RESUMEN
Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.
Asunto(s)
Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Metástasis de la Neoplasia , Neoplasias de la Próstata/patología , Microambiente Tumoral , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients' bone marrow samples revealed increased Th17 instead of Th1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral Th1 subsets and improves survival. However, ICT fails to elicit an anti-tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promote osteoclast-mediated bone resorption that releases TGF-ß, which restrains Th1 lineage development. Blocking TGF-ß along with ICT increases Th1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.
Asunto(s)
Linaje de la Célula , Inmunoterapia , Linfocitos T Colaboradores-Inductores/citología , Microambiente Tumoral , Animales , Antígenos/metabolismo , Neoplasias Óseas/secundario , Antígeno CTLA-4/metabolismo , Linaje de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Clonales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Memoria Inmunológica/efectos de los fármacos , Ipilimumab/farmacología , Masculino , Ratones , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/patología , Análisis de Supervivencia , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Células TH1/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral/efectos de los fármacosRESUMEN
The periosteum is the layer of cells that covers nearly the entire surface of every bone. Upon infection, injury or malignancy the bone surface undergoes new growth-the periosteal reaction-but the mechanism and physiological role of this process remain unknown1,2. Here we show that the periosteal reaction protects against cancer invasion into the bone. Histological analyses of human lesions of head and neck squamous cell carcinomas (HNSCCs) show that periosteal thickening occurs in proximity to the tumour. We developed a genetically dissectible mouse model of HNSCC and demonstrate that inducible depletion of periosteal cells accelerates cancerous invasion of the bone. Single-cell RNA sequencing reveals that expression of the gene encoding the protease inhibitor TIMP1 is markedly increased in the periosteum at the pre-invasive stage. This increase is due to upregulation of HIF1α expression in the tumour microenvironment, and increased TIMP1 inactivates matrix-degrading proteases, promoting periosteal thickening to inhibit cancer invasion. Genetic deletion of Timp1 impairs periosteal expansion, exacerbating bone invasion and decreasing survival in tumour-bearing mice. Together, these data show that the periosteal reaction may act as a functional stromal barrier against tumour progression, representing a unique example of tissue immunity mediated by stromal cells.
Asunto(s)
Neoplasias Óseas , Neoplasias de Cabeza y Cuello , Invasividad Neoplásica , Periostio , Inhibidor Tisular de Metaloproteinasa-1 , Microambiente Tumoral , Animales , Femenino , Humanos , Masculino , Ratones , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Modelos Animales de Enfermedad , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Invasividad Neoplásica/genética , Periostio/citología , Periostio/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Células del Estroma/metabolismo , Células del Estroma/patología , Inhibidor Tisular de Metaloproteinasa-1/deficiencia , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Análisis de Expresión Génica de una Sola CélulaRESUMEN
Skeletal metastases are frequent complications of many cancers, causing bone complications (fractures, bone pain, disability) that negatively affect the patient's quality of life. Here, we first discuss the burden of skeletal complications in cancer bone metastasis. We then describe the pathophysiology of bone metastasis. Bone metastasis is a multistage process: long before the development of clinically detectable metastases, circulating tumor cells settle and enter a dormant state in normal vascular and endosteal niches present in the bone marrow, which provide immediate attachment and shelter, and only become active years later as they proliferate and alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. The molecular mechanisms involved in mediating each of these steps are described, and we also explain how tumor cells interact with a myriad of interconnected cell populations in the bone marrow, including a rich vascular network, immune cells, adipocytes, and nerves. We discuss metabolic programs that tumor cells could engage with to specifically grow in bone. We also describe the progress and future directions of existing bone-targeted agents and report emerging therapies that have arisen from recent advances in our understanding of the pathophysiology of bone metastases. Finally, we discuss the value of bone turnover biomarkers in detection and monitoring of progression and therapeutic effects in patients with bone metastasis.
Asunto(s)
Neoplasias Óseas/secundario , Huesos/patología , Animales , Biomarcadores/metabolismo , Conservadores de la Densidad Ósea/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/metabolismo , Huesos/metabolismo , Denosumab/uso terapéutico , HumanosRESUMEN
In order to establish themselves in distal sites, metastatic cancer cells need to acquire organ-specific traits. Zhang et al. provide evidence in breast cancer that a tumor cell's acquisition of properties for successful bone metastasis is influenced by signals from the stroma of the primary tumor.
Asunto(s)
Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Metástasis de la Neoplasia , Transducción de Señal , Animales , HumanosRESUMEN
How organ-specific metastatic traits arise in primary tumors remains unknown. Here, we show a role of the breast tumor stroma in selecting cancer cells that are primed for metastasis in bone. Cancer-associated fibroblasts (CAFs) in triple-negative (TN) breast tumors skew heterogeneous cancer cell populations toward a predominance of clones that thrive on the CAF-derived factors CXCL12 and IGF1. Limiting concentrations of these factors select for cancer cells with high Src activity, a known clinical predictor of bone relapse and an enhancer of PI3K-Akt pathway activation by CXCL12 and IGF1. Carcinoma clones selected in this manner are primed for metastasis in the CXCL12-rich microenvironment of the bone marrow. The evidence suggests that stromal signals resembling those of a distant organ select for cancer cells that are primed for metastasis in that organ, thus illuminating the evolution of metastatic traits in a primary tumor and its distant metastases.
Asunto(s)
Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Metástasis de la Neoplasia , Transducción de Señal , Animales , Médula Ósea/metabolismo , Neoplasias Óseas/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Quimiocina CXCL12/metabolismo , Fibroblastos/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Ratones , Trasplante de Neoplasias , Transcripción Genética , Trasplante Heterólogo , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismoRESUMEN
To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-ß/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.
Asunto(s)
Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Telomerasa/metabolismo , Telómero/metabolismo , Animales , Neoplasias Óseas/secundario , Línea Celular Tumoral , Cruzamientos Genéticos , Variaciones en el Número de Copia de ADN , Modelos Animales de Enfermedad , Femenino , Inestabilidad Genómica , Humanos , Masculino , Ratones , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Immune checkpoint therapy has limited efficacy for patients with bone-metastatic castration-resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC-induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32-gene M2-like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206-positive (CD206+) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor-induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2-like gene signature, with activated canonical and noncanonical Wnt pathways, in tumor-associated macrophages isolated from osteogenic tumors (bone-TAMs) than in TAMs isolated from nonosteogenic tumors (ctrl-TAMs). Mechanistic studies showed that endothelial cells (ECs) that had undergone EC-to-osteoblast (EC-to-OSB) transition, the precursors of tumor-induced OSBs, produced paracrine factors, including Wnts, CXCL14, and lysyl oxidase, which induced M2 polarization and recruited M2-like TAMs to the bone-tumor microenvironment (bone-TME). Bone-TAMs suppressed CD8+ T cells' proliferation and cytolytic activity, and these effects were partially reversed by treating bone-TAMs with Wnt inhibitors. Genetic or pharmacological inhibition of Pca-induced EC-to-OSB transition reduced the levels of M2-like macrophages in osteogenic tumors. Our study demonstrates that Pca-induced EC-to-OSB transition drives immunosuppression in the bone-TME, suggesting that therapies that reduce Pca-induced bone formation may improve immunotherapeutic outcomes for bmCRPC.
Asunto(s)
Neoplasias Óseas , Células Endoteliales , Macrófagos , Osteoblastos , Microambiente Tumoral , Vía de Señalización Wnt , Masculino , Microambiente Tumoral/inmunología , Humanos , Neoplasias Óseas/inmunología , Neoplasias Óseas/secundario , Neoplasias Óseas/patología , Neoplasias Óseas/metabolismo , Animales , Ratones , Macrófagos/metabolismo , Macrófagos/inmunología , Células Endoteliales/metabolismo , Células Endoteliales/inmunología , Osteoblastos/metabolismo , Osteoblastos/inmunología , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Línea Celular Tumoral , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/metabolismo , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/inmunologíaRESUMEN
SMAD4 constrains progression of Pten-null prostate cancer and serves as a common downstream node of transforming growth factor ß (TGFß) and bone morphogenetic protein (BMP) pathways. Here, we dissected the roles of TGFß receptor II (TGFBR2) and BMP receptor II (BMPR2) using a Pten-null prostate cancer model. These studies demonstrated that the molecular actions of TGFBR2 result in both SMAD4-dependent constraint of proliferation and SMAD4-independent activation of apoptosis. In contrast, BMPR2 deletion extended survival relative to Pten deletion alone, establishing its promoting role in BMP6-driven prostate cancer progression. These analyses reveal the complexity of TGFß-BMP signaling and illuminate potential therapeutic targets for prostate cancer.
Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Neoplasias de la Próstata/fisiopatología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/secundario , Modelos Animales de Enfermedad , Eliminación de Gen , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genotipo , Estimación de Kaplan-Meier , Masculino , Ratones , Ratones Endogámicos C57BL , Fosfohidrolasa PTEN/genética , Neoplasias de la Próstata/genética , Receptor Tipo II de Factor de Crecimiento Transformador beta , Proteína Smad4/genética , Proteína Smad4/metabolismoRESUMEN
About 20%-30% of breast cancer (BC) patients will develop distant metastases, preferentially in bones, liver, lung, and brain. BCs with different intrinsic subtypes prefer different sites for metastasis. These subtypes vary in the abundance of genetic alterations which may influence the localization of metastases. Currently, information about the relation between metastatic site and mutational profile of BC is limited. In this study, n = 521 BC metastases of the most frequently affected sites (bone, brain, liver, and lung) were investigated for the frequency of AKT1, ERBB2, ESR1, PIK3CA, and TP53 mutations via NGS and pyrosequencing. Somatic mutations were present in 64% cases. PIK3CA and TP53 were the most frequently mutated genes under study. We provide an analysis of the mutational profile of BCs and the affected metastatic site. Genetic alterations differed significantly depending on the organ site affected by metastases. TP53 mutations were mostly observed in brain metastases (51.0%), metastases outside of the brain revealed a much lower proportion of TP53 mutated samples. PIK3CA mutations are frequent in liver (40.6%), lung (36.8%), and bone metastases (35.7%), whereas less common in brain metastases (18.4%). The highest percentage of ESR1 mutations was observed in liver and lung metastases (about 30% each), whereas metastatic lesions in the brain showed significantly less ESR1 mutations, only in 2.0% of the cases. In summary, we found significant differences of mutational status in mBC depending on the affected organ and intrinsic subtype. Organotropism of metastatic cancer spread may be influenced by the mutational profile of individual BCs.
Asunto(s)
Neoplasias Óseas , Neoplasias Encefálicas , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Mutación , Neoplasias Óseas/genética , Neoplasias Óseas/secundario , Neoplasias Encefálicas/genética , Fosfatidilinositol 3-Quinasa Clase I/genéticaRESUMEN
The aetiology of bone metastasis in prostate cancer (PCa) remains unclear. This study aims to identify hub genes involved in this process. We utilized machine learning, GO, KEGG, GSEA, Single-cell analysis, ROC methods to identify hub genes for bone metastasis in PCa using the TCGA and GEO databases. Potential drugs targeting these genes were identified. We validated these results using 16 specimens from patients with PCa and analysed the relationship between the hub genes and clinical features. The impact of APOC1 on PCa was assessed through in vitro experiments. Seven hub genes with AUC values of 0.727-0.926 were identified. APOC1, CFH, NUSAP1 and LGALS1 were highly expressed in bone metastasis tissues, while NR4A2, ADRB2 and ZNF331 exhibited an opposite trend. Immunohistochemistry further confirmed these results. The oxidative phosphorylation pathway was significantly enriched by the identified genes. Aflatoxin B1, benzo(a)pyrene, cyclosporine were identified as potential drugs. APOC1 expression was correlated with clinical features of PCa metastasis. Silencing APOC1 significantly inhibited PCa cell proliferation, clonality, and migration in vitro. This study identified 7 hub genes that potentially facilitate bone metastasis in PCa through mitochondrial metabolic reprogramming. APOC1 emerged as a promising therapeutic target and prognostic marker for PCa with bone metastasis.
Asunto(s)
Neoplasias Óseas , Proliferación Celular , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata , Humanos , Neoplasias Óseas/secundario , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Biología Computacional/métodos , Proliferación Celular/genética , Línea Celular Tumoral , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Movimiento Celular/genética , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , PronósticoRESUMEN
BACKGROUND: 99mTc radiolabeled nanobody NM-02 (99mTc-NM-02) is a novel single photon emission computed tomography (SPECT) probe with a high affinity and specificity for human epidermal growth factor receptor 2 (HER2). In this study, a clinical imaging trial was conducted to investigate the relationship between 99mTc-NM-02 uptake and HER2 expression in patients with breast cancer. METHODS: Thirty patients with pathologically confirmed breast cancer were recruited and imaged with both 99mTc-NM-02 SPECT/computed tomography (CT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT. According to the treatment conditions before recruitment, patients were divided into two groups, the newly diagnosed group (n = 24) and the treated group (n = 6). The maximal standard uptake value (SUVmax) of 18F-FDG and SUVmax and mean SUV (SUVmean) of 99mTc-NM-02 in the lesions were determined to analyze the relationship with HER2 expression. RESULTS: No meaningful relationship was observed between 18F-FDG uptake and HER2 expression in 30 patients with breast cancer. 99mTc-NM-02 uptake was positively correlated with HER2 expression in the newly diagnosed group, but no correlation was observed in the treated group. 99mTc-NM-02 uptake in HER2-positive lesions was lower in those with effective HER2-targeted therapy compared with the newly diagnosed group. 99mTc-NM-02 SPECT/CT detected brain and bone metastases of breast cancer with a different imaging pattern from 18F-FDG PET/CT. 99mTc-NM-02 showed no non-specific uptake in inflamed tissues and revealed intra- and intertumoral HER2 heterogeneity by SPECT/CT imaging in 9 of the 30 patients with breast cancer. CONCLUSIONS: 99mTc-NM-02 SPECT/CT has the potential for visualizing whole-body HER2 overexpression in untreated patients, making it a promising method for HER2 assessment in patients with breast cancer. TRIAL REGISTRATION: NCT04674722, Date of registration: December 19, 2020.
Asunto(s)
Neoplasias Óseas , Neoplasias de la Mama , Receptor ErbB-2 , Femenino , Humanos , Neoplasias Óseas/secundario , Neoplasias de la Mama/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/métodos , Receptor ErbB-2/inmunología , Receptor ErbB-2/metabolismo , Anticuerpos de Dominio ÚnicoRESUMEN
The drug efflux transporter P-glycoprotein, encoded by the ABCB1 gene, promotes acquired chemoresistance. We explored the presence and clinical relevance of circulating cell-free ABCB1 transcripts (cfABCB1tx) in ovarian cancer patients (173 longitudinal serum samples from 79 cancer patients) using digital droplet PCR. cfABCB1tx were readily detectable at primary diagnosis (median 354 mRNA copies/20 µl serum), paralleled FIGO-stage and predicted surgical outcome (p = 0.023, p=0.022, respectively). Increased cfABCB1tx levels at primary diagnosis indicated poor PFS (HR = 2.329, 95%CI:1.374-3.947, p = 0.0017) and OS (HR = 2.074, 95%CI:1.194-3.601, p = 0.0096). cfABCB1tx induction under platinum-based chemotherapy was an independent predictor for poor OS (HR = 2.597, 95%CI: 1.218-5.538, p = 0.013) and paralelled a micrometastatic phenotype, shaped by the presence of disseminated tumor cells in the bone marrow. A strong correlation was observed between cfABCB1tx and circulating transcripts of the metastasis-inducer MACC1, which is the transcriptional activator of ABCB1. Combined assessment of cfABCB1tx and circulating cell-free MACC1 transcripts (cfMACC1tx) resulted in an improved prognostic prediction, with the cfABCB1tx-high/cfMACC1tx-high phenotype bearing the highest risk for relapse and death. Conclusively, we provide proof of principle, that ABCB1 transcripts are readily traceable in the liquid-biopsy of ovarian cancer patients, advancing a new dimension for systemic monitoring of ABCB1/P-glycoprotein expression dynamics.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP , Neoplasias Óseas , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/sangre , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Pronóstico , Neoplasias Óseas/secundario , Neoplasias Óseas/genética , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/genética , Fenotipo , Adulto , ARN Mensajero/genética , ARN Mensajero/metabolismo , Platino (Metal)/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Estadificación de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC) are available, including radium-223 dichloride (223Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real-world evidence for 223Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223Ra was prescribed as part of routine practice by investigators. Patients with prior 223Ra treatment were excluded. The primary objective was to assess 223Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223Ra was first- or second-line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5-6 223Ra cycles was 68.8%; this proportion was greater with first-line use (84.3%) than second- (65.7%) or third-/fourth-line use (64.1%). More chemotherapy-naïve patients (61.9%) completed the 6-cycle 223Ra treatment than chemotherapy-exposed patients (56.7%). Any-grade treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223Ra-related adverse events. Median OS was 15.7 months (95% confidence interval 12.13-19.51); patients receiving 5-6 223Ra injections and earlier 223Ra use had longer OS than those receiving fewer injections and later 223Ra use. 223Ra provides a well-tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases.
Asunto(s)
Neoplasias Óseas , Neoplasias de la Próstata Resistentes a la Castración , Radio (Elemento) , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Radio (Elemento)/uso terapéutico , Radio (Elemento)/efectos adversos , Anciano , Neoplasias Óseas/secundario , Neoplasias Óseas/radioterapia , Estudios Prospectivos , Persona de Mediana Edad , Anciano de 80 o más Años , Taiwán/epidemiología , Resultado del Tratamiento , Radioisótopos/uso terapéutico , Radioisótopos/efectos adversosRESUMEN
BACKGROUND: The first approvals of novel systemic therapies within recent years for metastatic hormone-sensitive (mHSPC) were mainly based on improved overall survival (OS) and time to castration resistance (ttCRPC) in mHSPC patients stratified according to CHAARTED low (LV) versus high volume (HV) and LATITUDE low (LR) versus high-risk (HR) disease. METHODS: Relying on our institutional tertiary-care database we identified all mHSPC stratified according to CHAARTED LV versus HV, LATITUDE LR versus HR and the location of the metastatic spread (lymph nodes (M1a) versus bone (M1b) versus visceral/others (M1c) metastases. OS and ttCRPC analyses, as well as Cox regression models were performed according to different metastatic categories. RESULTS: Of 451 mHSPC, 14% versus 27% versus 48% versus 12% were classified as M1a LV versus M1b LV versus M1b HV versus M1c HV with significant differences in median OS: 95 versus 64 versus 50 versus 46 months (p < 0.001). In multivariable Cox regression models HV M1b (Hazard Ratio: 2.4, p = 0.03) and HV M1c (Hazard Ratio: 3.3, p < 0.01) harbored significant worse than M1a LV mHSPC. After stratification according to LATITUDE criteria, also significant differences between M1a LR versus M1b LR versus M1b HR versus M1c HR mHSPC patients were observed (p < 0.01) with M1b HR (Hazard Ratio: 2.7, p = 0.03) and M1c HR (Hazard Ratio: 3.5, p < 0.01), as predictor for worse OS. In comparison between HV M1b and HV M1c, as well as HR M1b versus HR M1c no differences in ttCRPC or OS were observed. CONCLUSIONS: Significant differences exist between different metastatic patterns of HV and LV and HR and LR criteria. Best prognosis is observed within M1a LV and LR mHSPC patients.
Asunto(s)
Neoplasias Óseas , Metástasis Linfática , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias Óseas/secundario , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Anciano , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/mortalidad , Persona de Mediana Edad , Estudios Retrospectivos , Ganglios Linfáticos/patología , Vísceras/patologíaRESUMEN
BACKGROUND: Preclinical models recapitulating the metastatic phenotypes are essential for developing the next-generation therapies for metastatic prostate cancer (mPC). We aimed to establish a cohort of clinically relevant mPC models, particularly androgen receptor positive (AR+) bone metastasis models, from LuCaP patient-derived xenografts (PDX) that reflect the heterogeneity and complexity of mPC. METHODS: PDX tumors were dissociated into single cells, modified to express luciferase, and were inoculated into NSG mice via intracardiac injection. The progression of metastases was monitored by bioluminescent imaging. Histological phenotypes of metastases were characterized by immunohistochemistry and immunofluorescence staining. Castration responses were further investigated in two AR-positive models. RESULTS: Our PDX-derived metastasis (PDM) model collection comprises three AR+ adenocarcinomas (ARPC) and one AR- neuroendocrine carcinoma (NEPC). All ARPC models developed bone metastases with either an osteoblastic, osteolytic, or mixed phenotype, while the NEPC model mainly developed brain metastasis. Different mechanisms of castration resistance were observed in two AR+ PDM models with distinct genotypes, such as combined loss of TP53 and RB1 in one model and expression of AR splice variant 7 (AR-V7) expression in another model. Intriguingly, the castration-resistant tumors displayed inter- and intra-tumor as well as organ-specific heterogeneity in lineage specification. CONCLUSION: Genetically diverse PDM models provide a clinically relevant system for biomarker identification and personalized medicine in metastatic castration-resistant prostate cancer.
Asunto(s)
Neoplasias Óseas , Neoplasias de la Próstata , Receptores Androgénicos , Animales , Humanos , Masculino , Ratones , Adenocarcinoma/patología , Adenocarcinoma/secundario , Adenocarcinoma/metabolismo , Adenocarcinoma/genética , Neoplasias Óseas/secundario , Neoplasias Óseas/metabolismo , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/metabolismo , Carcinoma Neuroendocrino/genética , Modelos Animales de Enfermedad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismoRESUMEN
OBJECTIVE: To critically examine the evidence-base for survival benefit of pulmonary metastasectomy (PM) for osteosarcoma (OS) in the pediatric population. BACKGROUND: PM for OS is recommended as the standard of care in both pediatric and adult treatment protocols. Recent results from the "Pulmonary Metastasectomy in Colorectal Cancer" trial demonstrate no survival benefit from PM in colorectal cancer in adults. METHODS: A systematic review was undertaken according to "Preferred Reporting Items for Systematic Reviews and Meta-Analysis" guidelines. Medline, Embase, and 2 clinical trial registers were searched for all studies detailing pediatric patients with OS (<18 years) undergoing PM with a comparison cohort group that did not receive PM. RESULTS: Eleven studies met inclusion criteria dating from 1984 to 2017. All studies were retrospective and none directly compared PM versus no PM in pediatric patients as its main objective(s). Three-year survival rates ranged from 0% to 54% for PM and 0% to 16% for no PM. No patients receiving PM were usually those with unresectable disease and/or considered to have a poor prognosis. All studies were at high risk of bias and there was marked heterogeneity in the patient selection. CONCLUSIONS: There is a weak evidence base (level IV) for a survival benefit of PM for OS in pediatric patients likely due to selection bias of "favorable cases." The included studies many of which detailed outdated treatment protocols were not designed in their reporting to specifically address the questions directly. A randomized controlled trial-while ethically challenging in a pediatric population-incorporating modern OS chemotherapy protocols is needed to crucially address any "survival benefit."
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Neoplasias Pulmonares , Metastasectomía , Osteosarcoma , Humanos , Osteosarcoma/cirugía , Osteosarcoma/mortalidad , Osteosarcoma/secundario , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/mortalidad , Metastasectomía/métodos , Niño , Neoplasias Óseas/secundario , Neoplasias Óseas/cirugía , Neoplasias Óseas/mortalidad , Neumonectomía/métodos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: Anti-osteoclast treatment with denosumab or zoledronate is known to effectively reduce the need for radiotherapy to bone and other skeletal-related events (SREs) in patients with metastatic castration-resistant prostate cancer (mCRPC). In this study, we analyze primary versus secondary initiation of bone-targeting agents (BTAs) relative to first palliative bone radiotherapy in patients dying of mCRPC. METHODS: Provincial administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, nâ =â 98 646) who received continuous androgen deprivation therapy (nâ =â 29 453), died of prostate cancer (2013-2018, nâ =â 3864), and received life-prolonging therapy for mCRPC (nâ =â 1850). Variables were collected looking back 3 years from death. Multivariable analysis explored the relationship between clinical variables and BTAs. RESULTS: Of the 58% (1066/1850) patients with mCRPC who received BTA, only 289 (25.4%) started BTA prior to first palliative bone radiotherapy as primary prevention. Eight hundred and forty-eight (74.6%) patients either never received BTA before death (nâ =â 447) or started BTA only after first bone radiotherapy (nâ =â 401). More patients received denosumab (nâ =â 825, 77%) than zoledronic acid (nâ =â 241, 23%). 51.2% (582/1137) of palliative bone radiotherapy was initiated in the last 12 months of life. Factors associated with the use of BTA included elevated alkaline phosphatase (ORâ =â 1.0, Pâ =â .023), de novo metastases (ORâ =â 1.4, Pâ =â .005), medical oncologist involvement (ORâ =â 2.0, Pâ =â .007), diagnosis 2012-2017 versus 2007-2011 (ORâ =â 0.75, Pâ =â .034), and academic center (ORâ =â 0.061, Pâ =â .007). CONCLUSION: A majority of patients with mCRPC never receive BTAs prior to first SRE, despite universal access and availability of these agents in Ontario. These results highlight an opportunity to improve outcomes by emphasizing early introduction of BTA in patients with mCRPC being started on systemic therapy.
Asunto(s)
Neoplasias Óseas , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Anciano , Neoplasias Óseas/secundario , Conservadores de la Densidad Ósea/uso terapéutico , Anciano de 80 o más Años , Persona de Mediana Edad , Denosumab/uso terapéutico , Ácido Zoledrónico/uso terapéutico , OntarioRESUMEN
BACKGROUND: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases. METHODS: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator's choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory). RESULTS: In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610-1.072), p = 0.1389; rPFS 0.956 (0.759-1.205), p = 0.7039; OS 0.889 (0.660-1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379-0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%. CONCLUSIONS: In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014.
Asunto(s)
Neoplasias Óseas , Neoplasias de la Mama , Neoplasias de la Próstata Resistentes a la Castración , Radio (Elemento) , Masculino , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Radio (Elemento)/efectos adversos , Supervivencia sin Progresión , Neoplasias Óseas/secundario , Método Doble Ciego , Resultado del TratamientoRESUMEN
BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor and is highly prone to metastasis. OS can metastasize to the lymph node (LN) through the lymphatics, and the metastasis of tumor cells reestablishes the immune landscape of the LN, which is conducive to the growth of tumor cells. However, the mechanism of LN metastasis of osteosarcoma and remodeling of the metastatic lymph node (MLN) microenvironment is not clear. METHODS: Single-cell RNA sequencing of 18 samples from paracancerous, primary tumor, and lymph nodes was performed. Then, new signaling axes closely related to metastasis were identified using bioinformatics, in vitro experiments, and immunohistochemistry. The mechanism of remodeling of the LN microenvironment in tumor cells was investigated by integrating single-cell and spatial transcriptomics. RESULTS: From 18 single-cell sequencing samples, we obtained 117,964 cells. The pseudotime analysis revealed that osteoblast(OB) cells may follow a differentiation path from paracancerous tissue (PC) â primary tumor (PT) â MLN or from PC â PT, during the process of LN metastasis. Next, in combination of bioinformatics, in vitro and in vivo experiments, and immunohistochemistry, we determined that ETS2/IBSP, a new signal axis, might promote LN metastasis. Finally, single-cell and spatial dissection uncovered that OS cells could reshape the microenvironment of LN by interacting with various cell components, such as myeloid, cancer-associated fibroblasts (CAFs), and NK/T cells. CONCLUSIONS: Collectively, our research revealed a new molecular mechanism of LN metastasis and clarified how OS cells influenced the LN microenvironment, which might provide new insight for blocking LN metastasis.