RESUMO
Neuroendocrine differentiation (NED) represents a possible androgen receptor pathway inhibitors (ARPI) resistance mechanism in metastatic castration resistance prostate cancer (mCRPC). As mCRPC with NED has been excluded from clinical trials evaluating ARPI efficacy, this study investigates the prognostic impact of NED in mCRPC patients treated with ARPIs. Methods: We retrospectively analyzed 327 mCRPC patient data treated with Enzalutamide or Abiraterone in the first and second or successive lines of treatment. NED was assessed using prostate biopsy samples through immunohistochemical staining. Results: NED was confirmed in 32/327 (9.8%) mCRPC patients. In the overall population, mCRPC with NED showed worse PFS (4.38 vs. 11.48 months HR 2.505 [1.71-3.68] p < 0.05), disease control rate (DCR), and PSA response. In the first line setting, mCRPC with NED demonstrated worse PFS (8.5 vs. 14.9 months HR 2.13 [1.18-3.88], p < 0.05). Similarly, in the second or successive lines, mCRPC with NED showed worse PFS (4.0 vs. 7.5 months HR 2.43 [1.45-4.05] p < 0.05), DCR, PSA response and OS (12.53 vs. 18.03 months HR 1.86 [1.12-3.10] p < 0.05). The adverse impact of NED on PFS was consistence across all subgroups; we also noted a trend of worse PFS in patients with high vs. low NED. Conclusions: In our study, mCRPC with NED treated with Enzalutamide or Abiraterone showed worse clinical outcomes. NED assessment should be considered to optimize treatment decisions in the mCRPC setting.
Assuntos
Androstenos , Benzamidas , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Feniltioidantoína/uso terapêutico , Feniltioidantoína/farmacologia , Nitrilas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Androstenos/uso terapêutico , Androstenos/farmacologia , Idoso , Pessoa de Meia-Idade , Diferenciação Celular/efeitos dos fármacos , Metástase Neoplásica , Idoso de 80 Anos ou mais , Resultado do Tratamento , Células Neuroendócrinas/patologia , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/efeitos dos fármacosRESUMO
BACKGROUND: Pulmonary fibrosis (PF) leads to excessive deposition of fibrous connective tissue in the lungs, increasing the risk of lung cancer due to the enhanced activity of fibroblasts (FBs). Fibroblast-mediated collagen fiber deposition creates a tumor-like microenvironment, laying the foundation for tumorigenesis. Clinically, numerous cases of lung cancer induced by pulmonary fibrosis have been observed. In recent years, the study of nucleotide point mutations, which provide more detailed insights than gene expression, has made significant advancements, offering new perspectives for clinical research. METHODS: We initially employed Mendelian randomization to ascertain that the initial stage of lung cancer induced by PF belongs to small cell lung cancer (SCLC). Subsequently, pulmonary neuroendocrine cells (PNECs) were identified by using pseudo-time series analysis as cell clusters with carcinogenic potential. We categorized FBs into four groups according to their cellular metabolism, and then analyzed the cellular communication between FBs and PNECs, as well as changes in intracellular pathways of PNECs. Additionally, we examined the characteristic genome of FBs which is significantly associated with PF and investigated the impact of FBs on immune cells in the PF microenvironment. Finally, we explored strategies for preventing the progression from PF to lung cancer. RESULTS: The genetic features of cells with carcinogenic potential in PF tissues were revealed, characterized by upregulation of Achaete-Scute Family BHLH Transcription Factor 1 (ASCL1), Homeobox B2 (HOXB2), Teashirt Zinc Finger Homeobox 2 (TSHZ2), Insulinoma-associated 1 (INSM1), and reduced activity of RE1 Silencing Transcription Factor (REST). FBs characterized by high glycolysis and low tricarboxylic acid (TCA) cycling played a key role in the progression of PF. The microenvironment of PF resembles the tumor microenvironment, providing a conducive immunosuppressive environment for the occurrence of cancer cells. In dendritic cells, rs9265808 is a susceptibility locus for progression from pulmonary fibrosis to lung cancer, mutations at this locus increase the expression of Complement Factor B (CFB), and excessive activation of the complement pathway is a crucial factor leading to lung cancer development in patients with pulmonary fibrosis. Ensuring adequate nutritional supply and physical function is one of the effective measures to prevent progression from pulmonary fibrosis to lung cancer. CONCLUSION: CFB promotes lung cancer occurrence by inducing the accumulation and polarization of a large number of monocytes/macrophages in the lungs, driving disease progression by reducing the physical fitness of patients with pulmonary fibrosis.
Assuntos
Progressão da Doença , Neoplasias Pulmonares , Fibrose Pulmonar , Análise de Célula Única , Neoplasias Pulmonares/genética , Humanos , Fibrose Pulmonar/genética , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Transcriptoma , Fibroblastos , Células Neuroendócrinas/patologia , Células Neuroendócrinas/metabolismo , Pulmão/patologia , Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/genéticaRESUMO
Vertebrate calcitonin-producing cells (C-cells) are neuroendocrine cells that secrete the small peptide hormone calcitonin in response to elevated blood calcium levels. Whereas mouse C-cells reside within the thyroid gland and derive from pharyngeal endoderm, avian C-cells are located within ultimobranchial glands and have been reported to derive from the neural crest. We use a comparative cell lineage tracing approach in a range of vertebrate model systems to resolve the ancestral embryonic origin of vertebrate C-cells. We find, contrary to previous studies, that chick C-cells derive from pharyngeal endoderm, with neural crest-derived cells instead contributing to connective tissue intimately associated with C-cells in the ultimobranchial gland. This endodermal origin of C-cells is conserved in a ray-finned bony fish (zebrafish) and a cartilaginous fish (the little skate, Leucoraja erinacea). Furthermore, we discover putative C-cell homologs within the endodermally-derived pharyngeal epithelium of the ascidian Ciona intestinalis and the amphioxus Branchiostoma lanceolatum, two invertebrate chordates that lack neural crest cells. Our findings point to a conserved endodermal origin of C-cells across vertebrates and to a pre-vertebrate origin of this cell type along the chordate stem.
Assuntos
Calcitonina , Linhagem da Célula , Ciona intestinalis , Endoderma , Crista Neural , Células Neuroendócrinas , Animais , Endoderma/metabolismo , Endoderma/citologia , Calcitonina/metabolismo , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/citologia , Ciona intestinalis/metabolismo , Ciona intestinalis/embriologia , Crista Neural/metabolismo , Crista Neural/citologia , Embrião de Galinha , Camundongos , Vertebrados/embriologia , Vertebrados/metabolismo , Peixe-Zebra/embriologia , Anfioxos/embriologia , Anfioxos/metabolismo , Anfioxos/genética , Corpo Ultimobranquial/metabolismoRESUMO
There is growing evidence that neurogenic inflammation contributes to the pathophysiology of upper airway diseases, with nasal hyperreactivity (NHR) being a key symptom. The rare neuroendocrine cells (NECs) in the epithelium have been linked to the pathophysiology of bronchial and intestinal hyperreactivity, however their presence in the nasal mucosa and their potential role in NHR remains unclear. Therefore, we studied the presence of NECs in the nasal epithelium of controls, allergic rhinitis patients and chronic rhinosinusitis with nasal polyps patients, and their link to NHR. The expression of typical NECs markers, CHGA, ASCL1 and CGRP, were evaluated on gene and protein level in human samples using real-time quantitative PCR (RT-qPCR), western blot, immunohistochemistry fluorescence staining, RNA scope assay, flow cytometry and single cell RNA-sequencing. Furthermore, the change in peak nasal inspiratory flow after cold dry air provocation and visual analogue scale scores were used to evaluate NHR or disease severity, respectively. Limited gene expression of the NECs markers CHGA and ASCL1 was measured in patients with upper airway diseases and controls. Gene expression of these markers did not correlate with NHR severity nor disease severity. In vitro, CHGA and ASCL1 expression was also evaluated in primary nasal epithelial cell cultures from patients with upper airway disease and controls using RT-qPCR and western blot. Both on gene and protein level only limited CHGA and ASCL1 expression was found. Additionally, NECs were studied in nasal biopsies of patients with upper airway diseases and controls using immunohistochemistry fluorescence staining, RNA scope and flow cytometry. Unlike in ileum samples, CHGA could not be detected in nasal biopsies of patients with upper airway diseases and control subjects. Lastly, single cell RNA-sequencing of upper airway tissue could not identify a NEC cluster. In summary, in contrast to the bronchi and gut, there is only limited evidence for the presence of NECs in the nasal mucosa, and without correlation with NHR, thereby questioning the relevance of NECs in upper airway pathology.
Assuntos
Mucosa Nasal , Pólipos Nasais , Células Neuroendócrinas , Humanos , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Mucosa Nasal/imunologia , Feminino , Adulto , Masculino , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/patologia , Pessoa de Meia-Idade , Pólipos Nasais/imunologia , Pólipos Nasais/patologia , Pólipos Nasais/metabolismo , Sinusite/metabolismo , Sinusite/patologia , Sinusite/imunologia , Rinite Alérgica/metabolismo , Rinite Alérgica/imunologia , Rinite Alérgica/patologia , Biomarcadores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células CultivadasRESUMO
Notch signaling can have either an oncogenic or tumor-suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine (NE) prostate cancer, where it functions as a tumor suppressor. Activation of Notch in NE and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion toward a more indolent, non-NE state with glandular features and expression of luminal lineage markers. This was accompanied by upregulation of MHC and type I IFN and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of NE differentiation in advanced prostate cancer and provide insights into how Notch signaling influences lineage plasticity and the tumor microenvironment (TME).
Assuntos
Diferenciação Celular , Neoplasias da Próstata , Transdução de Sinais , Microambiente Tumoral , Masculino , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Microambiente Tumoral/imunologia , Animais , Humanos , Transdução de Sinais/imunologia , Camundongos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Células Neuroendócrinas/patologia , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/imunologia , Receptores Notch/metabolismo , Receptores Notch/genética , Receptores Notch/imunologia , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Linhagem Celular TumoralRESUMO
Neuroendocrine prostate cancer (PCa) (NEPC), an aggressive subtype that is associated with poor prognosis, may arise after androgen deprivation therapy (ADT). We investigated the molecular mechanisms by which ADT induces neuroendocrine differentiation in advanced PCa. We found that transmembrane protein 1 (MCTP1), which has putative Ca2+ sensing function and multiple Ca2+-binding C2 domains, was abundant in samples from patients with advanced PCa. MCTP1 was associated with the expression of the EMT-associated transcription factors ZBTB46, FOXA2, and HIF1A. The increased abundance of MCTP1 promoted PC3 prostate cancer cell migration and neuroendocrine differentiation and was associated with SNAI1-dependent EMT in C4-2 PCa cells after ADT. ZBTB46 interacted with FOXA2 and HIF1A and increased the abundance of MCTP1 in a hypoxia-dependent manner. MCTP1 stimulated Ca2+ signaling and AKT activation to promote EMT and neuroendocrine differentiation by increasing the SNAI1-dependent expression of EMT and neuroendocrine markers, effects that were blocked by knockdown of MCTP1. These data suggest an oncogenic role for MCTP1 in the maintenance of a rare and aggressive prostate cancer subtype through its response to Ca2+ and suggest its potential as a therapeutic target.
Assuntos
Diferenciação Celular , Transição Epitelial-Mesenquimal , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Androgênios/metabolismo , Androgênios/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Fator 3-beta Nuclear de Hepatócito/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/patologia , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genéticaRESUMO
Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states.
Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Microambiente Tumoral , Humanos , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Células Neuroendócrinas/patologia , Células Neuroendócrinas/metabolismo , Feminino , Masculino , PrognósticoRESUMO
Despite accounting for only â¼0.5% of the lung epithelium, pulmonary neuroendocrine cells (PNECs) appear to play an outsized role in respiratory health and disease. Increased PNEC numbers have been reported in a variety of respiratory diseases, including chronic obstructive pulmonary disease and asthma. Moreover, PNECs are the primary cell of origin for lung neuroendocrine cancers, which account for 25% of aggressive lung cancers. Recent research has highlighted the crucial roles of PNECs in lung physiology, including in chemosensing, regeneration and immune regulation. Yet, little is known about the direct impact of PNECs on respiratory diseases. In this Review, we summarise the current associations of PNECs with lung pathologies, focusing on how new experimental disease models, such as organoids derived from human pluripotent stem cells or tissue stem cells, can help us to better understand the contribution of PNECs to respiratory diseases.
Assuntos
Pulmão , Modelos Biológicos , Células Neuroendócrinas , Humanos , Células Neuroendócrinas/patologia , Células Neuroendócrinas/metabolismo , Pulmão/patologia , Animais , Organoides/patologia , Doenças Respiratórias/patologiaRESUMO
Tumor cell plasticity contributes to intratumoral heterogeneity and therapy resistance. Through cell plasticity, some lung adenocarcinoma (LUAD) cells transform into neuroendocrine (NE) tumor cells. However, the mechanisms of NE cell plasticity remain unclear. CRACD (capping protein inhibiting regulator of actin dynamics), a capping protein inhibitor, is frequently inactivated in cancers. CRACD knockout (KO) is sufficient to de-repress NE-related gene expression in the pulmonary epithelium and LUAD cells. In LUAD mouse models, Cracd KO increases intratumoral heterogeneity with NE gene expression. Single-cell transcriptomic analysis showed that Cracd KO-induced NE cell plasticity is associated with cell de-differentiation and stemness-related pathway activation. The single-cell transcriptomic analysis of LUAD patient tumors recapitulates that the distinct LUAD NE cell cluster expressing NE genes is co-enriched with impaired actin remodeling. This study reveals the crucial role of CRACD in restricting NE cell plasticity that induces cell de-differentiation of LUAD.
Assuntos
Adenocarcinoma de Pulmão , Plasticidade Celular , Neoplasias Pulmonares , Células Neuroendócrinas , Animais , Humanos , Camundongos , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/patologia , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismoRESUMO
Castration-resistant prostate cancer (CRPC) is associated with resistance to androgen deprivation therapy, and an increase in the population of neuroendocrine (NE) differentiated cells. It is hypothesized that NE differentiated cells secrete neuropeptides that support androgen-independent tumor growth and induce aggressiveness of adjacent proliferating tumor cells through a paracrine mechanism. The cytochrome b561 (CYB561) gene, which codes for a secretory vesicle transmembrane protein, is constitutively expressed in NE cells and highly expressed in CRPC. CYB561 is involved in the α-amidation-dependent activation of neuropeptides, and contributes to regulating iron metabolism which is often dysregulated in cancer. These findings led us to hypothesize that CYB561 may be a key player in the NE differentiation process that drives the progression and maintenance of the highly aggressive NE phenotype in CRPC. In our study, we found that CYB561 expression is upregulated in metastatic and NE prostate cancer (NEPC) tumors and cell lines compared to normal prostate epithelia, and that its expression is independent of androgen regulation. Knockdown of CYB561 in androgen-deprived LNCaP cells dampened NE differentiation potential and transdifferentiation-induced increase in iron levels. In NEPC PC-3 cells, depletion of CYB561 reduced the secretion of growth-promoting factors, lowered intracellular ferrous iron concentration, and mitigated the highly aggressive nature of these cells in complementary assays for cancer hallmarks. These findings demonstrate the role of CYB561 in facilitating transdifferentiation and maintenance of NE phenotype in CRPC through its involvement in neuropeptide biosynthesis and iron metabolism pathways.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Linhagem Celular Tumoral , Fenótipo , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/patologia , Ferro/metabolismo , Diferenciação Celular , Regulação Neoplásica da Expressão GênicaRESUMO
Airway neuroendocrine (NE) cells have been proposed to serve as specialized sensory epithelial cells that modulate respiratory behavior by communicating with nearby nerve endings. However, their functional properties and physiological roles in the healthy lung, trachea, and larynx remain largely unknown. In this work, we show that murine NE cells in these compartments have distinct biophysical properties but share sensitivity to two commonly aspirated noxious stimuli, water and acid. Moreover, we found that tracheal and laryngeal NE cells protect the airways by releasing adenosine 5'-triphosphate (ATP) to activate purinoreceptive sensory neurons that initiate swallowing and expiratory reflexes. Our work uncovers the broad molecular and biophysical diversity of NE cells across the airways and reveals mechanisms by which these specialized excitable cells serve as sentinels for activating protective responses.
Assuntos
Trifosfato de Adenosina , Laringe , Células Neuroendócrinas , Reflexo , Traqueia , Animais , Camundongos , Trifosfato de Adenosina/metabolismo , Deglutição , Expiração/fisiologia , Laringe/citologia , Laringe/fisiologia , Células Neuroendócrinas/metabolismo , Reflexo/fisiologia , Células Receptoras Sensoriais/fisiologia , Traqueia/citologia , Traqueia/fisiologia , Água/metabolismoRESUMO
Pulmonary neuroendocrine (NE) cells are rare airway epithelial cells. The balance between Achaete-scute complex homolog 1 (ASCL1) and hairy and enhancer of split 1, one of the target molecules of the Notch signaling pathway, is crucial for NE differentiation. Small cell lung cancer (SCLC) is a highly aggressive lung tumor, characterized by rapid cell proliferation, a high metastatic potential, and the acquisition of resistance to treatment. The subtypes of SCLC are defined by the expression status of NE cell-lineage transcription factors, such as ASCL1, which roles are supported by SRY-box 2, insulinoma-associated protein 1, NK2 homeobox 1, and wingless-related integration site signaling. This network reinforces NE differentiation and may induce the characteristic morphology and chemosensitivity of SCLC. Notch signaling mediates cell-fate decisions, resulting in an NE to non-NE fate switch. The suppression of NE differentiation may change the histological type of SCLC to a non-SCLC morphology. In SCLC with NE differentiation, Notch signaling is typically inactive and genetically or epigenetically regulated. However, Notch signaling may be activated after chemotherapy, and, in concert with Yes-associated protein signaling and RE1-silencing transcription factor, suppresses NE differentiation, producing intratumor heterogeneity and chemoresistance. Accumulated information on the molecular mechanisms of SCLC will contribute to further advances in the control of this recalcitrant cancer.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular , Neoplasias Pulmonares , Receptores Notch , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Receptores Notch/metabolismo , Células Neuroendócrinas/patologia , Células Neuroendócrinas/metabolismoRESUMO
Gonadotropin-releasing hormone (GnRH) neurons are key neuroendocrine cells in the brain as they control reproduction by regulating hypothalamic-pituitary-gonadal axis function. In this context, anti-Müllerian hormone (AMH), growth hormone (GH), and insulin-like growth factor 1 (IGF1) were shown to improve GnRH neuron migration and function in vitro. Whether AMH, GH, and IGF1 signaling pathways participate in the development and function of GnRH neurons in vivo is, however, currently still unknown. To assess the role of AMH, GH, and IGF1 systems in the development of GnRH neuron, we evaluated the expression of AMH receptors (AMHR2), GH (GHR), and IGF1 (IGF1R) on sections of ex vivo mice at different development stages. The expression of AMHR2, GHR, and IGF1R was assessed by immunofluorescence using established protocols and commercial antibodies. The head sections of mice were analyzed at E12.5, E14.5, and E18.5. In particular, at E12.5, we focused on the neurogenic epithelium of the vomeronasal organ (VNO), where GnRH neurons, migratory mass cells, and the pioneering vomeronasal axon give rise. At E14.5, we focused on the VNO and nasal forebrain junction (NFJ), the two regions where GnRH neurons originate and migrate to the hypothalamus, respectively. At E18.5, the median eminence, which is the hypothalamic area where GnRH is released, was analyzed. At E12.5, double staining for the neuronal marker ß-tubulin III and AMHR2, GHR, or IGF1R revealed a signal in the neurogenic niches of the olfactory and VNO during early embryo development. Furthermore, IGF1R and GHR were expressed by VNO-emerging GnRH neurons. At E14.5, a similar expression pattern was found for the neuronal marker ß-tubulin III, while the expression of IGF1R and GHR began to decline, as also observed at E18.5. Of note, hypothalamic GnRH neurons labeled for PLXND1 tested positive for AMHR2 expression. Ex vivo experiments on mouse sections revealed differential protein expression patterns for AMHR2, GHR, and IGF1R at any time point in development between neurogenic areas and hypothalamic compartments. These findings suggest a differential functional role of related systems in the development of GnRH neurons.
Assuntos
Células Neuroendócrinas , Hormônios Peptídicos , Animais , Camundongos , Hormônio Antimülleriano , Hormônio Liberador de Gonadotropina , Hormônio do Crescimento , Fator de Crescimento Insulin-Like I , Neurônios , Hormônios Liberadores de Hormônios Hipofisários , Tubulina (Proteína) , Células Neuroendócrinas/metabolismoRESUMO
Pulmonary neuroendocrine (NE) cells represent a small population in the airway epithelium, but despite this, hyperplasia of NE cells is associated with several lung diseases, such as congenital diaphragmatic hernia and bronchopulmonary dysplasia. The molecular mechanisms causing the development of NE cell hyperplasia remains poorly understood. Previously, we showed that the SOX21 modulates the SOX2-initiated differentiation of epithelial cells in the airways. Here, we show that precursor NE cells start to develop in the SOX2 + SOX21 + airway region and that SOX21 suppresses the differentiation of airway progenitors to precursor NE cells. During development, clusters of NE cells start to form and NE cells mature by expressing neuropeptide proteins, such as CGRP. Deficiency in SOX2 resulted in decreased clustering, while deficiency in SOX21 increased both the numbers of NE ASCL1 + precursor cells early in development, and the number of mature cell clusters at E18.5. In addition, at the end of gestation (E18.5), a number of NE cells in Sox2 heterozygous mice, did not yet express CGRP suggesting a delay in maturation. In conclusion, SOX2 and SOX21 function in the initiation, migration and maturation of NE cells.
Assuntos
Células Neuroendócrinas , Fatores de Transcrição SOXB1 , Fatores de Transcrição SOXB2 , Animais , Camundongos , Peptídeo Relacionado com Gene de Calcitonina , Diferenciação Celular/genética , Epitélio , Hiperplasia , Células Neuroendócrinas/citologia , Células Neuroendócrinas/metabolismoRESUMO
The fusion of the secretory vesicle with the plasma membrane requires the assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein complexes formed by synaptobrevin, syntaxin-1, and SNAP-25. Within the pathway leading to exocytosis, the transitions between the "open" and "closed" conformations of syntaxin-1 function as a switch for the fusion of vesicles with the plasma membranes; rapid assembly and disassembly of syntaxin-1 clusters on the plasma membrane provide docking and fusion sites for secretory vesicles in neuroendocrine cells; and the fully zippered trans-SNARE complex, which requires the orderly, rapid and accurate binding of syntaxin-1 to other SNARE proteins, play key roles in triggering fusion. All of these reactions that affect exocytosis under physiological conditions are tightly regulated by multiple factors. Here, we review the current evidence for the involvement of syntaxin-1 in the mechanism of neuroendocrine cell exocytosis, discuss the roles of multiple factors such as proteins, lipids, protein kinases, drugs, and toxins in SNARE complex-mediated membrane fusion, and present an overview of syntaxin-1 mutation-associated diseases with a view to developing novel mechanistic therapeutic targets for the treatment of neuroendocrine disorders.
Assuntos
Células Neuroendócrinas , Sintaxina 1/genética , Proteínas Qa-SNARE/metabolismo , Células Neuroendócrinas/metabolismo , Proteínas R-SNARE , Exocitose/fisiologiaRESUMO
Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally treated and castration-resistant PCa (CRPC). In addition, close to 20% of hormonally treated tumors recur as small cell NE carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptors (ARs), they are resistant to hormonal therapy and contribute to therapy failure. Here, we describe the identification of glypican-3 (GPC3) as an oncofetal cell surface protein specific to NE cells in prostate cancer. Functional studies revealed that GPC3 is critical to the viability of NE tumor cells and tumors displaying NE differentiation and that it regulates calcium homeostasis and signaling. Since our results demonstrate that GPC3 is specifically expressed by NE cells, patients with confirmed SCNC may qualify for GPC3-targeted therapy which has been developed in the context of liver cancer and displays minimal toxicity due to its tumor-specific expression. © 2023 The Pathological Society of Great Britain and Ireland.
Assuntos
Adenocarcinoma , Células Neuroendócrinas , Neoplasias da Próstata , Masculino , Humanos , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/patologia , Glipicanas/metabolismo , Adenocarcinoma/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/patologia , Biomarcadores/metabolismoRESUMO
In Atlantic salmon (Salmo salar), seasonal photoperiod is shown to regulate the onset of sexual maturation, yet which brain region(s) is involved, and how light information impacts the neuroendocrine system are still not fully understood in teleosts. Detailed knowledge about the photoperiodic regulation of maturation in fish is still missing. In birds, it is shown that gonadotropin-releasing hormone (Gnrh) is located in the same neurons as vertebrate ancient (VA) opsin, suggesting a direct photoreceptive regulation for the onset of sexual maturity. This study presents a comprehensive topographic mapping of gnrh2, gnrh3, kisspeptin 2 (kiss2), gonadotropin-inhibiting hormone (gnih), and VA opsin using in situ hybridization on mature Atlantic salmon brains. Neurons positive for gnrh3 are expressed in the olfactory bulb and ventral telencephalon, while gnrh2-positive neurons are located dorsally in the midbrain tegmentum. Gonadotropin-inhibiting hormone (Gnih)-expressing cell bodies are present in the ventral thalamus and extend caudally to the hypothalamus with kiss2-expressing cells appearing in a lateral position. VA opsin-positive cells are present in the telencephalon, the rostro-dorsal ring of the left habenula, the ventral thalamus, and the midbrain tegmentum. The results show no similar co-location as found in birds, hypothesizing that the photoreceptive modulation of Gnrh in salmon may interact through neuronal networks. The topography analyses of the essential neuroendocrine cells related to sexual maturation in the Atlantic salmon brain show that diencephalic (thalamus, hypothalamus) and midbrain (tegmentum) regions seem central for controlling sexual maturation.
Assuntos
Células Neuroendócrinas , Salmo salar , Animais , Opsinas/metabolismo , Salmo salar/metabolismo , Células Neuroendócrinas/metabolismo , Maturidade Sexual , Hormônio Liberador de Gonadotropina/metabolismo , Encéfalo/metabolismo , Gonadotropinas/metabolismoRESUMO
Pulmonary neuroendocrine cells (PNECs) are sensory epithelial cells that transmit airway status to the brain via sensory neurons and locally via calcitonin gene-related peptide (CGRP) and γ- aminobutyric acid (GABA). Several other neuropeptides and neurotransmitters have been detected in various species, but the number, targets, functions, and conservation of PNEC signals are largely unknown. We used scRNAseq to profile hundreds of the rare mouse and human PNECs. This revealed over 40 PNEC neuropeptide and peptide hormone genes, most cells expressing unique combinations of 5-18 genes. Peptides are packaged in separate vesicles, their release presumably regulated by the distinct, multimodal combinations of sensors we show are expressed by each PNEC. Expression of the peptide receptors predicts an array of local cell targets, and we show the new PNEC signal angiotensin directly activates one subtype of innervating sensory neuron. Many signals lack lung targets so may have endocrine activity like those of PNEC-derived carcinoid tumors. PNECs are an extraordinarily rich and diverse signaling hub rivaling the enteroendocrine system.
Assuntos
Pulmão , Células Neuroendócrinas , Neuropeptídeos , Animais , Humanos , Camundongos , Células Epiteliais/metabolismo , Pulmão/patologia , Células Neuroendócrinas/metabolismo , Neuropeptídeos/metabolismo , Análise de Sequência de RNARESUMO
Little is known about the adaptor protein FAM159B. Recently, FAM159B was shown to be particularly expressed in neuroendocrine cells and tissues, such as pancreatic islets and neuroendocrine cells of the bronchopulmonary and gastrointestinal tracts, as well as in different types of neuroendocrine tumours. To gain insights into possible interactions of FAM159B with other proteins and/or receptors, we analysed the co-expression of FAM159B and various neuroendocrine-specific markers in the cancer cell lines BON-1, PC-3, NCI-h82, OH-1, and A431 and also in human pancreatic tissues and pancreatic neuroendocrine tumours. The markers included prominent markers of neuroendocrine differentiation, such as chromogranin A (CgA), neuron-specific enolase (NSE), synaptophysin (SYP), insulinoma-associated protein 1 (INSM1), neural cell adhesion molecule 1 (NCAM1), serotonin (5-HT), somatostatin-14/28 (SST), and several receptors that are typically expressed by neuroendocrine cells, such as dopamine receptor 2 (D2R), somatostatin receptor (SSTR) 1, 2, 3, 4 and 5, and regulator of G-protein signalling 9 (RGS9). FAM159B was expressed evenly throughout the cytosol in all five cancer cell lines. Immunocytochemical and immunohistochemical analyses revealed co-expression of FAM159B with SYP, INSM1, RGS9, D2R, SSTR2, SSTR3, SSTR4, and SSTR5 and strong overlapping co-localisation with NSE. Double-labelling and co-immunoprecipitation Western blot analyses confirmed a direct association between FAM159B and NSE. These results suggest the involvement of FAM159B in several intracellular signalling pathways and a direct or indirect influence on diverse membrane proteins and receptors.
Assuntos
Células Neuroendócrinas , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Células Neuroendócrinas/metabolismo , Biomarcadores Tumorais/metabolismo , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Cromogranina A/genética , Cromogranina A/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Repressoras/metabolismoRESUMO
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), a rare condition, is characterized by pathological proliferation of neuroendocrine cells. Some of them are localized to the airway mucosa, and others locally infiltrate to form tumorlets and nodules. Here, we present a patient with lung adenocarcinoma accompanied by DIPNECH, making the latter difficult to distinguish from multiple pulmonary metastases. The patient, a 72-year-old Japanese woman, was diagnosed as having stage IVA lung adenocarcinoma because she had multiple nodules in both lungs. Mutation of epidermal growth factor receptor gene having been found in the primary tumor, treatment with osimertinib was started. This resulted in shrinkage of the primary tumor, but not the multiple pulmonary nodules. To determine whether these lung nodules were indeed lung metastases, we performed right upper lobectomy with lymphadenectomy and wedge resection of the right lower lobe. On pathological examination, the primary tumor was diagnosed as invasive adenocarcinoma, whereas the multiple pulmonary nodules were diagnosed as DIPNECH manifesting as tumorlets. Therefore, the final diagnosis was stage IA1 lung adenocarcinoma accompanied by DINPECH. The patient had no recurrences 1 year after the operation without any additional treatment. This is a rare case of lung adenocarcinoma accompanied by DIPNECH presenting as multiple pulmonary nodules. DIPNECH should be included in the differential diagnosis of multiple pulmonary nodules.