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).

Introdução: a TC de tórax possui sensibilidade superior à do RX de tórax na detecção de metástases pulmonares do CCR. O uso rotineiro da TC de tórax préoperatória, no entanto, resulta na identificação de um alto número de lesões pulmonares indeterminadas (LPI), as quais raramente são malignas. Objetivo: nosso objetivo principal foi avaliar a eficácia da TC de tórax no estadiamento pré-operatório de pacientes com CCR. Investigamos, também, se os resultados da TC de tórax tiveram influência significativa no manejo oncológico e desfecho clínico dos pacientes. Métodos: realizamos uma revisão de todas as TCs e RXs de tórax realizados em pacientes operados eletivamente por CCR no período de 2005-2012 no serviço de coloproctologia do HCPA. Todos os exames de imagem foram analisados por um radiologista independente “cego”. Os achados dos exames foram classificados como benignos, malignos ou indeterminados. Os pacientes foram acompanhados por pelo menos 12 meses após a cirurgia para avaliar a evolução e real natureza das lesões indeterminadas. Resultados: duzentos e vinte e três pacientes foram incluídos. A TC de tórax demonstrou achados normais ou benignos em 157 (70,4%) pacientes, achados malignos em 17 (7,6%) e achados indeterminados (LPI) em 49 (22%). Dos 30 casos com metástases pulmonares comprovadas, o RX detectou as lesões em apenas 11 pacientes (36,7%). No seguimento pós-operatório (mediana de 27,5 meses), 14 pacientes (28,6%) com LPI tiveram progressão maligna das lesões. Dos 223 pacientes estudados, apenas 6 (2,7%) foram submetidos à ressecção pulmonar, 2 destes permanecendo em remissão até o fechamento do estudo. Conclusão: demonstramos que a TC é claramente superior ao RX na detecção de metástases pulmonares. Apesar das implicações médicas e financeiras do emprego da TC de tórax, apenas um número muito limitado de pacientes será eventualmente submetido à ressecção pulmonar. Nossos resultados contestam o uso da TC de tórax de rotina no estadiamento de pacientes com CCR. Sugerimos uma conduta mais seletiva, reservando a TC para aqueles pacientes com alto risco de metástases pulmonares. / Background: Chest computed tomography (CCT) has higher sensitivity than chest x-ray in detecting lung metastases from colorectal cancer (CRC). However, the routine use of pretreatment CCT results in a high number of indeterminate lung lesions (ILLs), which rarely prove to be malignant. Objective: our main goal was to evaluate the effectiveness of CCT in the preoperative staging of patients with CRC. We also tried to investigate whether the results of CCT have a significant influence on cancer management and clinical outcomes. Methods: we conducted a review of all preoperative CCTs and x-rays performed in patients submitted to an elective resection of CRC between 2005 and 2012 at our institution. All imaging tests were analyzed by a "blind" independent radiologist. Findings were classified as benign, malignant, or indeterminate. Patients were followed up for at least 12 months after surgery to assess clinical evolution of undetermined lesions and their oncological outcome. Results: Two hundred and twenty-three patients were included. CCTs showed normal or benign findings in 157 (70.4%) patients, malignant lesions in 17 (7.6%) patients, and indeterminate lung lesions (ILL) in 49 (22%) patients. Of the 30 cases with proven lung metastases, x-rays detected lesions in only 11 (36.7%) patients. During postoperative follow-up, 14 patients (28.6%) with the initial diagnosis ILL had malignant progression of their lung lesions. Of all 223 patients, only six (2.7%) underwent lung resection. Two of them remained in remission until the end of the study. Conclusion: We demonstrated that CCT is clearly superior to x-ray in the detection of lung metastases. Despite medical and financial implications of preoperative chest CT, only a very limited number of patients will eventually undergo lung resection. We call into question the role of routine chest CT in the staging of patients with CRC. A more selective approach, reserving CT for patients at high risk of lung metastases, is suggested.

Introdução: a TC de tórax possui sensibilidade superior à do RX de tórax na detecção de metástases pulmonares do CCR. O uso rotineiro da TC de tórax préoperatória, no entanto, resulta na identificação de um alto número de lesões pulmonares indeterminadas (LPI), as quais raramente são malignas. Objetivo: nosso objetivo principal foi avaliar a eficácia da TC de tórax no estadiamento pré-operatório de pacientes com CCR. Investigamos, também, se os resultados da TC de tórax tiveram influência significativa no manejo oncológico e desfecho clínico dos pacientes. Métodos: realizamos uma revisão de todas as TCs e RXs de tórax realizados em pacientes operados eletivamente por CCR no período de 2005-2012 no serviço de coloproctologia do HCPA. Todos os exames de imagem foram analisados por um radiologista independente “cego”. Os achados dos exames foram classificados como benignos, malignos ou indeterminados. Os pacientes foram acompanhados por pelo menos 12 meses após a cirurgia para avaliar a evolução e real natureza das lesões indeterminadas. Resultados: duzentos e vinte e três pacientes foram incluídos. A TC de tórax demonstrou achados normais ou benignos em 157 (70,4%) pacientes, achados malignos em 17 (7,6%) e achados indeterminados (LPI) em 49 (22%). Dos 30 casos com metástases pulmonares comprovadas, o RX detectou as lesões em apenas 11 pacientes (36,7%). No seguimento pós-operatório (mediana de 27,5 meses), 14 pacientes (28,6%) com LPI tiveram progressão maligna das lesões. Dos 223 pacientes estudados, apenas 6 (2,7%) foram submetidos à ressecção pulmonar, 2 destes permanecendo em remissão até o fechamento do estudo. Conclusão: demonstramos que a TC é claramente superior ao RX na detecção de metástases pulmonares. Apesar das implicações médicas e financeiras do emprego da TC de tórax, apenas um número muito limitado de pacientes será eventualmente submetido à ressecção pulmonar. Nossos resultados contestam o uso da TC de tórax de rotina no estadiamento de pacientes com CCR. Sugerimos uma conduta mais seletiva, reservando a TC para aqueles pacientes com alto risco de metástases pulmonares. / Background: Chest computed tomography (CCT) has higher sensitivity than chest x-ray in detecting lung metastases from colorectal cancer (CRC). However, the routine use of pretreatment CCT results in a high number of indeterminate lung lesions (ILLs), which rarely prove to be malignant. Objective: our main goal was to evaluate the effectiveness of CCT in the preoperative staging of patients with CRC. We also tried to investigate whether the results of CCT have a significant influence on cancer management and clinical outcomes. Methods: we conducted a review of all preoperative CCTs and x-rays performed in patients submitted to an elective resection of CRC between 2005 and 2012 at our institution. All imaging tests were analyzed by a "blind" independent radiologist. Findings were classified as benign, malignant, or indeterminate. Patients were followed up for at least 12 months after surgery to assess clinical evolution of undetermined lesions and their oncological outcome. Results: Two hundred and twenty-three patients were included. CCTs showed normal or benign findings in 157 (70.4%) patients, malignant lesions in 17 (7.6%) patients, and indeterminate lung lesions (ILL) in 49 (22%) patients. Of the 30 cases with proven lung metastases, x-rays detected lesions in only 11 (36.7%) patients. During postoperative follow-up, 14 patients (28.6%) with the initial diagnosis ILL had malignant progression of their lung lesions. Of all 223 patients, only six (2.7%) underwent lung resection. Two of them remained in remission until the end of the study. Conclusion: We demonstrated that CCT is clearly superior to x-ray in the detection of lung metastases. Despite medical and financial implications of preoperative chest CT, only a very limited number of patients will eventually undergo lung resection. We call into question the role of routine chest CT in the staging of patients with CRC. A more selective approach, reserving CT for patients at high risk of lung metastases, is suggested.

Head and neck cancer is the fifth most common cancer worldwide with an estimated annual global incidence of over 500 000 cases. These malignant tumours develop in the mucosal linings of the upper respiratory tract or in the salivary glands. The most common sites are in the oral cavity and larynx. Treatment modalities comprising surgery and chemoradiotherapy have improved significantly during the last 20 years, but not the long-term survival of patients. The aim of this thesis was to study the different factors affecting tumour growth in head and neck cancer that may have clinical implications in the future. Factors involving apoptosis, cell cycle activity, inflammation, and enzyme activity were of special interest. The results of the thesis indicate that patients with malignant salivary gland tumours having the lowest level of actively replicating cells have the best prognosis. The largest amount of replicating cells in tongue cancer specimens was found in the peripheral areas of tumour nests. Metallothionein, a protein that can hinder apoptosis, was found in excess in the same areas, whereas apoptosis activity was considerably lower. Taken together, these results indicate that the most aggressive cancer cells are found in the peripheral areas of tumours where apoptosis may be hindered. The expression of the death receptor Fas was higher in tongue cancer specimens than in normal mucosa. The expression of this receptor was studied further in two cell lines established from oral cancers. When a low dose of cisplatin was added to cell cultures, the Fas expression was enhanced in both cell lines and, furthermore, the Fas-induced apoptosis was increased in one of the cell lines. The results show that a common chemotherapeutic drug given in a low, less toxic dose may enhance receptor-mediated apoptosis of cancer cells. Malignant solid tumours are often distinguished by an increased proteolytic activity resulting in invasive growth, neo-angiogenesis, and metastases. This activity is conducted by enzymes that are secreted from tumour cells, or from normal cells in the tumour microenvironment. The regulation of enzyme secretion may be mediated by cytokines, small signalling molecules also present in cancer tissue. The results of this thesis show that two cytokines can synergistically induce enzyme secretion (matrix metalloproteinase-1 and -9) from oral cancer cells. Cytokine tumour necrosis factor-alpha and hepatocyte growth factor added alone to cell cultures strongly stimulated secretion of these enzymes. Thus, the tested cytokines, which are commonly secreted by fibroblasts and immune cells, may promote tumour growth. This thesis has contributed to an increased understanding of factors affecting tumour growth in head and neck cancer. The upcoming cancer therapies will be based on the increasing knowledge of these and other aberrant cellular mechanisms that may vary between different cancer forms.

La radiothérapie est souvent utilisée pour contrôler la progression d'un cancer. Cependant, la mauvaise spécificité de ciblage de la plupart des techniques de radiothérapie peut entraîner une réponse clinique ambiguë. Une stratégie alternative - et complémentaire - est d'utiliser des matériaux possédant un numéro atomique élevé et qui peuvent ainsi agir en synergie avec les rayonnements ionisants pour améliorer le ratio thérapeutique de la radiothérapie. Dans ce contexte, une nanoparticule (NP) théranostique à base de gadolinium (Gd) est particulièrement adaptée pour fournir simultanément une plus grande précision en Imagerie par Résonance Magnétique (IRM) et une meilleure efficacité en radiothérapie clinique. Au cours de cette thèse, nous avons étudié d'un point de vue préclinique la pharmacocinétique et le métabolisme de ces NP chez des rongeurs et des primates non humains afin d'élucider leurs voies d'élimination et de calculer la dose sans effet nocif observé (NOAEL). De plus, nous avons démontré la capacité d'imagerie et de thérapie de ces particules sur un modèle de souris porteuses de mélanome cérébral, ceci afin d'appuyer le potentiel des NP pour la radiothérapie guidée par IRM en clinique. Ces travaux de thèse - ainsi que des résultats précédents - ont contribué au début d'un essai clinique actuellement en cours / Combinations of chemotherapy and radiotherapy are often used to control cancer progression. However, the poor targeting specificity of most chemotherapies and radiotherapies can cause toxicity and ambiguous clinical response. In particular, dose escalation in radiotherapy inevitably increases radiation exposure for some surroundings normal tissues and organs, putting them at risk for debilitating damage. An alternative – and complementary – strategy is the use of materials with high atomic numbers (Z) that strongly interact with low energy photons to produce photoelectrons and Auger electrons In this context, a new efficient type of gadolinium (Gd)-based theranostic agent (AGuIX®) has recently been developed by the team of Prof. Tillement for MRI-guided radiotherapy. AGuIX® is a 3-nm size nanoparticles of 9 kDa, consist of a polysiloxane network surrounded by Gd chelates. In this thesis, we investigated the elimination kinetics of AGuIX nanoparticle’s (NPs) from sub-cellular to whole organ scale using original and complementary techniques. This combination of techniques allows the exact mechanism of AGuIX NPs elimination to be elucidated. We reported the preclinical pharmacokinetics and toxicology studies of intravenous AGuIX NPs administration in healthy and atherosclerosis non-human primates (NHP), the goal of which is to demonstrate the safety of AGuIX NPs, in particular, for pre-clinical evaluation. Subsequently, we performed experimental and theoretical studies to investigate the radiosensitization of AGuIX NPs, in particular with B16F10 mouse melanoma as a model for brain metastases. After, we implemented experimental and theoretical studies to precisely understand the mechanism of this radiosensitization, we suggest additional mechanism, potentially caused by chemical and biological effects induced by the combination of Gd and radiation (i.e. high yield of radicals formation and combination, and bystander effect)

Distant brain metastases from oral squamous cell carcinomas (OSCC) are extremely rare. Here we describe a case of a 53-year-old man with a primary OSCC who referred to the neurosurgical department because of epileptic seizures. MR imaging revealed an enhancing lesion in the right parietal lobe. A craniotomy with tumor removing was performed. Histopathological examination verified an invasive, minimally differentiated metastasis of the primary OSCC. The patient refused whole brain radiation therapy and died from pulmonary metastatic disease 10 months after the neurosurgical intervention without any cerebral recurrence. To the authors’ knowledge, only two similar cases have been previously reported.

Medulloblastoma is a common malignant brain tumor in childhood, but a rare disease amongst adults. The tendency to metastasize along cerebrospinal fluid pathways is well known. Extraneural metastases represent only a small number of recurrences and are associated with a poor outcome. Encouraging results of high-dose chemotherapy followed by autologous stem cell transplantation were reported previously in children with recurrent malignant brain tumors.

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.

Die Dissertation hat sich mit der Aufgabe befasst, durch Kombination von IR-Spektroskopie und chemometrischen Auswertungsalgorithmen eine Differenzierung und Klassifizierung von Hirnmetastasen-Dünnschnitten zu erreichen. Die Untersuchungen konzentrieren sich dabei auf jene fünf Primärtumoren, die besonders oft Metastasen im Gehirn bilden. Das sind kolorektale Karzinome, Mammakarzinome, maligne Melanome, Nierenzellkarzinome und Bronchialkarzinome. Metastasen tragen die molekularen Informationen der Gewebezellen des Primärtumors in sich. Die Anwendung von IR-spektroskopischen Methoden stellt deshalb einen innovativen Ansatz zur Identifikation des Primärtumors von Hirnmetastasen dar, da die Spektren einem molekularen Fingerabdruck entsprechen. Als Klassifizierungsalgorithmen wurden SIMCA (soft independent modeling of class analogies) und ANN (artificial neural networks) herangezogen. Die Entwicklung der Klassifizierungsverfahren gliederte sich in drei Teile. Im ersten Teil wurden Trainingsmodelle mit den ausgewählten homogenen Bereichen der Metastasengewebeschnitte erstellt und an unabhängigen Daten weiterer Proben bekannter und unbekannter Organherkunft getestet. Im zweiten Teil wurden die Modelle mit Hilfe homogener Tumorzelllinien optimiert und auf die Zuordnung der Hirnmetastasen zu den Primärtumoren angewandt. Eine zweistufige Klassifizierungsstrategie gewährleistet damit eine Genauigkeit der Klassifizierung von über 80%.

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