Investigating pulmonary neuroendocrine cells in human respiratory diseases with airway models.

Despite accounting for only ∼0.5% 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.

CYB561 supports the neuroendocrine phenotype in castration-resistant prostate cancer.

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.

Molecular pathology of small cell lung cancer: Overview from studies on neuroendocrine differentiation regulated by ASCL1 and Notch signaling.

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.

Three-dimensional ultrastructural and anatomical analysis of prostatic neuroendocrine cells in mice.

BACKGROUND: A few studies have examined the ultrastructure of prostatic neuroendocrine cells (NECs), and no study has focused on their ultrastructure in three dimensions. In this study, three-dimensional ultrastructural analysis of mouse prostatic NECs was performed to clarify their anatomical characteristics. METHODS: Three 13-week-old male C57BL/6 mice were deeply anesthetized, perfused with physiological saline and 2% paraformaldehyde, and then placed in 2.5% glutaraldehyde in 0.1 M cacodylate (pH 7.3) buffer for electron microscopy. After perfusion, the lower urinary tract, which included the bladder, prostate, coagulation gland, seminal vesicle, upper vas deferens, and urethra, was removed, and the specimen was cut into small cubes and subjected to postfixation and en bloc staining. Three-dimensional ultrastructural analysis was performed on NECs, the surrounding cells, tissues, and nerves using focused ion beam/scanning electron microscope tomography. RESULTS: Twenty-seven serial sections were used in the present study, and 32 mouse prostatic NECs were analyzed. Morphologically, the NECs could be classified into three types: flask, flat, and closed. Closed-shaped NECs were always adjacent to flask-shaped cells. The flask-shaped and flat NECs were in direct contact with the ductal lumen and always had microvilli at their contact points. Many of the NECs had accompanying nerves, some of which terminated on the surface in contact with the NEC. CONCLUSIONS: Three-dimensional ultrastructural analysis of mouse prostatic NECs was performed. These cells can be classified into three types based on shape. Novel findings include the presence of microvilli at their points of contact with the ductal lumen and the presence of accompanying nerves.

Neuroendocrine cells initiate protective upper airway reflexes.

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.

Investigation of Clinical, Laboratory, Imaging Findings and Histopathological Features of Patients with Gastric Neuroendocrine Cell Hyperplasia.

BACKGROUND/AIMS: Neuroendocrine cell hyperplasia is a non-neoplastic proliferation of enterochromaffin-like cells and is considered a premalignant lesion because of their potential to progress to neuroendocrine tumor. In this study, we aimed to evaluate the demographic and clinical features, laboratory, radiological and endoscopic findings, gastric biopsy histopathological features, follow-up frequency, and histopathological findings of patients diagnosed with gastric neuroendocrine cell hyperplasia as well as to investigate the factors that play a role in the development of neuroendocrine tumors on the basis of neuroendocrine cell hyperplasia. MATERIALS AND METHODS: The study has been conducted in 2 centers with 282 patients that were grouped as those with and without neuroendocrine tumor. Individuals with control endoscopy were separated as those with regression of neuroendocrine cell hyperplasia and those without regression, and the determined parameters were evaluated between the groups. RESULTS: The most common histological subtype of neuroendocrine cell hyperplasia was linear+micronodular (50.4%). Neuroendocrine tumor developed in 4.3% (12/282) of the patients with neuroendocrine cell hyperplasia after a mean of 36 months. The presence of polyps as confirmed via endoscopy and dysplasia as confirmed via histopathological examination was significantly higher in favor of the group with neuroendocrine tumor (P = .01). In patients with neuroendocrine cell hyperplasia regressed and patients in whom it did not regress were examined, the rate of asymptomatic patients and increased sedimentation rate were found in favor of the group that did not regress (P = .02 and P = .02), but no difference was found in other parameters. CONCLUSION: Neuroendocrine tumor development rate was found to be 4.3% in the background of neuroendocrine cell hyperplasia. Two factors predicting progression from neuroendocrine cell hyperplasia to neuroendocrine tumor can be elaborated as the presence of polypoid appearance due to neuroendocrine cell hyperplasia as confirmed via endoscopy and dysplasia as confirmed via histopathological examination.

A multi-lesional analysis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a single-centre analysis.

AIM: To conduct a multi-lesional computed tomography (CT) analysis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) patients to determine volumetric changes in lesions over 5 years. MATERIALS AND METHODS: A retrospective case-note review was undertaken to identify 16 patients with histological and radiological features of DIPNECH between 2012-2021. Area and volume were calculated for 17 sets of lesions identified on high-resolution CT. Clinical data were extracted from electronic patient records, which included demographic data, outpatient clinic letters, histology reports, and imaging reports. RESULTS: One hundred and twenty-eight lesions were identified in 16 patients (one male, 15 female) and followed-up annually over a median 1,985 days (range 1,450-2,290). At year 1 follow-up, lesion area ranged from 1-48 mm2, and lesion volume ranged from 8-18,380 mm3; lesion area ranged from 1-45mm2 and lesion volume ranged from 11-17,800 mm3 and year 5. Half (8/16) of the patients had concomitant typical carcinoid tumours and one patient had an atypical carcinoid tumour. No statistically significant correlation (p<0.05) was found between lesion cross-sectional area or volume and duration of follow-up (years and days). No metastatic spread was observed at the time of analysis. CONCLUSIONS: No significant increase was observed in the size of over 100 lesions in patients with DIPNECH over a 5-year period and no metastasis occurred during the study period affirming the relatively indolent course of the disease.

Integrated analysis of single-cell and bulk transcriptomics develops a robust neuroendocrine cell-intrinsic signature to predict prostate cancer progression.

Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options. The precise identification of NEPC cells holds paramount significance for both research and clinical applications, yet valid NEPC biomarker remains to be defined. Methods: Leveraging 11 published NE-related gene sets, 11 single-cell RNA-sequencing (scRNA-seq) cohorts, 15 bulk transcriptomic cohorts, and 13 experimental models of prostate cancer (PCa), we employed multiple advanced algorithms to construct and validate a robust NEPC risk prediction model. Results: Through the compilation of a comprehensive scRNA-seq reference atlas (comprising a total of 210,879 single cells, including 66 tumor samples) from 9 multicenter datasets of PCa, we observed inconsistent and inefficient performance among the 11 published NE gene sets. Therefore, we developed an integrative analysis pipeline, identifying 762 high-quality NE markers. Subsequently, we derived the NE cell-intrinsic gene signature, and developed an R package named NEPAL, to predict NEPC risk scores. By applying to multiple independent validation datasets, NEPAL consistently and accurately assigned NE feature and delineated PCa progression. Intriguingly, NEPAL demonstrated predictive capabilities for prognosis and therapy responsiveness, as well as the identification of potential epigenetic drivers of NEPC. Conclusion: The present study furnishes a valuable tool for the identification of NEPC and the monitoring of PCa progression through transcriptomic profiles obtained from both bulk and single-cell sources.

Radiological-pathological correlation in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): imaging and histopathology.

AIM: To review histologically confirmed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) cases and carry out a detailed pathological-radiological correlation to see if computed tomography (CT) can be used to confidently identify DIPNECH. MATERIALS AND METHODS: Twenty-three histologically confirmed DIPNECH patients in the shared database of two NHS Trusts were reviewed. CT images were reviewed by two independent radiologists, each of them with >10 years of experience in thoracic imaging. All histological specimens were reviewed by a single pathologist with >25 years of experience. The diagnosis of DIPNECH was made according to the current World Health Organization (WHO) definition included in the WHO 2015 classification of pulmonary tumours. The results on histology were compared to the presence of nodules and air trapping on CT. Demographic information and, when available, molecular imaging studies and pulmonary function tests were also considered. RESULTS: There are prototypal clinical and radiological findings reflecting the presence of underlying histological DIPNECH: middle-aged women with multiple small and scattered nodules due to the clustering and proliferation of neuroendocrine cells. At least one larger, dominant, lung nodule reflecting a carcinoid tumour is very common and mosaic attenuation/air trapping is seen approximately in 50% of cases in inspiratory scans. Airflow obstruction is rarely associated with histological bronchial or peribronchial fibrosis, which suggests other mechanisms must be involved in its development. CONCLUSION: CT can be used to predict pathological DIPNECH in the appropriate clinical setting. It is important to consider DIPNECH to avoid overdiagnosis of more sinister conditions such as lung cancer or metastases.

Insulin-like Growth Factor 1, Growth Hormone, and Anti-Müllerian Hormone Receptors Are Differentially Expressed during GnRH Neuron Development.

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.

DIPNECH: pragmatic approach, uncertainties, notable associations, and a proposal for an improved definition.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, but increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and is considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mechanistic target of rapamycin inhibitors are the most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms 'diffuse' and 'idiopathic.' We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.

Revealing Low Amplitude Signals of Neuroendocrine Cells through Disordered Silicon Nanowires-Based Microelectrode Array.

Today, the key methodology to study in vitro or in vivo electrical activity in a population of electrogenic cells, under physiological or pathological conditions, is by using microelectrode array (MEA). While significant efforts have been devoted to develop nanostructured MEAs for improving the electrophysiological investigation in neurons and cardiomyocytes, data on the recording of the electrical activity from neuroendocrine cells with MEA technology are scarce owing to their weaker electrical signals. Disordered silicon nanowires (SiNWs) for developing a MEA that, combined with a customized acquisition board, successfully capture the electrical signals generated by the corticotrope AtT-20 cells as a function of the extracellular calcium (Ca2+ ) concentration are reported. The recorded signals show a shape that clearly resembles the action potential waveform by suggesting a natural membrane penetration of the SiNWs. Additionally, the generation of synchronous signals observed under high Ca2+ content indicates the occurrence of a collective behavior in the AtT-20 cell population. This study extends the usefulness of MEA technology to the investigation of the electrical communication in cells of the pituitary gland, crucial in controlling several essential human functions, and provides new perspectives in recording with MEA the electrical activity of excitable cells.

Neuroendocrine hyperplasia of infancy; a rare form of childhood interstitial lung disease: a case report.

Interstitial lung disease in infancy is rare. In this case report, we discuss the case of a six-week-old male infant who presented with persistent tachypnoea, retraction and mild hypoxaemia corrected by low-dose supplemental oxygen since the age of 2 weeks. Birth history was unremarkable. Routine workup was done which turned out to be non-contributory. The child received multiple rounds of antibiotics along with bronchodilators and corticosteroids. There was no evidence of severe gastroesophageal reflux. Computed tomography of chest showed ground glass appearance, which was especially prominent in the right middle lobe and lingula ,and accompanied with air trapping. He was managed with mild respiratory supportive care, without positive pressure ventilation and nutritional management. He was discharged home, with instructions for in clinic follow up. A distinctive topographical picture and typical clinical symptoms were consistent with neuroendocrine hyperplasia of infancy (NEHI), which has a favourable prognosis. A high index of suspicion may enable a timely diagnosis. Adequate long-term respiratory and nutritional management without lung biopsy improves the outcome.

Distinct roles for SOX2 and SOX21 in differentiation, distribution and maturation of pulmonary neuroendocrine cells.

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.

Somatostatin receptor 2 in 10 different types of human non-neoplastic gastrointestinal neuroendocrine cells.

Somatostatin is known to inhibit the secretion of various hormones by acting on endocrine cells through the somatostatin receptor 2 (SSTR2). Immunohistochemical evaluation of SSTR2 has become increasingly important in clinical practice to determine treatment strategies for patients with a neuroendocrine tumor (NET). Gastrointestinal (GI) tracts contain various neuroendocrine cells that constitute a diffuse endocrine system and some NETs are derived from those cells. In addition, NETs have been well known to express a variable spectrum of proteins shared by their normal cell counterparts of the specific anatomical sites. Thus, we may derive the kinetics of SSTR2 expression of NETs, including de novo expression, from the SSTR2 expression of the corresponding normal neuroendocrine cells. Therefore, a detailed study on the distribution of SSTR2 in normal human neuroendocrine cells may contribute to understanding the expression of SSTR2 in GI-NETs. However, the detailed cellular localization of SSTR2 in non-neoplastic neuroendocrine cells remains unknown. Therefore, we immunolocalized SSTR2 in neuroendocrine cells of normal human GI tracts, including the stomach, duodenum, ileum, and rectum, obtained from 41 surgically resected tissue specimens. Double immunohistochemistry of SSTR2 and hormones or hormone-associated proteins was performed. In all GI neuroendocrine cells, cell types other than D- and EC-cells demonstrated a high percentage of SSTR2-positive cases or a high double-positive ratio. In particular, EC-cells showed lower SSTR2-positive ratios in all sites. Midgut NETs, which often produce serotonin, are excellent targets for somatostatin analogs and are positive for SSTR2. Thus, we speculated that EC-cell NETs might lead to the de novo expression of SSTR2. In addition, a previous report showed high SSTR2 expression in ECL-cell NETs and gastrinomas, which could be because they are derived from neuroendocrine cells with high SSTR2 expression. This study may contribute to understanding the expression of SSTR2 in GI-NETs.

Functional regulation of syntaxin-1: An underlying mechanism mediating exocytosis in neuroendocrine cells.

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.

Different neuroendocrine cell types in the pars intercerebralis of Periplaneta americana produce their own specific IGF-related peptides.

Of the nine genes of the American cockroach, Periplaneta americana, coding for peptides related to insulin and insulin-like growth factor, seven show significant expression in the central nervous system as demonstrated by the polymerase chain reaction on reverse transcribed RNA. In situ hybridisation shows that five of those are expressed by cells in the pars intercerebralis. Antisera raised to the predicted peptides show that these cells are neuroendocrine in nature and project to the corpora cardiaca. Interestingly, there are at least three cell types that each express different genes. This contrasts with Drosophila where a single cell type expresses a number of genes expressing several such peptides. Whereas in Drosophila the neuroendocrine cells producing insulin-like peptides also express sulfakinins, the arthropod orthologs of gastrin and cholecystokinin, in Periplaneta the sulfakinins are produced by different cells. Other neuropeptides known to be produced by the pars intercerebralis in Periplaneta and other insect species, such as the CRF-like diuretic hormone, neuroparsin, leucokinin or myosuppressin, neither colocalize with an insulin-related peptide. The separate cellular localization of these peptides and the existence of multiple insulin receptors in this species implies a more complex regulation by insulin and IGF-related peptides in cockroaches than in the fruit fly.

Oncofetal protein glypican-3 is a biomarker and critical regulator of function for neuroendocrine cells in prostate cancer.

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.

The Complex Histopathological and Immunohistochemical Spectrum of Neuroendocrine Tumors-An Overview of the Latest Classifications.

Neuroendocrine neoplasms (NENs) originate from the neuroendocrine cell system, which may either take the shape of organoid cell aggregations or be composed of dispersed cells across various organs. Therefore, these tumors are heterogenous regarding the site of origin, functional status, degree of aggressiveness, and prognosis. When treating patients with neuroendocrine tumors, one of the most significant challenges for physicians is determining the correct tumor grade and thus classifying patients into risk categories. Over the years, the classification of these tumors has changed significantly, often causing confusion due to clinical, molecular, and immunohistochemical variability. This review aims to outline the latest NENs classifications regardless of their site of origin. Thus, an overview of the key histopathological and immunohistochemical characteristics of NENs could pave the way to validate possible predictive and prognostic markers and also guide the therapeutic conduct.