Tumor growth and progression not only depend on properties of the malignant cells but are strongly influenced by the tumor microenvironment. The tumor stroma consists of various cell types such as inflammatory cells, endothelial cells and fibroblasts, which can either inhibit or promote tumor growth. Consequently, therapeutic targeting of the tumor stroma is increasingly recognized as an important tool to fight cancer. Two particularly important processes that contribute to the pathology of most types of tumors are angiogenesis and inflammation. In order to target these processes specifically and efficiently, it is fundamental to identify and understand the factors and signaling pathways involved. This thesis initially describes the multiple functions of the small heat shock protein αB-crystallin in the tumor microenvironment. αB-crystallin was first identified in a screen of proteins specifically up-regulated in endothelial cells forming vessel-like structures. We found that αB-crystallin is expressed in a subset of tumor vessels and promotes angiogenesis by inhibiting endothelial apoptosis, suggesting that targeting of αB-crystallin might inhibit angiogenesis and thereby decrease tumor growth. However, we also discovered an important role of αB-crystallin in regulation of inflammatory processes. We show that αB-crystallin increases the surface levels of E-selectin, an important leukocyte-endothelial adhesion molecule. Thereby, αB-crystallin may alter leukocyte recruitment to inflamed tissues such as the tumor stroma. In addition, we found that αB-crystallin is expressed in immature myeloid cells that accumulate in the periphery and at the tumor site during tumor development. Importantly, lack of αB-crystallin resulted in increased accumulation of immature myeloid cells, which might increase tumor associated inflammation. Finally, through combining laser microdissection of vessels from human tissue and microarray analysis, we identified a gene expression signature specifically associated with vessels in high grade glioma. Blood vessels in malignant glioma are highly abnormal and contribute to the pathology of the disease. Thus, knowledge about the molecular set-up of these vessels might contribute to the development of future vascular normalizing treatments.

Orientador: Prof. Dr. Roberto Venegeroles Nascimento / Dissertação (mestrado) - Universidade Federal do ABC, Programa de Pós-Graduação em Física, 2016. / Neste trabalho se estudaram aspectos básicos relacionados com a dinâmica de células cancerígenas do tipo B-Linfoma BCL1 e de gliomas fazendo ênfases neste último caso. O trabalho se iniciou revisando alguns modelos populacionais do câncer inspirados nos trabalhos de Lotka e Volterra o qual oferecem uma descrição muito simples da interação entre o câncer (presa) e o sistema imunológico (caçador). Posteriormente é revisado um modelo global espaço-temporal baseado nas equações de Fisher-Kolmogorov-Petrovsky- Piskounov (FKPP) [1] o qual permitiu aclarar a dicotomia entre proliferação e motilidade associada fortemente ao crescimento tumoral e à invasividade, respectivamente, das células cancerosas. A partir do modelo FKPP também se fez um estudo computacional mais detalhado aplicando diferentes protocolos de tratamentos para analisar seus efeitos sobre o crescimento e desenvolvimento de gliomas. O estudo sugere que um tratamento com maior tempo entre cada dose poderia ser mais ótimo do que um tratamento mais agressivo. Propõe-se também um modelo populacional local do câncer em que se tem em conta o caráter policlonal das células cancerígenas e as interações destas com o sistema imunológico natural e especifico. Neste último modelo se consegui apreciar fenômenos como dormancy state (estado de latência) e escape phase (fase de escape) para valores dos parâmetros correspondentes ao câncer de tipo B-Linfoma BCL1 [2] o qual explica os fenômenos de imunoedição e escape da imunovigilância [3] o qual poderia permitir propor novos protocolos de tratamentos mais apropriados.Depois se fez uma reparametrização do modelo baseado em algumas características mais próprias das células tumorais do tipo glioma e assumindo presença de imunodeficiência com o que se obtém coexistências oscilatórias periódicas tanto da população tumoral assim como das células do sistema imunológico o qual poderia explicar os casos clínicos de remissão e posterior reincidência tumoral. Finalmente se obtiveram baixo certas condições, uma dinâmica caótica na população tumoral o qual poderia explicar os casos clínicos em que se apresentam falta de controlabilidade da doença sobre tudo em pessoas idosas ou com algum quadro clinico que envolve alguma deficiência no funcionamento normal do sistema imunológico. / In this work we studied basic aspects of the dynamics of cancer cell type B-Lymphoma BCL1 and gliomas making strong emphasis in the latter case. We start reviewing some population models of cancer inspired in the work¿s of Lotka and Volterra, which offers a very simple description of the interaction between cancer (prey) and the immune system (Hunter). Subsequently revise a global model space-time based on the equations of Fisher-Kolmogorov-Petrovsky-Piskounov (FKPP) [1] which allowed elucidating the dichotomy between proliferation and strongly associated motility to tumor growth and invasiveness, respectively, of cancer cells. From the FKPP model also made a more detailed computer study applying different treatment protocols to analyze their effects on the growth and development of gliomas. The study suggests that treatment with longer time between each dose could be more optimal than a more aggressive treatment. Is studied also a local population cancer model that takes into account the polyclonal nature of cancer cells, and these interactions with the natural and specific immune system. In the latter model is able to appreciate phenomena as dormancy state and escape phase for values of parameters corresponding to lymphoma cancer BCL1 [2] which explains the phenomena of immunoediting and tumor escape immuno-surveillance [3] allowing elucidating treatments protocols more appropriate. A re-parameterization was made based on some features of tumor cells glioma type and assuming presence of immunodeficiency with that obtained coexistences periodic oscillatory both tumor populations as well as the immune system cells which could explain the clinical cases of remission and subsequent tumor recurrence. Finally obtained under certain conditions, a chaotic dynamics in tumor population which could explain the clinical cases that present lack of controllability of the disease on all in elderly or with some clinical picture involving some deficiency in the normal functioning of the immune system.

Gliomas are brain tumors arising from neuroglia. In most cases astrocytic or oligodendroglial component is the main element of the tumor. Non-random chromosomal abberations are found in tumor cells as was revealed previously. The aim of this study was a fluorescence in-situ hybridisation analysis (FISH) of tissue samples obtained during neurosurgical procedures, determine the frequence of selected chromosomal abberations, further correlation with morphological and clinical data and statistical analysis of the results. During six years 264 tissue samples were gained in which FISH with defined probes was performed. The acquired results were compared with histological analysis and selected clinical data (age, Karnofsky score, extent of resection, overall survival). The whole series was divided into 7 groups by tumor type for further statistical analysis. In every group median and mean survival time was calculated, Kaplan-Meier analysis was focused on influence of selected parameters to overall survival. In some categories Cox regression model was created to achieve a hazard ratio of selected parameters. In WHO Grade II and III tumors the risk of malignant progression and tumor upgrading is significantly higher in comparison with samples where specific abberations were not found (EGFR amplification, CDKN2A and...

Le gliome infiltrant du tronc cérébral est une tumeur gliale pédiatrique de très mauvais pronostic. La survie médiane des patients varie entre 9 et 12 mois. Son aspect typique en imagerie permet le diagnostic sans confirmation histologique mais a limité la compréhension de la physiopathologie de ces tumeurs pendant plusieurs années. L'identification des mutations des histones H3 K27M comme identité moléculaire des gliomes infiltrants du tronc cérébral définit cette tumeur comme une entité unique en 2012 et la sépare des autres tumeurs cérébrales. Il y a deux variantes des histones H3 à l’origine des tumeurs, la variante H.3.1 et la variante H3.3 qui forment deux sous-groupes présentant des phénotypes et des pronostics différents. L'objectif de cette thèse était d'utiliser les techniques d'imagerie multimodale pour mieux comprendre la physiopathologie des gliomes infiltrants du tronc cérébral, en observant l'évolution des effets des différents traitements à différents temps. Nous avons tout d'abord montré une augmentation des index de perfusion associée à une diminution de l'oedème lésionnel en post- radiothérapie. Puis nous avons décrit en imagerie le phénomène de pseudo-progression. Ce phénomène, qu’il ne faut pas prendre pour une vraie progression tumorale, est caractérisé par une augmentation du volume et du rehaussement tumoral associé à une augmentation importante des index de perfusion. Le ratio d’augmentation du flux sanguin lésionnel dans les suites de la radiothérapie permet identifier une pseudo-progression avec une sensibilité et une spécificité élevées. Ces 2 groupes de patients (sans et avec pseudo-progression) ont un comportement en imagerie très différents en fin de vie. Nous avons ensuite comparé les paramètres d'imagerie aux données histologiques pour mieux appréhender les deux types de mutation d'histones. Les tumeurs H3.1 présentent plus d'oedème, plus de nécrose et une perfusion moins élevée. Les tumeurs H3.3 ont une perfusion plus élevée et moins d'oedème. La valeur du volume sanguin lésionnel est positivement corrélée à la charge tumorale. L’imagerie multimodale est essentielle dans le suivi et la compréhension des mécanismes physiopathologiques des DIPG. Elle devra être incluse dans les protocoles de recherches (efficacité des nouvelles chimiothérapies ciblées et nouvelles techniques d’application, modèles murins, radiomics, corrélation avec les nouvelles quantifications histologiques) dans le but d’avancer puis un jour de guérir ces petits patients. / Diffuse Intrinsic Pontine Glioma is a pediatric tumor with very poor prognosis. Median survival is 9-12 months. Its typical MRI appearance allows for diagnosis without histological confirmation, but has limited understanding its pathophysiology for years. DIPGs molecular identity identified as histone H3K27M mutations in 2012 defined them as a separate entity. Two subgroups with different phenotypes and prognoses are associated with mutations in one of the two variants H3.1/H3.3 of histone H3. The aim of this thesis was to use multimodal imaging techniques to better understand the pathophysiology of DIPG, by observing the evolution of the effects of different treatments over time. 1st, we showed an increase in perfusion indices associated with decreased edema after radiotherapy. Secondly, we have described the phenomenon of pseudo-progression in MRI, an increase in tumor volume and enhancement associated with a significant increase in perfusion index. This shouldn’t be confused with true tumor progression. The ratio of increase in lesion’s blood flow after radiotherapy has high sensitivity and specificity to identify pseudo-progression. 3rd, we compared the imaging parameters with the histological data to better understand the differences between the histone mutations. The mutated tumors H3.1 have more edema, more necrosis and a lower perfusion. While mutated H3.3 tumors have a higher tumor burden. Tumor burden is positive correlated to lesion blood volume. Multimodal imaging is essential in monitoring and understanding the physiopathological mechanisms of DIPG. It should be included in the research protocols in order to advance and then one day to cure these small patients.

Abstract The findings on depression and anxiety among brain tumor patients have so far been based on case series and case samples. In Finland, psychiatric research in relation to psychiatric symptoms among patients with different types of brain tumors is lacking. The study population of this thesis consisted of 101 patients (39 males and 62 females) aged between 20 and 82 years with a solitary primary brain tumor treated surgically at the Oulu Clinic for Neurosurgery, Oulu University Hospital between February 1990 and March 1992. The major histological subgroup consisted of gliomas (40%), and the rest were meningiomas (33%), acoustic neurinomas (13%), pituitary adenomas (8%) and other types (6%). The psychiatric symptoms of the patients were assessed at three time points, namely before tumor operation as well as at three months and at one year after operation by two valid measurement instruments, the Beck Depression Inventory and the Crown Crisp Experiential Index. In addition, the patients' functional state was evaluated by the Karnofsky Performance Scale and their quality of life according to Sintonen 15 D. Prevalence of at least mild depression before tumor operation was 30% for males and 38% for females. The mean depressive scores decreased significantly for up to one-year during follow-up for both males and females, but they remained notably high in all patients. Decreased functional status (KPS under 70) in the patients was significantly associated with high depressive scores at all measurement points. The decrease in the mean depressive scores was significant among patients with an anterior tumor and those with a pituitary adenoma. Five-year survival of the brain tumor patients was found to be mainly associated with the histology of the tumor. Survival time in months (SD) of the patients with high-grade (III–IV) gliomas was shown to be 22.5 (21.4), while it was 50.2 (19.9) for the patients with low-grade (I–II) gliomas, and 58.2 (9.4) for the rest of the patients. Depression among low-grade glioma patients was significantly associated with worse survival at five years follow-up. The level of anxiety was shown to be significantly higher among patients with a primary brain tumor in the right hemisphere compared to the anxiety scores among patients with left hemispheric tumors. A significant increase was found in the level of obsessionality over time in the female patients with a brain tumor in the left anterior location of the brain at three months after operation. The level of quality of life (QOL) was significantly worse among female brain tumor patients compared to males. Depressive females had significantly lower quality of life compared to that of non-depressive females up to one-year follow-up after surgical operation of the tumor. Depression, anxiety and obsessive-compulsive symptoms have to be recognized and be treated by psychotherapy and pharmacotherapy as soon as possible at every unit where brain tumor patients are followed and encountered.

Glioblastoma multiform (GBM) is an aggressive primary brain tumour. Despite treatment advances in recent years, outcomes remain poor. Disease progression tends to occur adjacent to the original tumour or surgical resection bed, usually within the radiotherapy planning field. This local recurrence and progression is believed to be the result of invasive disease in the surrounding tissue at the time of diagnosis and treatment, which is not currently detectable by conventional non-invasive methods. A number of novel therapies are currently under development which target specific aspects of the tumour behaviour, to try and improve outcomes from this devastating disease. Imaging biomarkers are under development, therefore, in order to provide a non-invasive assessment of tumour extent and behaviour, to provide bespoke image-guided therapies, and detect recurrence or treatment failure at the earliest opportunity. These are also of value in the context of novel therapeutics, which may have a very specific affect on an aspect of tumour behaviour that is not readily apparent on standard clinical imaging. Key to the progression of GBM is the invasion into surrounding white matter. This is followed by a period of tumour growth and subsequent angiogenesis in which microvasculature is produce that is distinct from the highly regulated blood-brain barrier. This thesis covers the development of suite of advanced magnetic resonance imaging (MRI) techniques aimed at characterising those very traits of GBM responsible for the aggressiveness and treatment resistance. Repeatability studies are undertaken to determine the performance of the biomarkers in healthy tissues, and also in a range of gliomas. Dynamic Contrast Enhanced (DCE-) and dynamic susceptibility-enhanced (DSC-)MRI are used to provide estimates of perfusion and permeability in the tumour. In order to address the reasons behind preferential invasion of the corpus callosum, they are used in conjunction with ASL to non-invasively map perfusion territories and watershed regions in the brain through perfusion timing parameters. Diffusion Tensor Imaging (DTI) and quantitative magnetisation transfer (qMT) are used to provide complementary information about white matter integrity, in order to identify changes occurring with glioma invasion as early as possible and direct image-guided treatments at presentation. Their complementary nature is assessed by comparing the two parameters simultaneously in white matter. Additionally, one of the qMT parameters which may be related to tissue pH is shown to be sensitive and specific for the detection of high-grade tumour tissue. Finally, a novel multiparametric imaging biomarker is introduced. Tumour surface mapping assesses the boundary between the solid tumour and surrounding tissue in order to identify areas of potential aggressiveness and invasion. Multiple imaging parameters can be combined to improve specificity and sensitivity. Using the diffusion-weighted imaging parameter, mean diffusivity (MD - also referred to as the apparent diffusion coefficient (ADC)), it is shown to be predictive of clinical outcome in a retrospective and prospective study, while a multiparametric example is given indicating the utility as a predicative biomarker for regions of progression and recurrence, and as potential spatial discriminator for image-guided therapies.

Gliomas are brain tumors arising from neuroglia. In most cases astrocytic or oligodendroglial component is the main element of the tumor. Non-random chromosomal abberations are found in tumor cells as was revealed previously. The aim of this study was a fluorescence in-situ hybridisation analysis (FISH) of tissue samples obtained during neurosurgical procedures, determine the frequence of selected chromosomal abberations, further correlation with morphological and clinical data and statistical analysis of the results. During six years 264 tissue samples were gained in which FISH with defined probes was performed. The acquired results were compared with histological analysis and selected clinical data (age, Karnofsky score, extent of resection, overall survival). The whole series was divided into 7 groups by tumor type for further statistical analysis. In every group median and mean survival time was calculated, Kaplan-Meier analysis was focused on influence of selected parameters to overall survival. In some categories Cox regression model was created to achieve a hazard ratio of selected parameters. In WHO Grade II and III tumors the risk of malignant progression and tumor upgrading is significantly higher in comparison with samples where specific abberations were not found (EGFR amplification, CDKN2A and...

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19616号 / 医博第4123号 / 新制||医||1015(附属図書館) / 32652 / 京都大学大学院医学研究科医学専攻 / (主査)教授 佐藤 俊哉, 教授 富樫 かおり, 教授 藤渕 航 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Lower-grade glioma (LGG) is a group of tumors arising from the cells of the central nervous system. Although various therapy interventions are used, the prognosis remains different. Novel biomarkers are needed for the prognosis of disease and novel therapeutic strategies in LGG. The procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) family contains three members and is related to multiple cancers, yet it was not investigated in LGG. Data from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) cohorts were used to analyze the role of PLOD in LGG. As the PLOD family is involved in processes, such as tumor formation and cancer metastasis, we focused on its relationship to the tumor microenvironment (TME) in LGG. A high expression of the PLOD family relates to poor prognosis and high infiltration of immune cells within the TME. The expression level of the PLOD family might become a novel biomarker for prognosis and is a potential target for individual treatment decisions in LGG.

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