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京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22115号 / 医博第4528号 / 新制||医||1039(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 松田 道行, 教授 武藤 学, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Danial Alaei Faradonbeh, Natural drugs in the treatment and prevention of prostate diseases, Charles University in Prague, faculty of pharmacy in Hradec Králové, 2015, 86 pages. "Natural drugs in the treatment and prevention of prostate diseases" deals with prostate diseases which are some of the common ailments affecting men in different parts of the world. The etiology of prostate diseases has been identified but little progress has been witnessed as far as treatment is concerned. Of all prostate diseases identified so far, prostate cancer is the most common and affect me aged 40 and above. Prostate cancer affects the prostate gland and affects the normal function of other genitourinary tissues. Conventional prostate disease therapies have yielded minimal results, leading to increased calls for further research. Successful application of plants in the management of other conditions has attracted the interests of cancer researchers. Focus on a number of plants can provide the much needed reprieve and therapy against prostate cancer. Previous studies have identified a number of plants whose active component can act against cancer cells. Ficus pseudopalma, Nelumbo nuficera, Camptotheca acuminata, Rauvolfa vomitoria and Viscum album are some of the plants which have been identified to act against...

Prostate Cancer is one of the leading causes of male cancer related deaths. African American men who are diagnosed with this disease are over two times more likely to die from it than any other ethnic group. Even with this being a proven fact there are little to know studies that investigate why nor how to remedy the disparity. When a man begins the screening process and all the way until the beginning of treatment, the same guidelines are followed regardless of the patients’ ethnic background. This tactic has led to the developed of the disparity that: African American, even when diagnosed with prostate cancer of similar aggressiveness and receive the same treatments as other non-African American patients, are continuously found to have a less likely chance of survival. Despite all the research and the recurring disparity treatments are continued in the same manner. While the exact reasoning as to why African American males do not respond similarly to treatments as other ethnic groups remains unexplained. It could stem from internal differences, screening process, diagnosing methods, or the treatments themselves. Internal differences, like melanin levels, cannot be changed, but there are ways to circumvent these inevitable differences. Existing studies allow for parallels to be drawn about what effect these inevitable differences may have on the African American response to treatment methods; but clinical trials will need to be completed in order to determine if the parallels drawn hold any merit and if they have the ability to fix the disparity. Once those differences are understood, it will be time to conduct new research to determine if those changes are sufficient enough to eliminate the over two percent chance that African American men are more likely to die from a disease when compared to others.

acase@tulane.edu / 1 / Adedoyin Johnson

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Les antigènes testiculaires du cancer sont des cibles idéales pour l’immunothérapie du cancer car ce sont des protéines immunogéniques dont l’expression est restreinte aux cellules germinales et au cancer. Le but de cette étude est d’évaluer le potentiel de MAGE-A11, un antigène testiculaire du cancer, comme cible pour développer un vaccin contre le cancer de la prostate. Pour ce faire, l’anticorps monoclonal 5C4 qui a la capacité de reconnaître la présence de MAGE-A11 dans les tissus fixés et inclus en paraffine a été produit. De plus, l’expression de MAGE-A11 a été analysée sur plusieurs lignées de cellules cancéreuses. Il a été démontré que MAGE-A11 est exprimé dans plusieurs types de cancers notamment dans le cancer du côlon et du cerveau. Finalement, nous avons identifié trois épitopes du CMH classe II HLA-DR1 dans la protéine MAGE-A11 confirmant ainsi l’immunogénicité de cet antigène et son potentiel comme cible pour l’immunothérapie du cancer. / Cancer/testis antigens are ideal targets for cancer immunotherapy because of their limited expression in normal tissues, aberrant expression in malignancies and their immunogenic properties. The aim of this study was to evaluate the potential of cancer/testis antigen, MAGE-A11, as an immunotherapeutic target for development of a prostate cancer vaccine. To accomplish this, we produced the monoclonal antibody 5C4 that is capable of recognizing MAGE-A11 in formalin-fixed paraffin-embedded tissues. We also investigated the expression of MAGE-A11 in a wide variety of cancer cell lines to determine the scope of its expression in cancer. It was shown that MAGE-A11 is widely expressed in malignancies. The highest MAGE-A11 expression was observed in colon cancer and astrocytoma brain tumors. Finally, we identified three naturally processed MHC class II HLA-DR1 epitopes in MAGE-A11 protein, thus confirming its immunogenicity and its potential as a target for cancer immunotherapy.

Yes / Background: The HOX genes are a family of transcription factors that help to determine cell and tissue identity during early development, and which are also over-expressed in a number of malignancies where they have been shown to promote cell proliferation and survival. The purpose of this study was to evaluate the expression of HOX genes in prostate cancer and to establish whether prostate cancer cells are sensitive to killing by HXR9, an inhibitor of HOX function. Methods: HOX function was inhibited using the HXR9 peptide. HOX gene expression was assessed by RNA extraction from cells or tissues followed by quantitative PCR, and siRNA was used to block the expression of the HOX target gene, cFos. In vivo modelling involved a mouse flank tumour induced by inoculation with LNCaP cells. Results: In this study we show that the expression of HOX genes in prostate tumours is greatly increased with respect to normal prostate tissue. Targeting the interaction between HOX proteins and their PBX cofactor induces apoptosis in the prostate cancer derived cell lines PC3, DU145 and LNCaP, through a mechanism that involves a rapid increase in the expression of cFos, an oncogenic transcription factor. Furthermore, disrupting HOX/PBX binding using the HXR9 antagonist blocks the growth of LNCaP tumours in a xenograft model over an extended period. Conclusion: Many HOX genes are highly over-expressed in prostate cancer, and prostate cancer cells are sensitive to killing by HXR9 both in vitro and in vivo. The HOX genes are therefore a potential therapeutic target in prostate cancer. / The authors gratefully acknowledge the support of the Prostate Project charity (UK).

The Gleason Score (GS) is a powerful predictor of outcome among prostate cancer patients. Patients with tumours graded with a GS of 2 to 6 have a much greater chance of survival compared to those with a GS of 8 to 10. A significant proportion (~40%) of men present with early stage GS 7 tumours (indicating intermediate risk) for whom prognosis is highly variable. Three gene signatures were derived from publicly available gene expression profiles of prostate cancers from the Swedish Watchful Waiting cohort: 1) The Genomic Grade Index consisted of the top 24 genes discriminating between high (8, 9 & 10) and low (≤ 6) GS tumours, 2) The Lethal Gene Score consisted of the top 24 genes discriminating between lethal and indolent disease within GS 7 tumours only, and 3) The network-based gene signature consisted of 88 genes. When these gene signatures were tested in silico on the gene expression profiles of GS 7 patients in both the SWW and the Mayo cohort, patients were stratified into high and low risk for recurrence. These results demonstrate that gene signatures are capable of differentiating low risk and high risk patients within GS 7 tumours. The prognostic capacity of our gene signature will be tested prospectively in a retrospective collection of archived prostate cancer tissue blocks from a phase 3 clinical trial, and it is hypothesized that the patients can be stratified into good and poor outcome groups. NanoString Technology will be used to quantify mRNA values for the signature genes on selected paraffin blocks. Expression values of candidate genes will be correlated with patients’ long-term follow-up information to derive a clinically meaningful signature. Outcome will be defined as biochemical recurrence or metastatic event. The goal of this study is to identify multiple genes whose expression could be formulated into a clinically applicable assay, the implementation of which could serve to better stratify intermediate risk prostate cancer patients for appropriate treatment. / Thesis / Master of Science (MSc) / The over-treatment of prostate cancer patients is a significant concern, as recent clinical trials has shown that it can lead to significant patient morbidity. Although the Gleason Scoring system is a powerful predictor of lethal or indolent disease, a significant proportion of men who present with early stage Gleason Score 7 tumours experience poorer prognosis than expected. The goal of this study is to develop and optimize a gene signature that can be utilized on Gleason Score 7, intermediate risk prostate cancer patients to differentiate them into good and poor outcome groups. We hypothesize that this signature will be able to accurately predict outcome in a separate retrospective cohort of prostate cancer patients. In short, our study hopes to provide proof-of-principle that through the use of gene signatures, it is possible to better differentiate prostate cancer patients into different outcome groups so that they may receive more appropriate treatment specific to their disease type.

Avec une incidence de 23 300 nouveaux cas en 2020 (ce qui représente 20% de tous les nouveaux cas de cancer chez l'homme) et de 4200 décès (10% de tous les décès par cancer chez l'homme), le cancer de la prostate est le cancer le plus fréquemment diagnostiqué chez l'homme au Canada. Il s'agit d'un cancer hormono-dépendant, traité depuis plus de 70 ans par thérapie anti-androgénique. Le succès des nouvelles immunothérapies basées sur la réactivation des lymphocytes T dans certaines pathologies cancéreuses (vessie, poumon, peau, etc.) et leur échec retentissant dans d'autres (incluant le cancer de la prostate) poussent la communauté scientifique à explorer l'impact de la composante innée du système immunitaire dans la réponse aux immunothérapies. Les tumeurs évoluent en tant qu'écosystèmes complexes, constitués entre autres de cellules tumorales, stromales et de cellules immunitaires. Longtemps considéré comme une tumeur « froide »,caractérisée par une faible infiltration immunitaire et comme cancer peu immunogènique, une population de cellules d'origine myéloïdes, les macrophages, sont depuis quelques années reconnus pour leur rôle majeur dans cet écosystème. Dans un premier temps ils seraient impliqués dans une séquence inflammatoire qui favoriserait le développement de la tumeur, puis, une fois la tumeur installée, les macrophages associés aux tumeurs (Tumor-associated macrophages – TAM) grâce à leur très grande plasticité, favoriseraient un environnement immunosuppresseur, l'angiogenèse, l'invasion de cellules tumorales et la formation de niche pré-métastatiques tout en supprimant la réponse des lymphocytes T cytotoxiques. On parle alors de rééducation du système immunitaire par la tumeur. De plus, de solides évidences ont montré l'implication des macrophages dans la résistance à la chimiothérapie et à la radiothérapie dans le cancer de la prostate Basé sur ces observations, nous avons, dans un premier temps, étudié la rééducation de macrophages, au départ à vocation anti-tumorale, en TAM dans le microenvironnement du cancer de la prostate. Nous avons ainsi pu montrer par que les TAM qui apportent le plus d'information sur la progression de la maladie semblent localisés en dehors de la tumeur, dans le tissu adjacent d'apparence normale. Nous avons ainsi pu mettre en place un nouveau système de culture ex vivo de biopsies de patients et trouvé que des TAM avec un phénotypemixte M1 (CCR7+) /M2 (CD163+) étaient présents en grande quantité dans les cancers de prostate agressifs. Nous avons finalement recréé artificiellement dans un modèle de co-culture une façon innovante d'obtenir des macrophages avec le même phénotype et observé qu'indépendamment de leur phénotype de polarisation de base (M1 ou M2), les cellules de cancer de la prostate changeaient ces macrophages pour leur donner une fonction identique tout en les empêchant d'être rééduqués en macrophage M1. Le séquençage des différents macrophages subvertis nous a permis de déterminer que la ré-éducation des macrophages M2 vers un M1 en présence de cellules cancéreuses était accompagnée d'un changement dans le réseau de chimiokines transcrites vers un profil de chimiokines qui favorisent le recrutement de neutrophiles et le remodelage tissulaire et osseux. ans un second temps, nous avons utilisé les informations sur la localisation spatiale des TAM pour inclure plus de tissu adjacent d'apparence normale dans notre système de culture ex vivo. Nous avons alors évalué l'impact d'un traitement actuellement utilisé en clinique, l'enzalutamide, sur la composante immune du microenvironnement tumoral, plus précisément sur les macrophages. Nous avons pu déterminer que l'observation seule de marqueurs à la surface des macrophages via une dichotomie positive/négative ne permettait pas de visualiser de changements. À l'inverse, l'utilisation de sous-populations basées sur la forte/faible expression de marqueurs (CD163, CCR7, CD206) nous permettait d'observer un changement dans la composition du type de macrophages associé à une augmentation de points de contrôle immunologique à leur surface (PD-L1, PD-L2 et B7-H3). Une forte proportion de macrophages PD-L1+ était associée à un plus faible volume tumoral et un ratio neutrophiles/lymphocytes plus élevé tandis qu'une forte proportion de macrophages B7-H3+ était associée avec la présence de carcinome intracanalaire de la prostate, une forme agressive du cancer de la prostate. Ce projet nous a aussi permis de mettre en exergue l'importance de l'utilisation de la cytométrie de flux multiparamétrique comme technique de phénotypage de ces macrophages dans des échantillons biologiques mais surtout l'utilité de cibler à l'aide du multimarquage des sous-populations définies par l'expression de biomarqueurs spécifiques afin de mieux caractériser cette composante importante du microenvironement tumoral prostatique. Enfin, ce travail permet de mieux comprendre la plasticité des macrophages dans un contexte de cancer de prostate agressif ainsi que l'ontogénie des macrophages pro-tumoraux recrutés ou subvertis. Il permet d'amener une approche nouvelle sur l'obtention de macrophages pro-tumoraux et leur utilisation comme modèle pour mimer in vitro les TAM. / With an incidence of 23,300 new cases in 2020 (representing 20% of all new cancer cases in humans) and of4,200 deaths (10% of all cancer deaths in humans), prostate cancer is the non-cutaneous cancer most frequently diagnosed in men in Canada. It is a hormone-dependent cancer, treated for over 70 years with anti-androgen therapy. The success of new immunotherapies based on the reactivation of T lymphocytes in certain cancers(bladder, lung, skin, etc.) and their failure of checkpoint immunotherapy in prostate cancers and others have prompted further exploration of the impact of the innate component of the immune system in the response to immunotherapies. Tumors evolve as a complex ecosystem, mainly made up of tumor cells, stromal cells, andimmune cells. Long considered as a "cold" tumor characterized by low immune cell infiltration and poorlyimmunogenic, the role of innate immune cells such as macrophages within the prostate tumor ecosystem remainto be fully defined. Initially, macrophages may be involved in an inflammatory sequence which promotes tumor development. Later, tumor-associated macrophages (TAMs) due to their very high plasticity, may play a role inpromoting an immunosuppressive environment, angiogenesis, tumor cell invasion and pre-metastatic niche formation while suppressing the response of cytotoxic T cells. These activities mediated by TAMS which are effectively re-educated o by the tumor. This is consistent with the association of macrophages and resistance to chemotherapy and radiotherapy in prostate cancer. Based on these observations, first, we studied the re-education of macrophages, particularly thoses which first present with an anti-tumor phenotype within the prostate cancer microenvironment. We show that the TAMs,which coincide most strongly with clinical outcomes are in fact located peripherally to the tumor in the adjacent normal tissue. We developed a novel system for ex vivo culture of patient biopsies and observed in aggressive prostate cancers that TAMs with a mixed M1 (CCR7+) / M2 (CD163+) phenotype were present in larger quantities. We modeled in a co-culture system an innovative way to obtain TAMs with this same phenotype and observed that regardless of their starting polarization phenotype (M1 or M2), prostate cancer cells changed these macrophages to give them an identical function while preventing them from being re-educated as M1macrophage. The sequencing of the different subverted macrophages allowed us to determine that the reeducation of M2 macrophages to M1 in the presence of cancer cells was accompanied by a change in the chemokine network transcribed towards a profile of chemokines that promote the recruitment of neutrophils and tissue and bone remodeling. Second, we used the information on the spatial location of the TAMs to include more adjacent, apparently normaltissue in our ex vivo culture system. We then evaluated the impact of a treatment currently used in the clinic,enzalutamide, on the immune composition of the tumor microenvironment, more specifically on TAMs We were able to determine that the observation of markers on the surface of macrophages alone via a dichotomous classification did not permit identification of any induced changes. However, with macrophage subpopulations based on the high/low expression of markers (CD163, CCR7, CD206), we observed a change in the compositionof the type of macrophages associated with an increase in immune checkpoints on their surface (PD-L1, PD-L2and B7-H3). A high proportion of PD-L1+ macrophages was associated with a lower tumor volume and a highneutrophil to lymphocyte ratio with a high proportion of B7-H3+ macrophages was associated with the presenceof intracanal carcinoma of the prostate, an aggressive form of prostate cancer. This project allowed us to highlight the importance of the use of multiparametric flow cytometry as a technique of phenotyping on these macrophages in biological samples but above all the usefulness of targeting, using multiple markers, subpopulations defined by expression of specific biomarkers in order to better characterizethis important component of the tumor microenvironment. Finally, this work allows us to better understand the plasticity of macrophages in a context of aggressive PCa as well as the ontogeny of recruited or subverted protumoral macrophages. It provides a new approach to obtain human pro-tumoral macrophages and an in vitromodel which mimics TAMs.