Les métastases osseuses sont des complications fréquentes de nombreux cancers tels que le cancer du poumon, de la prostate et du sein. Chez la femme, 70% des patientes présentant un cancer du sein avancé développent des métastases qualifiées d’ostéolytiques. Le développement de ce type de métastases entraine la destruction massive de l’os causant chez les patientes des fractures pathologiques. Les traitements actuellement dispensés en clinique tels que les bisphosphonates et le dénosumab (anti-RANKL) ne sont pas curatifs mais seulement palliatifs. Pour cette raison, notre laboratoire s’intéresse particulièrement aux évènements moléculaires et cellulaires précoces aboutissant à l’émergence de métastases osseuses. Les récepteurs Roundabout (ROBO) ont été initialement décrits comme des régulateurs cruciaux de la migration neuronale et vasculaire lors du développement. ROBO4 est le dernier récepteur décrit et diverge des autres récepteurs ROBO, notamment par son expression spécifique et limitée aux cellules endothéliales et hématopoïétiques. Toutefois, lors d’une analyse transcriptomique comparative le récepteur ROBO4 a été retrouvé surexprimé dans la lignée tumorale ostéotropique MDA-B02. Les récentes expériences, réalisées par notre équipe, visant à inhiber l’activité du récepteur ROBO4, nous ont permis de considérer le récepteur ROBO4 comme un médiateur de l’ancrage à l’os des cellules tumorales MDA-B02. En effet, L’utilisation d’un anticorps anti-ROBO4 réduit considérablement l'adhérence des cellules MDA-B02 sur les cellules ostéoblastiques MC3T3-E1 in vitro et l’ancrage à l’os in vivo. La surexpression de ROBO4 dans un modèle cellulaire de cancer du sein murin nous a conduit à mettre en évidence la présence de deux formes de la protéine ROBO4 aux propriétés antagonistes : (i) une forme glycosylée détectée exclusivement dans les cellules endothéliales et (ii) une forme non glycosylée, issue d’un transcrit alternatif et présente en forte quantité dans les cellules tumorales MDA-B02. L’identification d’un variant protéique du récepteur ROBO4 aux propriétés fonctionnelles et structurales différentes nous a permis d’envisager de nouvelles pistes dans le décryptage des fonctions de ROBO4 dans le processus tumoral et pourrait conduire à la mise au point de thérapies innovantes pour empêcher la formation de métastases dans la moelle osseuse / Bone metastases are frequent complications of many cancers such as lung, prostate and breast cancer. In women, 70% of patients with advanced breast cancer develop metastases known as osteolytic. The development of this type of metastasis leads to the mass destruction of bone causing pathological fractures in patients. Current clinical treatments such as bisphosphonates and denosumab (anti-RANKL) only slow the progression of the disease. For this reason, our laboratory is particularly interested in early molecular and cellular events leading to the emergence of bone metastases. Roundabout receptors (ROBO) were initially described as crucial regulators of neuronal and vascular migration during development. ROBO4 is the last receptor described and diverges from other ROBO receptors, in particular by its specific expression and limited to endothelial and hematopoietic cells. However, in a comparative transcriptomic analysis, the ROBO4 receptor was found to be overexpressed in the MDA-B02 osteotropic tumor line. Recent experiments carried out by our team, aiming at inhibiting the activity of the ROBO4 receptor, allowed us to consider the ROBO4 receptor as a mediator of MDA-B02 tumor cells anchorage to the bone. Indeed, the use of an anti-ROBO4 antibody considerably reduces the adhesion of the MDA-B02 cells to the MC3T3-E1 osteoblastic cells in vitro and the anchoring to the bone in vivo. Overexpression of ROBO4 in a murine breast cancer cell model led us to demonstrate the presence of two forms of the ROBO4 protein with antagonistic properties: (i) a glycosylated form detected exclusively in endothelial cells and (ii) one unglycosylated form derived from an alternative transcript and present in high amounts in MDA-B02 tumor cells. The identification of a protein variant of the ROBO4 receptor with different functional and structural properties has allowed us to consider new opportunities in decoding the functions of ROBO4 in the tumor process and could lead to the development of innovative therapies to prevent the formation of metastases in the bone marrow

Résumé confidentiel / Résumé confidentiel

Background: Using a nude rat model of site-specific metastatic bone disease (MBD), we developed a semiquantitative histological score for rapid assessment of lytic lesions in bone. This provides additional information to conventional histological measurement by clarifying the extent and location of metastatic infiltration and the tumor growth pattern. The score can also be used to assess the action of bisphosphonates on bone metastases. Materials and Methods: Male nude rats (n = 12 per group) were inoculated with the human breast cancer cell line MDA-MB-231 via the femoral artery. Following appearance of radiographically visible osteolytic lesions on day 18, the animals received phosphate-buffered saline (PBS; controls) or ibandronate (IBN, 10 µg P/kg) daily until day 30. Whole body radiographs were obtained on days 18 and 30, and osteolytic areas (OA) were determined by radiographic computer-based analysis (CBA). On day 30, MBD was assessed in both tibias using conventional histological CBA and the new scoring system. Results: Metastatic tumor area correlated with the total sum of the new score in both PBS- (r = 0.762) and IBN-treated animals (r = 0.951; p < 0.001). OA correlated well with the total sum in both groups (r = 0.845 and 0.854, respectively; p < 0.001). Conclusion: Significant reduction of bone marrow and cortical infiltration of tumor cells with IBN suggested local control of metastases. / Hintergrund: Mit Hilfe eines etablierten Tiermodells zur Erzeugung lokalisationsspezifischer Knochenmetastasen in der Nacktratte wurde ein semiquantitatives histologisches Graduierungssystem zur schnellen Bewertung osteolytischer Knochenmetastasen entwickelt. Das Graduierungssystem liefert hinsichtlich der Metastasenlokalisation, deren Ausmaß und Infiltrationsmuster wertvolle Zusatzinformationen zu den konventionellen histologischen Untersuchungsmethoden. Damit kann beispielsweise auch die pharmakologische Wirkung von Bisphosphonaten auf die Knochenmetastasierung beurteilt werden. Material und Methoden: Männlichen Nacktratten (n = 12 pro Gruppe) wurden Zellen der humanen Brustkrebszellinie MDA-MB-231 in die Oberschenkelarterie inokuliert. Ab dem Auftreten radiologisch erkennbarer Osteolysen 18 Tage nach Inokulation erhielten die Tiere bis zum Studienende (Tag 30) täglich entweder eine subkutane Applikation einer Phosphat-Puffer-Lösung (Kontrollgruppe) oder Ibandronat (IBN, 10 µg P/kg; Behandlungsgruppe). Konventionelle Röntgenaufnahmen wurden an den Tagen 18 und 30 nach Tumorinokulation angefertigt und die Osteolysenflächen mittels Computerauswertung bestimmt. Nach Studienende wurde der Metastasenbefall in beiden Tibiae sowohl konventionell histologisch als auch mittels des neuen Graduierungssystems ausgewertet. Ergebnisse: Die Metastasenfläche korrelierte mit der kummulativen Punktsumme des Graduierungssystems sowohl in der Kontrollgruppe (r = 0,762; p < 0,001) als auch in der Ibandronat- Gruppe (r = 0,951; p < 0,001). Ebenso war die Osteolysenfläche eng mit der Punktesumme in beiden Gruppen korreliert (r = 0,845 und 0,854; p < 0,001). Schlussfolgerung: Die signifikante Reduktion von Knochenmark- und Kortikalisbefall durch IBN deuten auf eine gute lokale Kontrolle des Metastasenwachstums hin. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Introduction Prostate cancer (PCa) is the most common cancer among men in Sweden. The clinical course varies considerably, which makes it difficult to predict the prognosis in the individual case. In order to explore the early as well as the late course of the disease, large study groups and population-based cohorts are necessary. Aims To explore factors that influence the long-term outcome of men with low-risk tumours in a population-based register, to predict the long-term course, and to assess the mortality rate for men with prostate cancer (Paper I) To analyse long-term outcome and to investigate factors associated with long-term survival in patients with metastases to the skeleton (Paper II) To analyse early androgen deprivation treatment (ADT) failure and to define clinical predictors associated with short survival due to early ADT failure in prostate cancer patients with bone metastases (Paper III) To analyse the prognostic significance of the extent of bone metastases in relation to other pretreatment variables in prostate cancer patients, and to explore the impact of bone metastases on quality-of-life (Paper IV) Material and methods The study groups were assembled from The South East Region Prostate Cancer Register (SERPCR), and The Scandinavian Prostate Cancer Group (SPCG) Trial No. 5. In the first study, prognostic factors and long-term disease-specific mortality rates of low-risk prostate cancer patients from the early PSA era were analysed. In the second study, patient-related factors, quality-of-life (QoL) and long-term survival in 915 PCa patients with bone metastases (M1b) under ADT, were analysed. In Study III factors predicting primary failure to respond to ADT were identified. Study IV explored the impact of the extent of bone metastases on survival and QoL for these men. Result and conclusions The long-term disease-specific mortality of low-risk localised PCa is low, but the annual mortality rate gradually increases. This indicates that some tumours slowly develop into lethal cancer, particularly in men 70 years or older and with a PSA level ≥ 4 μg/L. From the SPCG Trial No. 5, a subgroup of patients with M1b disease and favourable set of predictive factors survived more than 10 years under ADT with an acceptable QoL. Independent predictors of long-term survival were identified as performance status (PS) &lt; 2, limited extent of bone metastases, and a PSA level &lt; 231 μg/L at the time of enrolment in the trial. However, four independent clinical predictors of early ADT failure could be defined. Men exhibiting these features should be considered for an alternative treatment. Patient grouping based on three categories of extent of bone metastases related to PS, haemoglobin, and QoL at presentation, as independent predictors of mortality, may provide improved accuracy of prognosis.

There is an ever increasing need of new technologies for identification of molecular markers for early diagnosis of fatal diseases to allow efficient treatment. In addition, there is great value in finding patterns of metabolites, proteins or genes altered in relation to specific disease conditions to gain a deeper understanding of the underlying mechanisms of disease development. If successful, scientific achievements in this field could apart from early diagnosis lead to development of new drugs, treatments or preventions for many serious diseases.  Metabolites are low molecular weight compounds involved in the chemical reactions taking place in the cells of living organisms to uphold life, i.e. metabolism. The research field of metabolomics investigates the relationship between metabolite alterations and biochemical mechanisms, e.g. disease processes. To understand these associations hundreds of metabolites present in a sample are quantified using sensitive bioanalytical techniques. In this way a unique chemical fingerprint is obtained for each sample, providing an instant picture of the current state of the studied system. This fingerprint or picture can then be utilized for the discovery of biomarkers or biomarker patterns of biological and clinical relevance. In this thesis the focus is set on evaluation and application of strategies for studying metabolic alterations in human tissues associated with disease. A chemometric methodology for processing and modeling of gas chromatography-mass spectrometry (GC-MS) based metabolomics data, is designed for developing predictive systems for generation of representative data, validation and result verification, diagnosis and screening of large sample sets. The developed strategies were specifically applied for identification of metabolite markers and metabolic pathways associated with prostate cancer disease progression. The long-term goal was to detect new sensitive diagnostic/prognostic markers, which ultimately could be used to differentiate between indolent and aggressive tumors at diagnosis and thus aid in the development of personalized treatments. Our main finding so far is the detection of high levels of cholesterol in prostate cancer bone metastases. This in combination with previously presented results suggests cholesterol as a potentially interesting therapeutic target for advanced prostate cancer. Furthermore we detected metabolic alterations in plasma associated with metastasis development. These results were further explored in prospective samples attempting to verify some of the identified metabolites as potential prognostic markers.

Ο μυελός των οστών επηρεάζεται από λεμφοϋπερπλαστικές διαταραχές, μεταστατική νόσο, αλλά και από διάφορες θεραπευτικές προσεγγίσεις. Η μαγνητική τομογραφία είναι η πιο κατάλληλη μέθοδος για την ανίχνευση των μεταστάσεων και την παρακολούθηση μετά τη θεραπεία. Τεχνικές ανάλυσης εικόνας χρησιμοποιούνται επιπλέον προκειμένου να αντλήσουμε πρόσθετες διαγνωστικές πληροφορίες. Η παρούσα μελέτη επικεντρώνεται στις πρώιμες αλλαγές που προκαλούνται στον οστικό μυελό μετά από ακτινοβόληση και συγκρίνει καθιερωμένες μεθόδους για την ταυτοποίηση και τον χαρακτηρισμό αυτών των βλαβών με τη χρήση ενός αυτοματοποιημένου συστήματος ταξινόμησης. ΜΕΘΟΔΟΙ: 36 ασθενείς με ιστολογικά επιβεβαιωμένη πρωτοπαθή κακοήθεια και οστικές μεταστάσεις συμπεριλήφθηκαν στη μελέτη. Όλοι οι ασθενείς υποβλήθηκαν σε ακττινοθεραπεία για την αντιμετώπιση οστικών μεταστάσεων στη σπονδυλική στήλη ή τη λεκάνη. Η μαγνητική τομογραφία πραγματοποιήθηκε ακριβώς πριν, 12 έως 18 ημέρες και 3 μήνες μετά την έναρξη της ακτινοθεραπείας. Ελήφθησαν εικόνες εντός, πλησίον και εκτός του πεδίου ακτινοβόλησης. Η ποιοτική αξιολόγηση πραγματοποιήθηκε ανεξάρτητα από δύο έμπειρους ακτινολόγους. Για την ποσοτική αξιολόγηση, συγκεκριμένες μετρήσεις επιλέχθηκαν και αξιολογήθηκαν με τη μέθοδο της περιοχής ενδιαφέροντος. Επιπλέον, χαρακτηριστικά υφής 1ης και 2ης τάξης εξήχθησαν και τοποθετήθηκαν σε ένα πιθανοτικό νευρωνικό δίκτυο, προκειμένου να δημιουργηθεί ένα σύστημα αυτόματης ταξινόμησης των βλαβών. ΑΠΟΤΕΛΕΣΜΑΤΑ: Σύμφωνα με την ποιοτική και ποσοτική αξιολόγηση, εντός του πεδίου ακτινοβολίας 22.22% και 33.33% των ασθενών αντίστοιχα παρουσίασε λιπώδη μεταστροφή του μυελού, 19.44% και 16.67% των ασθενών παρουσίασε αιμορραγία, ενώ 11.11% και 16.67% των ασθενών εμφάνισε οίδημα του οστικού μυελού. Παρακείμενα του πεδίου ακτινοβόλησης 11.11% και 19.44% των ασθενών παρουσίασε λιπώδη μεταστροφή, 8.33% παρουσίασε αιμορραγία, ενώ 2.78% και 8.33% έδειξε οίδημα του μυελού των οστών. Εκτός του πεδίου ακτινοβολίας 5.56% των ασθενών παρουσίασαν αλλαγές συμβατές με λιπώδη μεταστροφή, ενώ το υπόλοιπο 94.44% δεν έδειξε σημαντικές μεταβολές. Δεν υπήρξε στατιστικά σημαντική μεταβολή του δείκτη σκιαγραφικής ενίσχυσης μετά τη χορήγηση γαδολινίου. Με βάση την πολυπαραγοντική ανάλυση, καμία από τις παραμέτρους που μελετήθηκαν δεν φάνηκε να επηρεάζει στατιστικά σημαντικά την εμφάνιση οποιασδήποτε από τις μετακτινικές αλλοιώσεις. Η μέγιστη συνολική ακρίβεια ταξινόμησης του συστήματός μας, ως προς τη διάκριση μεταξύ προ και μετακτινικών εικόνων ήταν 93.02%, με χρήση του συστήματος ταξινόμησης LSFT - PNN και της μεθόδου ECV. Η ακρίβεια του συστήματος στη διάκριση μεταξύ των τριών κυρίων τύπων των μετακτινικών βλαβών ήταν 86.67% . ΣΥΜΠΕΡΑΣΜΑΤΑ: Η παρούσα μελέτη δείχνει ότι σημαντικό ποσοστό των ασθενών που υποβάλλονται σε ακτινοθεραπεία θα εμφανίσει τουλάχιστον μία από τις κοινές μετακτινικές μεταβολές του οστικού μυελού. Η λιπώδης μεταστροφή του μυελού είναι η πιο συχνά εμφανιζόμενη πρώιμη μεταβολή. Η ποιοτική ανάλυση των εικόνων μαγνητικής τομογραφίας υστερεί σε ευαισθησία σε σύγκριση με τις ποσοτικές μετρήσεις. Το βασζόμενο σε νευρικό δίκτυο προτεινόμενο σύστημα ταξινόμησης μπορεί να αποδειχθεί χρήσιμο εργαλείο για το χαρακτηρισμό αυτών των βλαβών. / Bone marrow can be affected by lymphoproliferative disorders and metastatic disease but also by several therapeutic approaches. MRI is the most suitable method for the detection of metastases and post-treatment follow-up. Image analysis techniques are now used to extract additional diagnostic information. This study focuses on the early radiation-induced changes that can be detected by MRI and compares the established methods for the identification and characterization of these lesions with an automated classification system. METHODS: 36 patients with histologically confirmed primary malignancy and associated bone metastases were included in the study. All patients underwent radiation therapy (RT) to treat bone metastases to the spinal column or the pelvis. Magnetic resonance imaging (MRI) was performed just before the start of RT, 12 to 18 days and up to 3 months after the start of RT. Images were obtained within, adjacent and outside the radiation field. Qualitative assessment was performed independently by two experienced radiologists. For quantitative assessment, specific measurements were selected and evaluated by the method of the region of interest (ROI). In addition, textural features of 1st and 2nd class were exported and inserted into a probabilistic neural network classifier, in order to create an automatic classification system for these lesions. RESULTS: Following qualitative and quantitative assessment, within the radiation field, 22.22% and 33.33% of patients respectively showed fatty conversion of the bone marrow, 19.44% and 16.67% of patients showed haemorrhage, while 11.11% and 16.67% of the patients demonstrated bone marrow oedema. Adjacent to the radiation field, 11.11% and 19.44% of patients showed fatty conversion, 8.33% showed haemorrhage, while 2.78% and 8.33% demonstrated bone marrow oedema. Outside of the radiation field, 5.56% of patients showed changes compatible with fatty conversion, while the remaining 94.44% showed no significant change. There was no statistically significant change of the enhancement index after gadolinium administration. In multivariate analysis, none of the studied parameters did not appear to affect significantly the appearance of any of the radiation-induced lesions. The largest overall classification accuracy of the system designed to distinguish between the pre- radiation and radiation-induced images was 93.02% using the LSFT-PNN classification system of multiple sequences and the ECV method. Discrimination accuracy of the classification system designed to distinguish between the three main types of post-radiation lesions was 86.67%. CONCLUSIONS: This study shows that a significant proportion of patients undergoing RT will experience at least one of the common radiation-induced bone marrow changes. Fatty marrow conversion is the most often featured change in the examined period. Qualitative analysis of the MRI images lacks sensitivity comparing to quantitative measurements. The proposed classification system, based on the neural network, can be used as a very helpful tool for the characterization of these lesions.

No description available.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / This doctoral thesis involved the study of three groups of neoplasms that affect bones of dogs (primary bone neoplasms, bone metastases, and multicentric neoplasms with bone involvement) and a bone lesion, often paraneoplastic, known as hypertrophic osteopathy. The study of primary bone neoplasms covered important pathological and epidemiological aspects for the diagnosis of this group of tumors, with emphasis on osteosarcomas. It was retrospectively performed, covering a period of 22 years. Reports of biopsy and necropsy cases of dogs received at the Laboratório de Patologia Veterinária, Universidade Federal de Santa Maria (LPVUFSM) were analyzed. Out of the 90 primary bone neoplasms diagnosed in this period, 89 were malignant. Osteosarcoma was the most prevalent (86.7%) neoplasm. Regarding osteosarcomas, most cases occurred in large and giant breed dogs, between six and 10 years of age. The neoplasms predominantly involved the appendicular skeleton and were 3.5 times more prevalent in the forelimbs than in the hindlimbs. The predominant histologic subtype was the osteoblastic. For the study of neoplasms that comprise the second and third groups, i.e., neoplasms with bone metastases or with bone involvement by multicentric neoplasms, a prospective study was conducted over a period of three years. The skeleton of 110 dogs, with 118 malignant neoplasms of different origins received in the necropsy service of the LPV-UFSM were examined for bone lesions. Twenty-one cases of bone metastases or bone involvement by multicentric neoplasms (19.1%) were detected. In general, the bone lesions affected more female dogs. However, when mammary gland neoplasms were not considered, the distribution of cases according to the sex was very similar. The mean age was 9-years-old and dogs of different breeds were affected. The mammary gland was the primary site of most bone metastases, followed by neoplasms of the musculoskeletal and respiratory systems. Most metastases were observed grossly and occurred in multiple bones. However, in 23% of the cases metastases could only be observed microscopically. Vertebrae and humerus were the mosdt frequently affected bones. Simultaneously, seven cases of hypertrophic osteopathy, diagnosed in a period of 11 years at the LPV-UFSM, were retrospectively and prospectively studied. Affected dogs had clinical signs of bone involvement and lesions mainly in the long bones of the limbs. The lesions consisted of periosteal bone neoformation, detected on radiographs, bone inspection during necropsy, and with great level of detail, in macerated bone specimens. The bone proliferation was partially circumferential and occurred mainly in the diaphysis of long bones. It consisted of bone trabeculae of irregular size and thickness, which were arranged perpendicularly to the original cortical bone. In all cases, the lesions of hypertrophic osteopathy were associated with lung neoplasms (primary or metastatic). In two of the seven cases, the lung metastases were of primary bone sarcomas and, in one case, there was a primary lung osteosarcoma (extra-skeletic). / Esta tese envolveu o estudo de três grupos de neoplasmas que afetam os ossos de cães (neoplasmas ósseos primários, metástases ósseas e neoplasmas multicêntricos com envolvimento ósseo) e uma alteração óssea, muitas vezes paraneoplásica, conhecida como osteopatia hipertrófica. O estudo dos neoplasmas ósseos primários envolveu aspectos epidemiológicos e patológicos importantes para o diagnóstico deste grupo de tumores, com ênfase nos osteossarcomas. Foi realizado de forma retrospectiva, compreendo um período de 22 anos. Foram analisados laudos de casos de biópsias e necropsias de cães recebidos no Laboratório de Patologia Veterinária da Universidade Federal de Santa Maria (LPV-UFSM). Dos 90 neoplasmas ósseos primários diagnosticados neste período, 89 eram malignos, sendo os osteossarcomas os mais prevalentes (86,7%). Em relação aos osteossarcomas, a maioria dos casos ocorreu em cães de raças grandes e gigantes e entre seis e 10 anos de idade. Os neoplasmas envolvendo o esqueleto apendicular predominaram e foram 3,5 vezes mais prevalentes nos membros anteriores que nos posteriores. O subtipo histológico predominante foi o osteoblástico. Para o estudo dos neoplasmas que compreenderam o segundo e o terceiro grupos, ou seja, neoplasmas com metástases ósseas ou o envolvimento ósseo em neoplasmas multicêntricos, foi realizado um estudo prospectivo durante um período de três anos. Neste período, cães provenientes do serviço de necropsias do LPV-UFSM foram avaliados. O esqueleto de 110 cães portadores de 118 neoplasmas malignos de diferentes origens foi examinado em busca de lesões ósseas. Foram encontrados vinte e um casos de metástases ou neoplasmas multicêntricos com envolvimento ósseo (19,1%). Em geral, as lesões ósseas afetaram mais as fêmeas. No entanto, quando os neoplasmas originados na glândula mamária foram desconsiderados, a distribuição dos casos de acordo com o sexo foi muito semelhante. Foram afetados cães com idade média de 9 anos e de diferentes raças. A glândula mamária foi a origem da maioria dos tumores que metastatizaram para os ossos, seguida do sistema músculo-esquelético e respiratório. A maioria das metástases foi detectada macroscopicamente e ocorreu em múltiplos ossos. Entretanto, em 23% dos casos as metástases só puderam ser observadas microscopicamente. Dentre os ossos afetados, vértebras e úmero foram os mais frequentemente acometidos. Paralelamente foram estudados, de forma retrospectiva, sete casos de osteopatia hipertrófica diagnosticados em um período de 11 anos no LPV-UFSM. Os cães afetados apresentavam sinais clínicos indicativos de envolvimento ósseo e lesões macroscópicas principalmente nos ossos longos dos membros. As lesões consistiram de neo-formação óssea periosteal, detectada em exame radiográfico, na inspeção óssea durante a necropsia e, com grande nível de detalhamento, em espécimes ósseos macerados. A proliferação óssea observada era parcialmente circunferencial e ocorreu principalmente na diáfise dos ossos longos. Era constituída por trabéculas ósseas de tamanho e espessura irregulares que estavam dispostas de forma perpendicular ao córtex ósseo original. Em todos os casos, as lesões de osteopatia hipertrófica foram associadas a neoplasmas pulmonares (primários ou metastáticos). Em dois dos sete casos, as metástases pulmonares eram de sarcomas ósseos e, em um caso, havia um osteossarcoma primário pulmonar (extraesquelético).

The skeletal system is the most common site of metastatic cancer spread. Bone metastases are often associated with severe morbidity, pain and functional impairment. Timely diagnosis and proper treatment may decrease morbidity, improve quality of life and in some cases even improve survival. External beam radiotherapy may effectively give pain relief in patients with painful bone metastases. In bone metastases from castration-resistant prostate cancer or urothelial bladder cancer, treatment with zoledronic acid or denosumab may reduce skeletal-related events. In contrast to castration-resistant prostate cancer, in patients with bone metastases from bladder cancer such treatment may even improve survival. On the other hand, the efficacy of these agents is questionable in patients with bone involvement from metastatic renal cell carcinoma or germ cell tumors. When bisphosphonates or denosumab are considered in such cases, the potential benefits of treatment should be critically weighed against the risk of side effects. In germ cell tumors, bone metastases may be cured by cisplatin-based chemotherapy, however, there are only limited data on the specific management of residual disease. Oligometastases may be treated by stereotactic radiotherapy or – especially in patients with renal cell carcinoma – by surgical resection and endoprosthetic replacement. Limited data are available on the management of bone involvement in germ cell tumors. Decisions on the resection or local radiotherapy of residual disease should be individualized considering the overall response and the feasibility and risks of resection.

Malgré les avancées thérapeutiques récentes, le pronostic des patients porteurs de métastases osseuses (MO) reste faible, ce qui incite à chercher des nouvelles stratégies thérapeutiques. Les chimiokines sont des acteurs majeurs de la réponse immune, et apparaissent comme des cibles potentielles de l’immunothérapie anti-cancéreuse. Nous avons recherché à définir si la chimiokine CX3CL1 pouvait représenter un axe thérapeutique efficace dans le contexte des MO. Pour cela nous avons développé des modèles murins de MO de cancer du rein et du poumon. Dans le modèle de MO de cancer du poumon, notre travail a démontré que l'expression de CX3CL1 inhibe la croissance tumorale. L’analyse transcriptomique des tumeurs a montré que CX3CL1 diminue (i) l’ostéloyse via un effet sur la triade OPG/RANKL/RANK (ii) l'expression de certains checkpoints, en faveur d’une réponse immune antitumorale. En revanche, dans le modèle de MO de cancer du rein, l’expression de CX3CL1 stimule le développement tumoral et l'ostéolyse via une action sur la triade OPG/RANKL/RANK et inhibe la réponse immune antitumorale via une augmentation de l'expression de certains checkpoints immunitaires. Les bisphosphonates (BPs) sont des agents utilisés pour le traitement des MO. Afin de réduire leurs effets indésirables, nous avons utilisé des ciments de phosphate de calcium (CPC), pour délivrer localement dans l’os des BPs (alendronate, ALN). Notre travail a mis en évidence que (i) ces ciments chargés en ALN relarguent en continue les BPs, (ii) le relarguage d’ALN est efficace pour induire des effets cytotoxiques et pro-apoptotiques vis à vis des cellules de cancer du sein / Despite recent therapeutic improvments, the prognosis for a patient with bone metastases (BM) remains poor, this situation prompting the research of new therapeutic strategies. Chemokines are central players in the immune response, and appear as potential targets in anti-cancer immunotherapies. We are interested to determine whether the CX3CL1 chemokine exerted pro or anti-tumor actions within the bone metastatic context. To address this issue, we developed mouse models of lung or renal cancer BM. In lung cancer BM model, our work demonstrated that CX3CL1 expression led to tumor growth inhibition. Tumors transcriptomic analysis revealed that CX3CL1: (i) impacted bone metabolism by modulating the OPG/RANKL/RANK triad (ii) decreased the expression of certain immune checkpoints, this up-regulating the anti-tumor immune response. By contrast, in renal cancer BM model, CX3CL1 expression stimulated bone tumor development and transcriptomic analysis showed that CX3CL1 (i) promoted osteolysis through an action on the OPG/RANKL/RANK triad (ii) -induced tumor development correlated with an increased expression of certain immune checkpoints, this down-regulating the anti-tumor immune response. Bisphosphonates (BPs) are targeted agents used for BM treatment. In order to reduce their side effects, we used resorbable calcium phosphate cements (CPC), which are frequently used as bone void fillers, as platform for a local delivery of BPs (alendronate, ALN). As a whole, our in vitro data demonstrated that: (i) ALN-CPC cements continuous released ALN; (ii) this ALN release was effective in inducing cytotoxic and pro-apoptotic effects in breast cancer cells