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INTRODUCTION/AIM: The epidemiology, demographic, clinical, treatment, and healthcare resource utilization (HRU) characteristics of desmoid tumor (DT) patients treated at two sarcoma centers in Denmark is described. METHODS: Using Danish health registers, we studied DT patients treated at two sarcoma centers between 2009 and 2018. For each patient, ten persons from the general population were randomly matched on birth year, sex, and region of residence. RESULTS: Of the 179 DT patients identified, 76% were female and the median patient age was 38 years at diagnosis (interquartile range: 31-50). An average annual incidence of DTs over the study period was 3.2 per 1000,000 individuals with the observed annual incidence of DTs ranging from 2.2 (2011) to 4.3 (2017) per 1000,000 individuals. No notable linear time trend in incidence was observed. Anatomical DT sites included extra-abdominal (49%), abdominal wall (40%), and intra-abdominal or retroperitoneal areas (8%). In total, 56% of patients were initially treated surgically. However, while 75% of patients diagnosed with DT between 2009 and 2014 were initially treated surgically, this was true for only 32% of patients diagnosed with DT between 2015 and 2018. A total of 56% of DT patients used chemotherapeutic agents, tyrosine kinase inhibitors, NSAIDs, opioids, antidepressants, or steroids at some point during the three years before their DT diagnoses. In contrast, 70% of surgically treated and 63% of non-surgically treated patients used one of these drugs in the subsequent three years, including NSAIDs (45% surgical vs. 33% non-surgical), opioids (39% surgical vs. 27% non-surgical), and steroids (22% surgical vs. 18% non-surgical). The average number of inpatient and outpatient visits, days of hospitalization, and additional surgical procedures were higher among DT patients than the comparison cohort. CONCLUSION: DTs are rare but have a large impact on patients' health, HRU, and medication utilization.
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Fibromatose Agressiva , Sarcoma , Adulto , Analgésicos Opioides , Anti-Inflamatórios não Esteroides , Dinamarca/epidemiologia , Feminino , Fibromatose Agressiva/diagnóstico , Fibromatose Agressiva/epidemiologia , Fibromatose Agressiva/terapia , Humanos , MasculinoRESUMO
Leiomyosarcoma (LMS) is a mesenchymal cancer that occurs throughout the body. Although LMS is easily recognized histopathologically, the cause of the disease remains unknown. Versican, an extracellular matrix proteoglycan, increases in LMS. Microarray analyses of 80 LMSs and 24 leiomyomas showed a significant elevated expression of versican in human LMS versus benign leiomyomas. To explore the importance of versican in this smooth muscle cell tumor, we used versican-directed siRNA to knock down versican expression in a LMS human cell line, SK-LMS-1. Decreased versican expression was accompanied by slower rates of LMS cell proliferation and migration, increased adhesion, and decreased accumulation of the extracellular matrix macromolecule hyaluronan. Addition of purified versican to cells expressing versican siRNA restored cell proliferation to the level of LMS controls, increased the pericellular coat and the retention of hyaluronan, and decreased cell adhesion in a dose-dependent manner. The presence of versican was not only synergistic with hyaluronan in increasing cell proliferation, but the depletion of versican decreased hyaluronan synthase expression and decreased the retention of hyaluronan. When LMS cells stably expressing versican siRNA were injected into nude mice, the resulting tumors displayed significantly less versican and hyaluronan staining, had lower volumes, and had reduced levels of mitosis as compared with controls. Collectively, these results suggest a role for using versican as a point of control in the management and treatment of LMS.
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Regulação Neoplásica da Expressão Gênica , Ácido Hialurônico/metabolismo , Leiomiossarcoma/genética , Neoplasias Musculares/genética , Versicanas/genética , Animais , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Perfilação da Expressão Gênica , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Hialuronan Sintases , Leiomiossarcoma/metabolismo , Leiomiossarcoma/patologia , Camundongos , Camundongos Nus , Neoplasias Musculares/metabolismo , Neoplasias Musculares/patologia , Músculo Liso/metabolismo , Músculo Liso/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise Serial de Tecidos , Versicanas/antagonistas & inibidores , Versicanas/metabolismo , Versicanas/farmacologiaRESUMO
Acquired resistance to imatinib is a significant problem for the clinical management of gastrointestinal stromal tumor (GIST) patients, and second-line small molecules have shown limited efficacy in this setting. We have recently demonstrated that a monoclonal antibody targeting KIT could potentially bypass imatinib resistance in preclinical models of GIST.
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Thymic involution during aging is a major cause of decreased production of T cells and reduced immunity. Here we show that inactivation of Rb family genes in young mice prevents thymic involution and results in an enlarged thymus competent for increased production of naive T cells. This phenotype originates from the expansion of functional thymic epithelial cells (TECs). In RB family mutant TECs, increased activity of E2F transcription factors drives increased expression of Foxn1, a central regulator of the thymic epithelium. Increased Foxn1 expression is required for the thymic expansion observed in Rb family mutant mice. Thus, the RB family promotes thymic involution and controls T cell production via a bone marrow-independent mechanism, identifying a novel pathway to target to increase thymic function in patients.
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Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Inativação Gênica , Genes do Retinoblastoma , Linfócitos T/fisiologia , Timo/fisiologia , Animais , Fatores de Transcrição E2F/genética , Fatores de Transcrição E2F/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Epitélio/metabolismo , Epitélio/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Linfócitos T/metabolismo , Timo/metabolismoRESUMO
Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract and arises from the interstitial cells of Cajal. It is characterized by expression of the receptor tyrosine kinase CD117 (KIT). In 70-80% of GIST cases, oncogenic mutations in KIT are present, leading to constitutive activation of the receptor, which drives the proliferation of these tumors. Treatment of GIST with imatinib, a small-molecule tyrosine kinase inhibitor, inhibits KIT-mediated signaling and initially results in disease control in 70-85% of patients with KIT-positive GIST. However, the vast majority of patients eventually develop resistance to imatinib treatment, leading to disease progression and posing a significant challenge in the clinical management of these tumors. Here, we show that an anti-KIT monoclonal antibody (mAb), SR1, is able to slow the growth of three human GIST cell lines in vitro. Importantly, these reductions in cell growth were equivalent between imatinib-resistant and imatinib-sensitive GIST cell lines. Treatment of GIST cell lines with SR1 reduces cell-surface KIT expression, suggesting that mAb-induced KIT down-regulation may be a mechanism by which SR1 inhibits GIST growth. Furthermore, we also show that SR1 treatment enhances phagocytosis of GIST cells by macrophages, indicating that treatment with SR1 may enhance immune cell-mediated tumor clearance. Finally, using two xenotransplantation models of imatinib-sensitive and imatinib-resistant GIST, we demonstrate that SR1 is able to strongly inhibit tumor growth in vivo. These results suggest that treatment with mAbs targeting KIT may represent an alternative, or complementary, approach for treating GIST.
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Anticorpos Monoclonais/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/imunologia , Pirimidinas/uso terapêutico , Animais , Anticorpos Monoclonais/farmacologia , Benzamidas , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Mesilato de Imatinib , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fagocitose/efeitos dos fármacos , Piperazinas/farmacologia , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Macrophages promote the growth of leiomyosarcoma (LMS), a malignant soft-tissue tumor. CD47 on tumor cells binds to the macrophagic receptor signal regulatory protein α (SIRPα) and prevents phagocytosis. We showed that anti-CD47 monoclonal antibodies (mAbs) allow macrophages to engulf LMS cells and prevent tumor growth and metastases. Therefore, anti-CD47 mAbs represent a promising targeted immunotherapy for LMS.
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BACKGROUND: Molecular characterization of tumors has been critical for identifying important genes in cancer biology and for improving tumor classification and diagnosis. Long non-coding RNAs, as a new, relatively unstudied class of transcripts, provide a rich opportunity to identify both functional drivers and cancer-type-specific biomarkers. However, despite the potential importance of long non-coding RNAs to the cancer field, no comprehensive survey of long non-coding RNA expression across various cancers has been reported. RESULTS: We performed a sequencing-based transcriptional survey of both known long non-coding RNAs and novel intergenic transcripts across a panel of 64 archival tumor samples comprising 17 diagnostic subtypes of adenocarcinomas, squamous cell carcinomas and sarcomas. We identified hundreds of transcripts from among the known 1,065 long non-coding RNAs surveyed that showed variability in transcript levels between the tumor types and are therefore potential biomarker candidates. We discovered 1,071 novel intergenic transcribed regions and demonstrate that these show similar patterns of variability between tumor types. We found that many of these differentially expressed cancer transcripts are also expressed in normal tissues. One such novel transcript specifically expressed in breast tissue was further evaluated using RNA in situ hybridization on a panel of breast tumors. It was shown to correlate with low tumor grade and estrogen receptor expression, thereby representing a potentially important new breast cancer biomarker. CONCLUSIONS: This study provides the first large survey of long non-coding RNA expression within a panel of solid cancers and also identifies a number of novel transcribed regions differentially expressed across distinct cancer types that represent candidate biomarkers for future research.
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Neoplasias da Mama/genética , Perfilação da Expressão Gênica , RNA Longo não Codificante/genética , Carcinoma/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , HumanosRESUMO
Leiomyosarcoma (LMS) is a malignant, soft-tissue tumor for which few effective therapies exist. Previously, we showed that there are three molecular subtypes of LMS. Here, we analyzed genes differentially expressed in each of the three LMS subtypes as compared to benign leiomyomas and then used the Connectivity Map (cmap) to calculate enrichment scores for the 1309 cmap drugs in order to identify candidate molecules with the potential to induce a benign, leiomyoma-like phenotype in LMS cells. 11 drugs were selected and tested for their ability to inhibit the growth of three human LMS cell lines. We identified two drugs with in vitro efficacy against LMS, one of which had a strongly negative enrichment score (Cantharidin) and the other of which had a strongly positive enrichment score (MG-132). Given MG-132's strong inhibitory effect on LMS cell viability, we hypothesized that LMS cells may be sensitive to treatment with other proteasome inhibitors and demonstrated that bortezomib, a clinically-approved proteasome inhibitor not included in the original cmap screen, potently inhibited the viability of the LMS cell lines. These findings suggest that systematically linking LMS subtype-specific expression signatures with drug-associated expression profiles represents a promising approach for the identification of new drugs for LMS.
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CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.
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Antígenos de Diferenciação/metabolismo , Antígeno CD47/imunologia , Neoplasias/imunologia , RNA Mensageiro/genética , Receptores Imunológicos/metabolismo , Anticorpos/imunologia , Antígeno CD47/genética , Divisão Celular/imunologia , Citometria de Fluxo , Humanos , Neoplasias/patologia , Neoplasias/terapia , Fagocitose/imunologia , Prognóstico , Análise de SobrevidaRESUMO
Antibodies against CD47, which block tumor cell CD47 interactions with macrophage signal regulatory protein-α, have been shown to decrease tumor size in hematological and epithelial tumor models by interfering with the protection from phagocytosis by macrophages that intact CD47 bestows upon tumor cells. Leiomyosarcoma (LMS) is a tumor of smooth muscle that can express varying levels of colony-stimulating factor-1 (CSF1), the expression of which correlates with the numbers of tumor-associated macrophages (TAMs) that are found in these tumors. We have previously shown that the presence of TAMs in LMS is associated with poor clinical outcome and the overall effect of TAMs in LMS therefore appears to be protumorigenic. However, the use of inhibitory antibodies against CD47 offers an opportunity to turn TAMs against LMS cells by allowing the phagocytic behavior of resident macrophages to predominate. Here we show that interference with CD47 increases phagocytosis of two human LMS cell lines, LMS04 and LMS05, in vitro. In addition, treatment of mice bearing subcutaneous LMS04 and LMS05 tumors with a novel, humanized anti-CD47 antibody resulted in significant reductions in tumor size. Mice bearing LMS04 tumors develop large numbers of lymph node and lung metastases. In a unique model for neoadjuvant treatment, mice were treated with anti-CD47 antibody starting 1 wk before resection of established primary tumors and subsequently showed a striking decrease in the size and number of metastases. These data suggest that treatment with anti-CD47 antibodies not only reduces primary tumor size but can also be used to inhibit the development of, or to eliminate, metastatic disease.
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Anticorpos/uso terapêutico , Antígeno CD47/imunologia , Modelos Animais de Doenças , Imunoterapia , Leiomiossarcoma/terapia , Animais , Anticorpos/imunologia , Linhagem Celular Tumoral , Leiomiossarcoma/patologia , Camundongos , Metástase Neoplásica , Fagocitose/imunologiaRESUMO
Soft-tissue sarcomas are a group of malignant tumours whose clinical management is complicated by morphological heterogeneity, inadequate molecular markers and limited therapeutic options. Receptor tyrosine kinases (RTKs) have been shown to play important roles in cancer, both as therapeutic targets and as prognostic biomarkers. An initial screen of gene expression data for 48 RTKs in 148 sarcomas showed that ROR2 was expressed in a subset of leiomyosarcoma (LMS), gastrointestinal stromal tumour (GIST) and desmoid-type fibromatosis (DTF). This was further confirmed by immunohistochemistry (IHC) on 573 tissue samples from 59 sarcoma tumour types. Here we provide evidence that ROR2 expression plays a role in the invasive abilities of LMS and GIST cells in vitro. We also show that knockdown of ROR2 significantly reduces tumour mass in vivo using a xenotransplantation model of LMS. Lastly, we show that ROR2 expression, as measured by IHC, predicts poor clinical outcome in patients with LMS and GIST, although it was not independent of other clinico-pathological features in a multivariate analysis, and that ROR2 expression is maintained between primary tumours and their metastases. Together, these results show that ROR2 is a useful prognostic indicator in the clinical management of these soft-tissue sarcomas and may represent a novel therapeutic target.
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Biomarcadores Tumorais/metabolismo , Tumores do Estroma Gastrointestinal/enzimologia , Leiomiossarcoma/enzimologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Neoplasias Uterinas/enzimologia , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular , Intervalo Livre de Doença , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/terapia , Perfilação da Expressão Gênica/métodos , Terapia Genética , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Leiomiossarcoma/genética , Leiomiossarcoma/mortalidade , Leiomiossarcoma/patologia , Leiomiossarcoma/terapia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Análise Multivariada , Invasividade Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Modelos de Riscos Proporcionais , Interferência de RNA , RNA Mensageiro/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Fatores de Tempo , Transfecção , Carga Tumoral , Neoplasias Uterinas/genética , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Leiomyosarcoma (LMS) is a malignant tumor of smooth muscle cells for which few effective therapies exist. A subset of LMS cases express macrophage colony-stimulating factor (CSF1) and the resultant tumor-associated macrophage (TAM) infiltration predicts poor clinical outcome. Further, TAMs have been shown to increase tumor angiogenesis. Here, we analyzed 149 LMS cases by immunohistochemistry for vascular marker CD34 and show that high microvessel density (MVD) in nongynecological LMS cases significantly predicts poor patient outcome. The majority of high MVD cases were also CSF1-positive, and when combining high MVD with CSF1 expression, an even stronger prognostic correlation with patient outcome was obtained. Gene expression profiling revealed that MVD has a stronger correlation with CSF1 expression than with expression of vascular endothelial growth factor isoforms, which have traditionally been used as markers of angiogenesis and as anti-angiogenic therapeutic targets. Finally, patterns of CSF1 expression and TAM recruitment remained consistent between primary tumors and their metastases, and between primary tumors and those grown as xenografts in mice, highlighting the stability of these features to the biology of LMS tumors. Together, these findings suggest an important role for CSF1 and the resulting TAM infiltration in the pathological neovascularization of LMS tumors and provide a rationale for CSF1-targeted therapies in LMS.
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Leiomiossarcoma/irrigação sanguínea , Leiomiossarcoma/patologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Neovascularização Patológica/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos CD34/metabolismo , Biomarcadores Tumorais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leiomiossarcoma/genética , Fator Estimulador de Colônias de Macrófagos/genética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Microvasos/metabolismo , Microvasos/patologia , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Prognóstico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto JovemRESUMO
PURPOSE: Macrophages play an important role in breast carcinogenesis. The pathways that mediate the macrophage contribution to breast cancer and the heterogeneity that exists within macrophages are incompletely understood. Macrophage colony-stimulating factor 1 (CSF1) is the primary regulator of tissue macrophages. The purpose of this study was to define a novel CSF1 response signature and to evaluate its clinical and biological significance in breast cancer. EXPERIMENTAL DESIGN: We defined the CSF1 response signature by identifying genes overexpressed in tenosynovial giant cell tumor and pigmented villonodular synovitis (tumors composed predominantly of macrophages recruited in response to the overexpression of CSF1) compared with desmoid-type fibromatosis and solitary fibrous tumor. To characterize the CSF1 response signature in breast cancer, we analyzed the expression of CSF1 response signature genes in eight published breast cancer gene expression data sets (n = 982) and did immunohistochemistry and in situ hybridization for CSF1 response genes on a breast cancer tissue microarray (n = 283). RESULTS: In both the gene microarray and tissue microarray analyses, a consistent subset (17-25%) of breast cancers shows the CSF1 response signature. The signature is associated with higher tumor grade, decreased expression of estrogen receptor, decreased expression of progesterone receptor, and increased TP53 mutations (P < 0.001). CONCLUSIONS: Our data show that the CSF1 response signature is consistently seen in a subset of breast carcinomas and correlates with biological features of the tumor. Our findings provide insight into macrophage biology and may facilitate the development of personalized therapy for patients most likely to benefit from CSF1-targeted treatments.