RESUMO
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.
Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Metástase Neoplásica , Neoplasias da Próstata/patologia , Microambiente Tumoral , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proliferação de Células , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Linhagem da Célula , Imunoterapia , Linfócitos T Auxiliares-Indutores/citologia , Microambiente Tumoral , Animais , Antígenos/metabolismo , Neoplasias Ósseas/secundário , Antígeno CTLA-4/metabolismo , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Clonais , Citocinas/metabolismo , Modelos Animais de Doenças , Memória Imunológica/efeitos dos fármacos , Ipilimumab/farmacologia , Masculino , Camundongos , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Análise de Sobrevida , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral/efeitos dos fármacosRESUMO
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.
Assuntos
Neoplasias Ósseas/secundário , Osso e Ossos/patologia , Animais , Biomarcadores/metabolismo , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Osso e Ossos/metabolismo , Denosumab/uso terapêutico , HumanosRESUMO
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.
Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Metástase Neoplásica , Transdução de Sinais , Animais , HumanosRESUMO
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.
Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Metástase Neoplásica , Transdução de Sinais , Animais , Medula Óssea/metabolismo , Neoplasias Ósseas/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Quimiocina CXCL12/metabolismo , Fibroblastos/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Transplante de Neoplasias , Transcrição Gênica , Transplante Heterólogo , Quinases da Família src/genética , Quinases da Família src/metabolismoRESUMO
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.
Assuntos
Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Telomerase/metabolismo , Telômero/metabolismo , Animais , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Cruzamentos Genéticos , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Feminino , Instabilidade Genômica , Humanos , Masculino , Camundongos , Proteína Supressora de Tumor p53/metabolismoRESUMO
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.
Assuntos
Neoplasias Ósseas , Células Endoteliais , Macrófagos , Osteoblastos , Microambiente Tumoral , Via de Sinalização Wnt , Masculino , Microambiente Tumoral/imunologia , Humanos , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/secundário , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Animais , Camundongos , Macrófagos/metabolismo , Macrófagos/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/imunologia , Osteoblastos/metabolismo , Osteoblastos/imunologia , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Linhagem Celular Tumoral , Neoplasias da Próstata/patologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologiaRESUMO
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.
Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Neoplasias da Próstata/fisiopatologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Modelos Animais de Doenças , Deleção de Genes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genótipo , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PTEN Fosfo-Hidrolase/genética , Neoplasias da Próstata/genética , Receptor do Fator de Crescimento Transformador beta Tipo II , Proteína Smad4/genética , Proteína Smad4/metabolismoRESUMO
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.
Assuntos
Neoplasias Ósseas , Neoplasias Encefálicas , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Mutação , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/genética , Classe I de Fosfatidilinositol 3-Quinases/genéticaRESUMO
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.
Assuntos
Neoplasias Ósseas , Proliferação de Células , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata , Humanos , Neoplasias Ósseas/secundário , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Biologia Computacional/métodos , Proliferação de Células/genética , Linhagem Celular Tumoral , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , PrognósticoRESUMO
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.
Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Receptor ErbB-2 , Feminino , Humanos , Neoplasias Ósseas/secundário , Neoplasias da Mama/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Anticorpos de Domínio ÚnicoRESUMO
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.
Assuntos
Neoplasias Ósseas , Neoplasias de Próstata Resistentes à Castração , Rádio (Elemento) , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Rádio (Elemento)/uso terapêutico , Rádio (Elemento)/efeitos adversos , Idoso , Neoplasias Ósseas/secundário , Neoplasias Ósseas/radioterapia , Estudos Prospectivos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Taiwan/epidemiologia , Resultado do Tratamento , Radioisótopos/uso terapêutico , Radioisótopos/efeitos adversosRESUMO
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.
Assuntos
Neoplasias Ósseas , Neoplasias da Próstata , Receptores Androgênicos , Animais , Humanos , Masculino , Camundongos , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Adenocarcinoma/metabolismo , Adenocarcinoma/genética , Neoplasias Ósseas/secundário , Neoplasias Ósseas/metabolismo , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/genética , Modelos Animais de Doenças , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismoRESUMO
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."
Assuntos
Neoplasias Pulmonares , Metastasectomia , Osteossarcoma , Humanos , Osteossarcoma/cirurgia , Osteossarcoma/mortalidade , Osteossarcoma/secundário , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/mortalidade , Metastasectomia/métodos , Criança , Neoplasias Ósseas/secundário , Neoplasias Ósseas/cirurgia , Neoplasias Ósseas/mortalidade , Pneumonectomia/métodos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
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.
Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Neoplasias de Próstata Resistentes à Castração , Rádio (Elemento) , Masculino , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Rádio (Elemento)/efeitos adversos , Intervalo Livre de Progressão , Neoplasias Ósseas/secundário , Método Duplo-Cego , Resultado do TratamentoRESUMO
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.
Assuntos
Neoplasias Ósseas , Linfonodos , Metástase Linfática , Osteossarcoma , Análise de Célula Única , Transcriptoma , Microambiente Tumoral , Osteossarcoma/patologia , Osteossarcoma/genética , Humanos , Neoplasias Ósseas/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Linfonodos/patologia , Metástase Linfática/patologia , Animais , Camundongos , Linhagem Celular Tumoral , Perfilação da Expressão GênicaRESUMO
Bone metastasis is the leading cause of tumor-related deaths in patients with prostate cancer (PCa). The interactions between PCa and the bone microenvironment form a vicious cycle. However, the complex molecular mechanism by which PCa regulates the bone microenvironment remains unclear. To determine the role of glucose-regulated protein (GRP78) in bone metastasis and growth, we established intracardiac injection and tibial injection models, and performed their histological staining. To assess the effect of GRP78 on the differentiation of osteoblasts and osteoclasts, we performed cell co-culture, enzyme-linked immunosorbent assay, alizarin red staining, and tartrate-resistant acid phosphatase staining. We found that GRP78 is upregulated in PCa tissues and that its upregulation is associated with PCa progression in patients. Functional experiments showed that GRP78 overexpression in PCa cells considerably promotes bone metastasis and induces bone microstructure changes. Silencing GRP78 substantially inhibits the migration and invasion of PCa cells in vitro and bone metastasis and tumor growth in vivo. Mechanistically, GRP78 promotes the migration and invasion of PCa cells via the Sonic hedgehog (Shh) signaling pathway. Cell co-culture showed that GRP78 promotes the differentiation of osteoblasts and osteoclasts through Shh signaling. Our findings suggest that tumor-bone matrix interactions owing to GRP78-activated paracrine Shh signaling by PCa cells regulate the differentiation of osteoblasts and osteoclasts. This process promotes bone metastasis and the proliferation of PCa cells in the bone microenvironment. Targeting the GRP78/Shh axis can serve as a therapeutic strategy to prevent bone metastasis and improve the quality of life of patients with PCa.
Assuntos
Neoplasias Ósseas , Neoplasias da Próstata , Humanos , Masculino , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Chaperona BiP do Retículo Endoplasmático , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Neoplasias da Próstata/patologia , Qualidade de Vida , Transdução de Sinais/fisiologia , Microambiente TumoralRESUMO
BACKGROUND: This study sought to identify associations between the Yost Index, a geocoded area neighborhood socioeconomic status (nSES) score, and race/ethnicity with patient refusal of recommended surgery for metastatic bone disease. METHODS: Patients with metastatic bone disease were extracted from the Surveillance, Epidemiology, and End Results database. The Yost Index was geocoded using factor analysis and categorized into quintiles using census tract-level American Community Service (ACS) 5-year estimates and seven nSES measures. Multivariable logistic regression models calculated odds ratios (ORs) of refusal of recommended surgery and 95% confidence intervals (CIs), adjusting for clinical covariates. RESULTS: A total of 138,257 patients were included, of which 14,943 (10.8%) were recommended for surgical resection. Patients in the lowest nSES quintile had 57% higher odds of refusing surgical treatment than those in the highest quintile (aOR = 1.57, 95% CI 1.30-1.91, p < 0.001). Patients in the lowest nSES quintile also had a 31.2% higher age-adjusted incidence rate of not being recommended for surgery compared with those in the highest quintile (186.4 vs. 142.1 per 1 million, p < 0.001). Black patients had 34% higher odds of refusing treatment compared with White patients (aOR = 1.34, 95% CI 1.14-1.58, p = 0.003). Advanced age, unmarried status, and patients with aggressive cancer subtypes were associated with higher odds of refusing surgery (p < 0.001). CONCLUSIONS: nSES and race/ethnicity are independent predictors of a patient refusing surgery for metastatic cancer to bone, even after adjusting for various clinical covariates. Effective strategies for addressing these inequalities and improving the access and quality of care of patients with a lower nSES and minority backgrounds are needed.
Assuntos
Neoplasias Ósseas , Programa de SEER , Classe Social , Recusa do Paciente ao Tratamento , Humanos , Feminino , Masculino , Neoplasias Ósseas/secundário , Neoplasias Ósseas/cirurgia , Idoso , Pessoa de Meia-Idade , Recusa do Paciente ao Tratamento/estatística & dados numéricos , Seguimentos , Prognóstico , Adulto , Características da Vizinhança , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Breast cancer (BrCa) is a predominant malignancy, with metastasis occurring in one in eight patients, nearly half of which target the bone, leading to serious complications such as pain, fractures, and compromised mobility. Structural rigidity, crucial for bone strength, becomes compromised with osteolytic lesions, highlighting the vulnerability and increased fracture risk in affected areas. Historically, two-dimensional radiographs have been employed to predict these fracture risks; however, their limitations in capturing the three-dimensional structural and material changes in bone have raised concerns. Recent advances in CT-based Structural Rigidity Analysis (CTRA), offer a promising, more accurate non-invasive 3D approach. This study aims to assess the efficacy of CTRA in monitoring osteolytic lesions' progression and response to therapy, suggesting its potential superiority over existing methodologies in guiding treatment strategies. METHODS: Twenty-seven female nude rats underwent femoral intra-medullary inoculation with MDA-MB-231 human breast cancer cells or saline control. They were divided into Control, Cancer Control, Ibandronate, and Paclitaxel groups. Osteolytic progression was monitored weekly using biplanar radiography, quantitative computed tomography (QCT), and dual-energy X-ray absorptiometry (DEXA). CTRA was employed to predict fracture risk, normalized using the contralateral femur. Statistical analyses, including Kruskal-Wallis and ANOVA, assessed differences in outcomes among groups and over time. RESULTS: Biplanar radiographs showed treatment benefits over time; however, only certain time-specific differences between the Control and other treatment groups were discernible. Notably, observer subjectivity in X-ray scoring became evident, with significant inter-operator variations. DEXA measurements for metaphyseal Bone Mineral Content (BMC) did not exhibit notable differences between groups. Although diaphyseal BMC highlighted some variance, it did not reveal significant differences between treatments at specific time points, suggesting a limited ability for DEXA to differentiate between treatment effects. In contrast, the CTRA consistently demonstrated variations across different treatments, effectively capturing bone rigidity changes over time, and the axial- (EA), bending- (EI), and torsional rigidity (GJ) outcomes from the CTRA method successfully distinguished differences among treatments at specific time points. CONCLUSION: Traditional approaches, such as biplanar radiographs and DEXA, have exhibited inherent limitations, notably observer bias and time-specific inefficacies. Our study accentuates the capability of CTRA in capturing real-time, progressive changes in bone structure, with the potential to predict fractures more accurately and provide a more objective analysis. Ultimately, this innovative approach may bridge the existing gap in clinical guidelines, ushering in enhanced Clinical Decision Support Tool (CDST) for both surgical and non-surgical treatments.
Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Tomografia Computadorizada por Raios X , Animais , Feminino , Ratos , Humanos , Tomografia Computadorizada por Raios X/métodos , Neoplasias Ósseas/secundário , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias da Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Absorciometria de Fóton/métodos , Densidade Óssea , Ratos Nus , Paclitaxel/uso terapêutico , Paclitaxel/farmacologia , Paclitaxel/administração & dosagem , Linhagem Celular Tumoral , Osteólise/diagnóstico por imagem , Ácido Ibandrônico/uso terapêutico , Ácido Ibandrônico/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologiaRESUMO
In this case report, we describe an uncommon case of neuroendocrine cancer of unknown origin began with cauda equina syndrome in a patient affected by Paget disease of bone (PDB). A 76-year-old man with diagnosis of PDB, without history of pain or bone deformity, developed sudden severe low back pain. Bone alkaline phosphatase was increased and MRI and whole-body scintigraphy confirmed the localization of the disease at the third vertebra of the lumbar spine. Treatment with Neridronic Acid was started, but after only 2 weeks of therapy anuria and bowel occlusion occurred together with lower limb weakness and walking impairment. Cauda equina syndrome consequent to spinal stenosis at the level of L2-L3 was diagnosed after admission to Emergency Department and the patient underwent neurosurgery for spinal medulla decompression. The histologic results showed a complete subversion of bone structure in neoplastic tissue, consistent with metastatic neuroendocrine carcinoma of unknown origin. In conclusion, low back pain in the elderly may require deep investigation to individuate rare diseases. In asymptomatic patients with apparently stable PDB, the sudden appearance of pain or neurologic symptoms may alert the clinician for the possibility of other superimposing diseases, like bone metastases.