genetic mutations and epigenetic alterations, expressing overall dynamic heterogeneity.
Matlab code for the image analysis software is available for. Application of morphologic imaging to the evaluation of tumor response to treatment has led to the emergence of response criteria such as those proposed by the world health organization 1 and the response evaluation criteria in solid tumors 2. Irradiated tumor cellderived microparticles mediate tumor. Our fluorescent imaging probes provide a variety of tools for quantifying key receptors associated with proliferation and nutrient uptake as well as biomarkers of. As an example, the resistance of cancer mitochondria against apoptosisassociated permeabilization and the altered contribution of these organelles to metabolism are closely related.
When tumor cells enhance glycolysis and produce large quantities of lactic acid, they generate an environment that is more toxic to the adjacent normal cells than to the malignant cells because tumor cells have developed survival mechanisms. In the fight against cancer, half of the battle is won based on its early detection. Aug 25, 2016 in vivo imaging of hypoxia, perfusion, and mismatch of metabolism and perfusion has the potential to identify specific features of tumor microenvironment associated with poor treatment outcome and, thus, contribute to personalized treatment approaches. The essential hallmarks of cancer are intertwined with an altered cancer cell intrinsic metabolism, either as a consequence or as a cause.
Cell metabolism, volume 24 supplemental information. Tumor cell metabolism imaging journal of nuclear medicine. Some commonly used chemotherapies, such as methotrexate, target metabolic enzymes. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Multiparametric imaging of tumor response to therapy radiology. Metabolic imaging is increasingly combined with ct and mri for precise anatomic localization 3,10,11. Each mouse harboring xenografted tumors was imaged 24 h before prestudy and at various times 30 min 24 h after poststudy drug treatment, thus serving as its own control. This success of metabolic imaging is perhaps unexpected, since the metabolic pathways targeted by these imaging probes are present in virtually all cells in the human body. In veh animals, tumors grew rapidly and reached the maximal tolerable tumor size at week 3 w3. Torok, md cancer is one of the leading causes of morbidity and mortality in developed countries such as the united states.
Lipid metabolic reprogramming in cancer cells oncogenesis. Spcimage software was used to analyze fluorescence lifetime images becker. Metabolic reprogramming in cancer cells is driven by activation of oncogenes. A map of human type 1 diabetes progression by imaging mass. Molecular imaging of tumor metabolism has gained considerable interest, since preclinical studies have indicated a close relationship between the activation of various oncogenes and alterations of cellular metabolism.