Metabolic Tumor Microenvironment Characterization of Contrast Enhancing Brain Tumors Using Physiologic MRI.

Gertraud Heinz,Elisabeth Heynold,Michael Buchfelder,Stefan Oberndorfer,Thomas M. Kinfe,Franz Marhold,Max Zimmermann,Andreas Stadlbauer

doi:10.3390/metabo11100668

Abstract

The tumor microenvironment is a critical regulator of cancer development and progression as well as treatment response and resistance in brain neoplasms. The available techniques for investigation, however, are not well suited for noninvasive in vivo characterization in humans. A total of 120 patients (59 females; 61 males) with newly diagnosed contrast-enhancing brain tumors (64 glioblastoma, 20 brain metastases, 15 primary central nervous system (CNS) lymphomas (PCNSLs), and 21 meningiomas) were examined with a previously established physiological MRI protocol including quantitative blood-oxygen-level-dependent imaging and vascular architecture mapping. Six MRI biomarker maps for oxygen metabolism and neovascularization were fused for classification of five different tumor microenvironments: glycolysis, oxidative phosphorylation (OxPhos), hypoxia with/without neovascularization, and necrosis. Glioblastoma showed the highest metabolic heterogeneity followed by brain metastasis with a glycolysis-to-OxPhos ratio of approximately 2:1 in both tumor entities. In addition, glioblastoma revealed a significant higher percentage of hypoxia (24%) compared to all three other brain tumor entities: brain metastasis (7%; p < 0.001), PCNSL (8%; p = 0.001), and meningioma (8%; p = 0.003). A more aggressive biological brain tumor behavior was associated with a higher percentage of hypoxia and necrosis and a lower percentage of remaining vital tumor tissue and aerobic glycolysis. The proportion of oxidative phosphorylation, however, was rather similar (17–26%) for all four brain tumor entities. Tumor microenvironment (TME) mapping provides insights into neurobiological differences of contrast-enhancing brain tumors and deserves further clinical cancer research attention. Although there is a long roadmap ahead, TME mapping may become useful in order to develop new diagnostic and therapeutic approaches.

Highlights

Brain tumors represent solid neoplasm inside the skull that may have developed from the brain tissue itself, other tissues such as the lymphatic tissue or from the membranes that envelop the brain, the meninges
We demonstrated relevant distinct characteristics of the Tumor microenvironment (TME) indicating indicative for diagnostic-supporting differences in the appearance of the four most common brain tumor entities that are inaccessible even with modern magnetic resonance imaging (MRI) methods currently available
We found that increasing aggressiveness of the brain tumor type, i.e., from meningioma to glioblastoma, was associated with an enhanced intratumoral heterogeneity of TME compartments due to higher degree of hypoxia and necrosis

Summary

Introduction

Brain tumors represent solid neoplasm inside the skull that may have developed from the brain tissue itself (primary brain tumors), other tissues such as the lymphatic tissue (primary central nervous system lymphomas, PCNSLs) or from the membranes that envelop the brain, the meninges (meningiomas). Brain tumors may arise as a result of the spread of cancers primarily located in other parts of the body, which are known as secondary brain tumors or brain metastases [1]. GBM, PCNSL, brain metastases, and meningiomas together represent a large proportion of brain tumors encountered in clinical neurooncology. GBMs comprise 40% to 50% of primary brain tumors in adults, while PCNSL comprise up to 4% of primary CNS tumors, with an additional small contribution of secondary CNSL [2,3]. Brain metastases are found in 10% to 30% of adult neurooncologic patients with cancer at another location in the body, and nearly half of cases became clinical apparent as solitary metastases on clinical imaging [4,5]. Meningiomas are among the most common intracranial tumors, with an estimated incidence of eight cases per 100,000 persons per year [6,7] with the common type (meningioma WHO grade I) as a slow developing benign tumor [8]

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