Cancer is a complex illness that affects millions of people every year. Amongst the most frequently encountered variants of this illness are solid tumours. The growth of solid tumours depends on a large number of factors such as oxygen concentration, cell reproduction, cell movement, cell death, and vascular environment. The aim of this thesis is to provide further insight in the interconnections between these factors by means of numerical simulations. We present a multiscale model for tumor growth by coupling a microscopic, agent-based model for normal and tumor cells with macroscopic mean-field models for oxygen and extracellular concentrations. We assume the cell movement to be dominated by Brownian motion. The temporal and spatial evolution of the oxygen concentration is governed by a reaction-diffusion equation that mimics a balance law.To complement this macroscopic oxygen evolution with microscopic information, we propose a lattice-free approach that extends the vascular distribution of oxygen. We employ a Markov chain to estimate the sprout probability of new vessels. The extension of the new vessels is modeled by enhancing the agent-based cell model with chemotactic sensitivity. Our results include finite-volume discretizations of the resulting partial differential equations and suitable approaches to approximate the stochastic differential equations governing the agent-based motion. We provide a simulation framework that evaluates the effect of the various parameters on, for instance, the spread of oxygen. We also show results of numerical experiments where we allow new vessels to sprout, i.e. we explore angiogenesis. In the case of a static vasculature, we simulate the full multiscale model using a coupled stochastic/deterministic discretization approach which is able to reduce variance at least for a chosen computable indicator, leading to improved efficiency and a potential increased reliability on models of this type.

Yes / Glycogen synthase kinase-3 (GSK3) is over-expressed and hyperactivated in non-small cell lung carcinoma (NSCLC) and plays a role in ensuring the correct alignment of chromosomes on the metaphase plate during mitosis through regulation of microtubule stability. This makes the enzyme an attractive target for cancer therapy. We examined the effects of a selective cell-permeant GSK3 inhibitor (CHIR99021), used alone or in combination with paclitaxel, using an in vitro cell growth assay, a quantitative chromosome alignment assay, and a tumor xenograft model. CHIR99021 inhibits the growth of human H1975 and H1299 NSCLC cell lines in a synergistic manner with paclitaxel. CHIR99021 and paclitaxel promoted a synergistic defect in chromosomal alignment when compared to each compound administered as monotherapy. Furthermore, we corroborated our in vitro findings in a mouse tumor xenograft model. Our results demonstrate that a GSK3 inhibitor and paclitaxel act synergistically to inhibit the growth of NSCLC cells in vitro and in vivo via a mechanism that may involve converging modes of action on microtubule spindle stability and thus chromosomal alignment during metaphase. Our findings provide novel support for the use of the GSK3 inhibitor, CHIR99021, alongside taxol-based chemotherapy in the treatment of human lung cancer. / Cancer Research UK Project Grant (C16929/A14402) and the Elizabeth Blackwell Institute, through its Wellcome Trust ISSF Award (105612/Z/14/Z). The Imperial NIHR/Biomedical Research Centre and the CR-UK/Dept of Health funded Imperial Experimental Cancer Medicine Centre.

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Experimentelle Studien zeigten, dass durch die perioperative, intraperitoneale Therapie antiadhärenter und zytotoxischer Substanzen das intra- und extraperitoneale Tumorwachstum nach Operationen vermindert werden kann. Nach intraperitonealen und subkutanen Applikationen von 104 Tumorzellen (DHD/K12/TRb) wurden BD IX Ratten in 14 Gruppen randomisiert: 7 Gruppen wurden mit CO2 laparoskopiert und 7 konventionell operiert. Die Operationszeiten betrugen 30 Minuten. Am Ende der Intervention wurde Ringerlösung, Taurolidin oder Taurolidin/Heparin intraperitoneal oder in die V. femoralis appliziert. Die Veränderungen des Differentialblutbildes auf das Operationstrauma und auf die Applikation der therapeutischen Substanzen wurden ermittelt. Taurolidin und die zusätzliche Therapie mit Heparin reduzierten im Tierexperiment nach intraperitonealer sowie simultaner intraperitonealer und intravenöser Therapie das intraperitoneale Tumorwachstum und die Inzidenz von Trokar- beziehungsweise Inzisionsmetastasen. Die intravenöse Therapie von Taurolidin und der Kombination aus Taurolidin/Heparin hatte keinen tumorsupprimierenden Effekt. Die Verschiebungen der Leukozytenzahlen des Differentialblutbildes wurden hauptsächlich durch das Operationstrauma bewirkt. In diesem Tierversuch wurden nach der Therapie mit Taurolidin und der Kombination mit Heparin keine Nebenwirkungen beobachtet. / Following subcutaneous and intraperitoneal injection of 104 colon adenocarcinoma cells (DHD/K12/TRb) the influences of both taurolidine or taurolidine/heparin on intraperitoneal and subcutaneous tumor growth was investigated in 210 rats undergoing midline laparotomy or insufflation with carbon dioxide. The animals were randomized into 14 groups. To investigate the intraperitoneal (local) influence of either taurolidine or heparin on tumor growth the substances were applied intraperitoneally. Systemic and intraperitoneal effects were evaluated after intravenous injection of the substances. Both application forms were also combined to analyze synergistic effects. Tumor weights, as well as the incidence of abdominal wound metastases were determined four weeks after the intervention. In order to evaluate the effects of the agents blood was taken to determine the peripheral leukocytes counts. Intraperitoneal therapy of either taurolidine or in combination with heparin inhibits local tumor growth and abdominal wound recurrences in rats undergoing midline laparotomy or insufflation with carbon dioxide. Neither the intraperitoneal nor the intravenous application or the combination of the two agents did influence the subcutaneous tumor growth. The substances did not alter the changes of peripheral leukocytes.

Cholangiocarcinoma (CCA) is a fatal primary malignancy that is formed in the bile ducts. Cancer-associated myofibroblasts play a crucial role in CCA proliferation and invasion. Furthermore, there is a growing interest in the role of the exosome in the interaction between the cancer-associated myofibroblasts and cholangiocarcinoma which lead to CCA growth. However how cholangiocarcinoma-derived exosome affect the cancer-associated myofibroblasts in the tumor microenvironment remain unknown. In this study, we examined whether exosome produced by cholangiocarcinoma could involve in the prompt of CCA cells growth by regulation of myofibroblast. We found that cholangiocarcinoma-derived exosome could prompt elevated α-smooth muscle actin and stromal cell-derived factor one expression that induces myofibroblast proliferation. We then demonstrated that cholangiocarcinoma-derived exosome upregulated periostin expression that plays an important role in cancer metastasis. In 3D organotypic rat CCA coculture model, TCA and S1P considerably increase the growth of CCA cell. Conclusion: cholangiocarcinoma-derived exosome trigger cancer-associated myofibroblasts proliferation in the tumor microenvironment that leads to prompt CCA growth.

<p>Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy in man with stromal fibrosis as one of the main features. Carcinoma cells synthesized no or little collagen I protein. Pro-α1(I) collagen mRNA was expressed by stromal cells throughout the tumor, but expression of procollagen type I protein was restricted to stromal cells situated close to nests of carcinoma cells. These data suggest that the carcinoma cells stimulated collagen type I deposition by increasing pro-α1(1) collagen mRNA translation. </p><p>Cocultures, of the human ATC cell line KAT-4, with fibroblasts under conditions that allow the study of stimulatory factors on collagen mRNA translation, showed that the KAT-4 cells stimulated collagen type I protein synthesis in fibroblasts. Specific inhibitors of PDGF and TGF-β1 and -β3 were able to inhibit this carcinoma cell-induced stimulation of collagen type I synthesis. These findings suggest that tumor cells were able to stimulate collagen mRNA translation in stromal fibroblasts by, at least in part, transferring PDGF and/or TGF-β1 and -β3.</p><p>Xenograft transplantation of different ATC cell lines into athymic mice demonstrated that the low collagen producing carcinoma cell lines were less tumorigenic compared to non-collagen producing carcinoma cell lines. The morphology of tumors derived from non-collagen producing ATC cell lines showed a well demarked stroma surrounding carcinoma cell nests. </p><p>TGF-β1 and -β3 were found to play a role in generating a high tumor interstitial fluid pressure (TIPF) in experimental KAT-4 tumors. A specific inhibitor of TGF-β1 and -β3 was able to lower TIPF and reduce tumor growth after a prolonged period of treatment, suggesting that TGF-β1 and -β3 have a role in maintaining a stroma that support tumor growth.</p>

Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy in man with stromal fibrosis as one of the main features. Carcinoma cells synthesized no or little collagen I protein. Pro-α1(I) collagen mRNA was expressed by stromal cells throughout the tumor, but expression of procollagen type I protein was restricted to stromal cells situated close to nests of carcinoma cells. These data suggest that the carcinoma cells stimulated collagen type I deposition by increasing pro-α1(1) collagen mRNA translation. Cocultures, of the human ATC cell line KAT-4, with fibroblasts under conditions that allow the study of stimulatory factors on collagen mRNA translation, showed that the KAT-4 cells stimulated collagen type I protein synthesis in fibroblasts. Specific inhibitors of PDGF and TGF-β1 and -β3 were able to inhibit this carcinoma cell-induced stimulation of collagen type I synthesis. These findings suggest that tumor cells were able to stimulate collagen mRNA translation in stromal fibroblasts by, at least in part, transferring PDGF and/or TGF-β1 and -β3. Xenograft transplantation of different ATC cell lines into athymic mice demonstrated that the low collagen producing carcinoma cell lines were less tumorigenic compared to non-collagen producing carcinoma cell lines. The morphology of tumors derived from non-collagen producing ATC cell lines showed a well demarked stroma surrounding carcinoma cell nests. TGF-β1 and -β3 were found to play a role in generating a high tumor interstitial fluid pressure (TIPF) in experimental KAT-4 tumors. A specific inhibitor of TGF-β1 and -β3 was able to lower TIPF and reduce tumor growth after a prolonged period of treatment, suggesting that TGF-β1 and -β3 have a role in maintaining a stroma that support tumor growth.

Proopiomelanocortin (POMC) is a 241 amino acids precursor protein, which encodes various neuropeptides including corticotropin (ACTH), a-melanocyte-stimulating hormone (a-MSH), and b-endorphin (b-EP). POMC plays an important role in stress response, metabolism, energy homeostasis and anti-inflammation. Recent studies demonstrated that systemic POMC gene delivery potently suppresses the tumor growth and metastasis of B16-F10 melanoma in vitro and in vivo via inhibition of NF-£eB/COX2 pathway. However, systemic POMC expression also led to elevated urine excretion and water intake in mice. This was attributed to enhanced steroidgenesis as evidence by elevated plasma corticosteroids levels in animals and increased cortisol production in adrenal H295R cells after POMC gene delivery. Since corticosteroids are also potent anti-inflammatory agents, it remains unclear whether the ACTH-mediated cortisol synthesis also contributed to the POMC-induced tumor suppression. To address this issue, we generated a series of adenovirus vectors encoding POMC genes with mutation or deletion in ACTH domain including ACTH (K15A/R17A). Unlike the wild type POMC, gene delivery of ACTH (K15A/R17A) resulted in significantly lower cortisol production, CYP11B1 mRNA level, and glucocorticoid responsive element (GRE)-driven luciferase activities in H295R cells. ACTH (K15A/R17A) gene delivery did not affect the urination and water intake in mice. Above all, ACTH (K15A/R17A) gene delivery remained capable of inhibiting the colonies formation and invasiveness of B16-F10 melanoma cells. In summary, steroidgenesis is not essential to POMC-mediated melanoma suppression. In addition, ACTH (K15A/R17A) gene delivery may provide a better alternative for melanoma control.

Les espèces réactives de l’oxygène (ERO) contrôlent plusieurs aspects de la carcinogenèse, étant donné leur capacité àpromouvoir la prolifération mais aussi à induire la sénescence et l’apoptose. Dans les stades avancés de cancer, les EROpeuvent également participer au développement de l’atrophie musculaire, engendrant une détérioration de la qualité de viedes patients. L’activité physique (AP), connue pour augmenter les défenses antioxydants de l’organisme et lasupplémentation en antioxydants sont considérées comme deux stratégies susceptibles de moduler la croissance tumorale, d’améliorer la performance physique et de réduire les effets secondaires liés à la maladie et aux traitements anticancéreux. Néanmoins, plusieurs questions restent aujourd’hui sans réponse. En effet, bien que l’AP puisse réduire la progression du cancer du sein, du colon et de la prostate, son impact sur les cancers se développant au sein du muscle (ex : le liposarcome), donc soumis aux contractions musculaires répétées, reste méconnu. En utilisant des approches in vivo et in vitro, nous avons démontré que maintenir une AP régulière accélère la croissance du liposarcome intramusculaire, probablement, via la réduction des taux circulants d’insuline et l’inhibition de la voie « P38 MAPK-P21 ». Pour les patients ne pouvant pas pratiquer d’AP, la consommation d’antioxydants pourrait être un moyen de réduire les ERO tumorales et musculaires et ainsi être prometteuse. Toutefois, les études actuelles restent très controversées. Nos travaux ont montré dans un modèle murin de cachexie cancéreuse que des doses nutritionnelles d’un produit antioxydant commercialisé en France, étaient suffisantes pour accélérer la croissance de la tumeur colique, favoriser la perte de masse corporelle totale et musculaire et engendrer la mort prématurée des souris. L’ensemble de nos résultats suggère que la pratique d’AP et la consommation en antioxydants peuvent induire des effets différents selon le type de tumeur et leur implantation, nécessitant une prise en charge individualisée des patients. En effet, (1) les patients atteints d’un LS intramusculaire devraient éviter de pratiquer une AP durant la période préopératoire mais ces résultats doivent être confirmés par une étude clinique, (2) les patients avec un stade avancé de cancer devraient être vigilants quant à l’utilisation de suppléments antioxydants ; une telle pratique pouvant avoir des répercussions dangereuses sur leur santé. / Reactive oxygen species (ROS) control several aspects of carcinogenesis as they can either promote tumor growth andprogression or senescence and apoptosis. In advanced stages of cancer, ROS can also drive the development of other cancerrelated complications like, muscle wasting. Physical activity (PA) and antioxidant supplementation have been proposed as two adjuvant strategies to better control tumor growth, ameliorate performance and alleviate secondary symptoms related to cancer itself or to the heavy anticancer therapies. However, several issues remain to be elucidated. First of all, although PA could reduce colon, breast and prostate cancer growth and progression, its impact remains unknown on orthotopic intramuscular tumors like liposarcoma, which directly affect the musculoskeletal apparatus and reduce physical function. Secondly, given the limitedness of PA application in some advanced stages of cancer, patients may increase their dependency on nutritional and antioxidant complements as an alternative strategy, but such practice has spark a lot of polemic and inconsistent results. In this thesis, we have addressed the effectiveness of PA and antioxidants in two distinct animal models of cancer. Using in vivo and in vitro approaches, we found that voluntary PA accelerated the growth of intramuscular liposarcoma tumors and exacerbated skeletal muscle dysfunction, mainly, by decreasing circulating insulin levels and the subsequent activation of the tumor suppressor pathway “P38 MAPK-P21”. We also demonstrated that nutritional doses of commercial antioxidants enhanced colon tumor growth, total body/skeletal muscle weight loss and caused premature death of mice. Such mechanism was due to selective changes in oxidative damage profiles, which decreased in tumor but increased in skeletal muscle, in a way driving tumor growth and skeletal muscle wasting/dysfunction. Clinically, it seems that (1) patients with intramuscular liposarcoma may, at least, not increase their levels of PA or undergo hospital-supervised exercise program, during the preoperative period; until the confirmation of our findings with clinical data and (2) patients with advanced stages of cancer must be very careful against the use of antioxidants as it could lifethreatening. Accordingly, health agencies in France, Europe and USA prohibit the use of synthetic antioxidant supplements without dietary counseling by a cancer patient’s physician and/or nutritionist.

Le mésothéliome pleural malin (MPM) est une tumeur rare et agressive qui se développe au niveau de la plèvre.L'Adrénomedulline (AM) est un peptide de 52 acides aminés. Il intervient dans plusieurs processus physiologiques et physiopathologiques. Il est surexprimé dans plusieurs tumeurs où il joue un rôle important dans la croissance tumorale.Dans un premier temps nous avons montré que l'AM et ses récepteurs sont exprimés dans des biopsies de patients atteints de MPM suggérant son implication dans la croissance tumorale du MPM. In vitro l'incubation de lignées de MPM: H2452 et MSTO_211H avec des anticorps αAM ou αAMR inhibent la prolifération, l'invasion et la migration cellulaires. In vivo, le traitement avec un anticorps αAM ou l'antagoniste AM22-52, inhibe la croissance tumorale des xénogreffes de MSTO_211H par rapport au groupe contrôle. L'analyse histologique montre une augmentation significative de l'apoptose et une diminution importante de la vascularisation chez les tumeurs traitées par rapport aux tumeurs contrôles. Ces résultats démontrent le rôle important joué par l'AM dans la croissance tumorale du MPM et fait du système de l'AM une cible thérapeutique potentielle.Dans un deuxième temps, Nous avons émis l'hypothèse de la transactivation de l'EGFR par l'AM. Notre hypothèse s'est concrétisée dans la mesure où L'inhibition de l'EGFR par un inhibiteur spécifique l'AG1478 abolie l'activation de ERK par l'AM,La phosphorylation de l'EGFR par l'AM,La neutralisation de l'EGFR avec son propre anticorps inhibe la phosphorylation par l'AM suggérant une activation ligand dépendante. Ces résultats nous permettent de mieux comprendre le mécanisme d'action de l'AM. / Malignant pleural mesothelioma (MPM) grows aggressively in the thoracic cavity without curative possibilities, underlining the need for new therapeutic targets. Adrenomedullin (AM), a multifunctional peptide, is highly expressed in several tumors and plays an important role in angiogenesis and tumor. In the first part of our work, QRT-PCR showed an increase of AM mRNA levels in MPM when compared to normal pleura tissue. Immunohistochemically, AM and its receptors were localized in the carcinomatous epithelial compartment of MPM. The MPM cell lines H2452 and MSTO_211H expressed AM with a significant increase under hypoxia. The proliferation, migration and invasion of MPM cells are decreased by anti-AM and anti-AM receptors antibodies (αAM and αAMR) supporting that MPM cells can be regulated by AM. In vivo, αAM and AM22-52 antagonist therapies of MSTO_211H xenografts blocked angiogenesis and stimulated apoptosis, resulting in tumor regression. Histologic examination of treated tumors showed evidences of disruption of tumor vasculature. These findings highlight the implication of the AM pathway in the MPM growth and in neovascularization by supplying/amplifying signals essential for pathologic neoangiogenesis and lymphangiogenesis.In the second part of this work, we reported that the EGFR becomes rapidly tyrosine-phosphorylated upon stimulation of lung cancer cells lines with AM, suggesting that there is an intracellular mechanism for transactivation. Specific inhibition of EGFR function by the AG1478 or EGFR blocking antibody suppressed MAPK activation. These results suggest strongly a ligand-dependent mechanism of EGFR transactivation by AM.