Small Cell Neuroendocrine Carcinoma Of Prostate Research Articles

Discovery of a novel natural compound, vitekwangin B, with ANO1 protein reduction properties and anticancer potential.

Background: Prostate cancer and non-small cell lung cancer (NSCLC) present significant challenges in the development of effective therapeutic strategies. Hormone therapies for prostate cancer target androgen receptors and prostate-specific antigen markers. However, treatment options for prostatic small-cell neuroendocrine carcinoma are limited. NSCLC, on the other hand, is primarily treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors but exhibits resistance. This study explored a novel therapeutic approach by investigating the potential anticancer properties of vitekwangin B, a natural compound derived from Vitex trifolia. Methods: Vitekwangin B was chromatographically isolated from the fruits of V. trifolia. ANO1 protein levels in prostate cancer and NSCLC cells were verified and evaluated again after vitekwangin B treatment. Results: Vitekwangin B did not inhibit anoctamin1 (ANO1) channel function but significantly reduced ANO1 protein levels. These results demonstrate that vitekwangin B effectively inhibited cancer cell viability and induced apoptosis in prostate cancer and NSCLC cells. Moreover, it exhibited minimal toxicity to liver cells and did not affect hERG channel activity, making it a promising candidate for further development as an anticancer drug. Conclusion: Vitekwangin B may offer a new direction for cancer therapy by targeting ANO1 protein, potentially improving treatment outcomes in patients with prostate cancer and NSCLC. Further research is needed to explore its full potential and overcome existing drug resistance challenges.

Characterization of transcriptomic signature of primary prostate cancer analogous to prostatic small cell neuroendocrine carcinoma.

Prostatic small cell neuroendocrine carcinoma (SC/NE) is well studied in metastatic castration‐resistant prostate cancer; however, it is not well characterized in the primary setting. Herein, we used gene expression profiling of SC/NE prostate cancer (PCa) to develop a 212 gene signature to identify treatment‐naïve primary prostatic tumors that are molecularly analogous to SC/NE (SC/NE‐like PCa). The 212 gene signature was tested in several cohorts confirming similar molecular profile between prostatic SC/NE and small cell lung carcinoma. The signature was then translated into a genomic score (SCGScore) using modularized logistic regression modeling and validated in four independent cohorts achieving an average AUC >0.95. The signature was evaluated in more than 25,000 primary adenocarcinomas to characterize the biology, prognosis and potential therapeutic response of predicted SC/NE‐like tumors. Assessing SCGScore in a prospective cohort of 17,967 RP and 6,697 biopsy treatment‐naïve primary tumors from the Decipher Genomic Resource Information Database registry, approximately 1% of the patients were found to have a SC/NE‐like transcriptional profile, whereas 0.5 and 3% of GG1 and GG5 patients respectively showed to be SC/NE‐like. More than 80% of these patients are genomically high‐risk based on Decipher score. Interrogating in vitro drug sensitivity analyses, SC/NE‐like prostatic tumors showed higher response to PARP and HDAC inhibitors.

Multi-Omics Analyses Detail Metabolic Reprogramming in Lipids, Carnitines, and Use of Glycolytic Intermediates between Prostate Small Cell Neuroendocrine Carcinoma and Prostate Adenocarcinoma.

As the most common cancer in men, prostate cancer is molecularly heterogeneous. Contributing to this heterogeneity are the poorly understood metabolic adaptations of the two main types of prostate cancer, i.e., adenocarcinoma and small cell neuroendocrine carcinoma (SCNC), the latter being more aggressive and lethal. Using transcriptomics, untargeted metabolomics and lipidomics profiling on LASCPC-01 (prostate SCNC) and LNCAP (prostate adenocarcinoma) cell lines, we found significant differences in the cellular phenotypes of the two cell lines. Gene set enrichment analysis on the transcriptomics data showed 62 gene sets were upregulated in LASCPC-01, while 112 gene sets were upregulated in LNCAP. ChemRICH analysis on metabolomics and lipidomics data revealed a total of 25 metabolite clusters were significantly different. LASCPC-01 exhibited a higher glycolytic activity and lower levels of triglycerides, while the LNCAP cell line showed increases in one-carbon metabolism as an exit route of glycolytic intermediates and a decrease in carnitine, a mitochondrial lipid transporter. Our findings pinpoint differences in prostate neuroendocrine carcinoma versus prostate adenocarcinoma that could lead to new therapeutic targets in each type.

Differential Modulation of Transcription Factors and Cytoskeletal Proteins in Prostate Carcinoma Cells by a Bacterial Lactone.

The present study tested the effect of a bacterial lactone N-(3-oxododecanoyl)-homoserine lactone (C12-HSL) on the cytoskeletal and transcriptional genes and proteins in prostate adenocarcinoma (PA) cells (DU145 and LNCaP) and prostate small cell neuroendocrine carcinoma (SCNC) PC3 cells including their cellular viability and apoptosis. Our data indicate that cell migration and colony formation were affected in the presence of C12-HSL. C12-HSL induced apoptosis and altered viability of both PA and SCNC cells in a concentration dependent manner as measured by fluorescence and chemiluminescence assays. Compared to PCa cells, noncancerous prostate epithelial cells (RWPE1) were resistant to modification by C12-HSL. Further, the viability of PC3 cells in 3D matrix was suppressed by C12-HSL treatment as detected using calcein AM fluorescence in situ. C12-HSL treatment induced cytoskeletal associated protein expression of vinculin and RhoC, which may have implications in cancer cell motility, adhesion, and metastasis. IQGAP protein expression was reduced in DU145 and RWPE1 cells in the presence of C12-HSL. C12-HSL decreased STAT3 phosphorylation in DU145 cells but increased STAT1 protein phosphorylation in PC3 and LNCaP cells. Overall, these studies indicate that C12-HSL can trigger changes in transcription factors and cytoskeletal proteins and thereby modulate growth and migration properties of PCa cells.

The Role of CD44 in Glucose Metabolism in Prostatic Small Cell Neuroendocrine Carcinoma.

While prostatic adenocarcinomas are relatively indolent, some patients with advanced adenocarcinomas recur with small cell neuroendocrine carcinoma which is highly aggressive and lethal. Because glycolysis is a feature of malignancy and the degree of glycolysis generally correlates with tumor aggressiveness, we wanted to compare the metabolic differences and the molecular mechanisms involved between the two tumor types. In this study, and based on previous characterization, LNCaP and PC-3 prostate cancer cell lines were selected as models of prostatic adenocarcinoma and small cell neuroendocrine carcinoma, respectively. In addition to measuring glucose consumption, lactate secretion, and reactive oxygen species (ROS) levels, we performed metabolic profiling in these two model systems. The role of CD44 was studied by RNAi and lentivirus-mediated overexpression. Expression of key enzymes in glycolysis was studied using human tissue microarrays containing benign prostate, adenocarcinoma, and small cell neuroendocrine carcinoma. Results showed that glycolytic features of PC-3 cells were higher than that of LNCaP cells. PFKFB4 was overexpressed in human small cell carcinoma tissue versus adenocarcinoma tissue. CD44 regulated glucose metabolism, intracellular ROS, and cell proliferation in PC-3 cells. Inhibition of CD44 also sensitized PC-3 cells to carboplatin. In conclusion, this study suggests different pathways of glucose metabolism contribute to the disparate biologic behaviors of these two tumor types. CD44 is an important regulator of glucose metabolism in small cell neuroendocrine carcinoma and may be an important therapeutic target.

A basal stem cell signature identifies aggressive prostate cancer phenotypes

Evidence from numerous cancers suggests that increased aggressiveness is accompanied by up-regulation of signaling pathways and acquisition of properties common to stem cells. It is unclear if different subtypes of late-stage cancer vary in stemness properties and whether or not these subtypes are transcriptionally similar to normal tissue stem cells. We report a gene signature specific for human prostate basal cells that is differentially enriched in various phenotypes of late-stage metastatic prostate cancer. We FACS-purified and transcriptionally profiled basal and luminal epithelial populations from the benign and cancerous regions of primary human prostates. High-throughput RNA sequencing showed the basal population to be defined by genes associated with stem cell signaling programs and invasiveness. Application of a 91-gene basal signature to gene expression datasets from patients with organ-confined or hormone-refractory metastatic prostate cancer revealed that metastatic small cell neuroendocrine carcinoma was molecularly more stem-like than either metastatic adenocarcinoma or organ-confined adenocarcinoma. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common between prostate small cell neuroendocrine carcinoma and primary prostate basal cells. Taken together, our data suggest that aggressive prostate cancer shares a conserved transcriptional program with normal adult prostate basal stem cells.

P53 Mutation Directs AURKA Overexpression via miR-25 and FBXW7 in Prostatic Small Cell Neuroendocrine Carcinoma.

Prostatic small cell neuroendocrine carcinoma (SCNC) is a rare but aggressive form of prostate cancer that is negative for androgen receptor (AR) and not responsive to hormonal therapy. The molecular etiology of this prostate cancer variant is not well understood; however, mutation of the p53 (TP53) tumor suppressor in prostate neuroendocrine cells inactivates the IL8-CXCR2-p53 pathway that normally inhibits cellular proliferation, leading to the development of SCNC. SCNC also overexpresses Aurora kinase A (AURKA) which is considered to be a viable therapeutic target. Therefore, the relationship of these two molecular events was studied, and we show that p53 mutation leads to increased expression of miR-25 and downregulation of the E3 ubiquitin ligase FBXW7, resulting in elevated levels of Aurora kinase A. This study demonstrates an intracellular pathway by which p53 mutation leads to Aurora kinase A expression, which is critically important for the rapid proliferation and aggressive behavior of prostatic SCNC. The pathogenesis of prostatic SCNC involves a p53 and Aurora Kinase A signaling mechanism, both potentially targetable pathways.

A brief literature review on an unusual prostate cancer - a case presentation

Background Small-cell neuroendocrine (NE) carcinoma accounts for only 1 % of all prostate cancers. However, it represents a distinct clinicopathological category and can pose certain difficulties to reporting pathologists in terms of determining primary or secondary status, and appropriate interpretation of immunohisto-chemical stains particularly in metastatic lesions. Case presentation Morphological and immunohistochemical (synaptophysin and thyroid-transcrition-factor-1 or TTF-1 positive; prostatic specific antigen negative) profiles of a metastatic small-cell NE carcinoma of prostate in a patient previously treated with antiandrogen and radiotherapy are presented. Literature review Immunohistochemical staining for all NE markers may be negative in 10% of cases, making morphological features the main diagnostic criteria. Prostatic-specific markers are negative in the majority of cases, which proves to be a diagnostic challenge. TTF-1 is not useful to exclude secondary disease from lung origin. The fact that many patients have a previous history of a hormonally treated prostatic adenocarcinoma of usual acinar type is important for correct diagnosis. Evidence suggests that NE carcinoma cells ‘transdifferentiate’ from non-NE cancer cells, and that among inducers of the process androgen deprivation is the most significant. Patients frequently present with metastatic disease to bone, liver, lung, and lymph nodes, and generally do not respond to hormonal or radiation therapy.

Neuroendocrine differentiation of prostate cancer

Benign prostate and prostatic adenocarcinoma contain rare quiescent neuroendocrine cells while small cell neuroendocrine carcinoma (SCNC), a variant form of prostate cancer, contains highly proliferative neuroendocrine tumor cells. We provide evidence that IL-8-CXCR2-P53 pathway keeps the NE cells in a quiescent state normally. P53 mutation inactivates this pathway, resulting in hyper-proliferation and aggressive behavior of the NE cells in SCNC. Therefore, we have identified potential cells of origin and a molecular target for prostatic SCNC that are different from those of adenocarcinoma, which explains SCNC′s distinct biology and the clinical observation that it does not respond to hormonal therapy. Prostate cancer is a major health risk for men in Western countries as it is the most common malignancy and the second leading cause of cancer-related deaths. In some countries where prostate cancer is traditionally uncommon such as China, the incidence of prostate cancer has also shown a dramatic increase in recent years. Low grade, organ-confined prostate cancers are curable by surgery or radiation therapy. For patients with recurrent or metastatic prostate cancer, hormonal therapy, by inhibiting androgen production and/or blocking androgen receptor (AR) function, is the treatment of choice. Unfortunately, hormonal therapy is not curative and the cancer nearly always recurs after an initial period of response and inevitably progresses to the castration resistant stage. Newer agents have been developed to inhibit intratumoral androgen production or more effectively block AR function, but resistance occurs quickly. In this article, we will focus our discussion on cellular heterogeneity of human prostate cancer and molecular mechanisms responsible for the development of small cell neuroendocrine carcinoma (SCNC), a lethal form of prostate cancer often seen in patients who have received hormonal therapy.

A useful treatment for patients with advanced mixed-type small cell neuroendocrine carcinoma of the prostate: A case report

Treating extended prostatic small cell neuroendocrine carcinoma (PSCNC) is extremely difficult and no standard treatment has yet been established. We experienced a case of advanced mixed-type PSCNC in which the patient achieved long-term survival and local control following combined therapy. Locally advanced PSCNC causing lower urinary obstruction was detected during androgen-ablation therapy for stage D2 mixed adenocarcinoma PSCNC. The patient was treated with intra-arterial infusion chemotherapy using a reservoir system and external-beam radiotherapy (EBRT) to the whole pelvis and local tumor. After chemoradiotherapy, the patient’s lower urinary obstruction was reduced and did not return during the remaining 40 months of the patient’s life. The patient survived for 70 months following the start of the androgen-ablation therapy. The present study reports a useful treatment for advanced mixed-type PSCNC, androgen-ablation therapy and chemoradiotherapy. The present results also suggest that the prognostic factors for advanced mixed-type PSCNC are the sensitivity of the conventional adenocarcinoma to androgen-ablation therapy, degree of metastasis and extent of the small cell neuroendocrine carcinoma component.

Pathogenesis of prostatic small cell carcinoma involves the inactivation of the P53 pathway

Small cell neuroendocrine carcinoma (SCNC) of the prostate is a variant form of prostate cancer that occurs de novo or as a recurrent tumor in patients who received hormonal therapy for prostatic adenocarcinoma. It is composed of pure neuroendocrine (NE) tumor cells, but unlike the scattered NE cells in benign prostate and adenocarcinoma that are quiescent, the NE cells in SCNC are highly proliferative and aggressive, causing death in months. In this study, we provide evidence that interleukin 8 (IL8)-CXCR2-P53 (TP53) signaling pathway keeps the NE cells of benign prostate and adenocarcinoma in a quiescent state normally. While P53 appears to be wild-type in the NE cells of benign prostate and adenocarcinoma, immunohistochemical studies show that the majority of the NE tumor cells in SCNC are positive for nuclear p53, suggesting that the p53 is mutated. This observation is confirmed by sequencing of genomic DNA showing p53 mutation in five of seven cases of SCNC. Our results support the hypothesis that p53 mutation leads to inactivation of the IL8-CXCR2-p53 signaling pathway, resulting in the loss of an important growth inhibitory mechanism and the hyper-proliferation of NE cells in SCNC. Therefore, we have identified potential cells of origin and a molecular target for prostatic SCNC that are very different from those of conventional adenocarcinoma, which explains SCNC's distinct biology and the clinical observation that it does not respond to hormonal therapy targeting androgen receptor signaling, which produces short-term therapeutic effects in nearly all patients with prostatic adenocarcinoma.

PC3 is a cell line characteristic of prostatic small cell carcinoma

The majority of the prostatic cancers are adenocarcinomas characterized by glandular formation and the expression of luminal differentiation markers androgen receptor (AR) and prostate-specific antigen (PSA). Most adenocarcinomas are indolent and androgen-dependent. Hormonal therapy that inhibits AR signaling produces symptomatic relief in patients with advanced and metastatic adenocarcinomas. Prostatic small cell neuroendocrine carcinoma (SCNC) is a variant form of prostate cancer (PC). In contrast to adenocarcinoma, the tumor cells of SCNC do not form glands and are negative for AR and PSA. SCNC is extremely aggressive and does not respond to hormonal therapy. The purpose of this study was to compare the important and relevant features of two most commonly used PC cell lines, LNCaP and PC3, with prostatic adenocarcinoma and SCNC. Xenograft tumors of LNCaP and PC3 were prepared and compared with human prostatic adenocarcinoma and SCNC for the expression of key signaling molecules by immunohistochemistry and Western blot analysis. LNCaP cells express AR and PSA and their growth is inhibited by androgen withdrawal, similar to human prostatic adenocarcinoma. PC3 cells do not express AR and PSA and their proliferation is independent of androgen, similar to SCNC. Adenocarcinoma cells and LNCaP cells are negative for neuroendocrine markers and stem cell-associated marker CD44 while SCNC and PC3 cells are positive. LNCaP cells have identical cytokeratin profiles to adenocarcinoma while PC3 cells have cytokeratin profiles similar to SCNC. LNCaP cells share common features with adenocarcinoma while PC3 cells are characteristic of SCNC.

CD44 expression is a feature of prostatic small cell Carcinoma and Distinguishes it from its Mimickers

Small cell neuroendocrine carcinoma of the prostate is a rare variant of prostatic cancer that shares morphologic similarity with prostatic adenocarcinoma of Gleason 5 pattern. It has also been considered morphologically and immunohistochemically indistinguishable from small cell neuroendocrine carcinomas of other origins. CD44 is a cell-surface molecule proposed to identify cancer stem/progenitor cells in prostate cancer. We performed immunohistochemical study for CD44 expression in 11 cases of prostatic small cell neuroendocrine carcinoma and compared its patterns of expression with 73 cases of prostatic adenocarcinoma and 47 cases of small cell neuroendocrine carcinomas of other organs. Strong and diffuse membrane staining for CD44 was observed in 100% of the prostatic small cell neuroendocrine carcinomas. In conventional adenocarcinomas of the prostate, positive staining was only seen in rare, scattered tumor cells; and CD44 staining was negative in most of the small cell neuroendocrine carcinomas of nonprostate origin. The difference in CD44 expression between small cell neuroendocrine carcinomas of the prostate and those of other organs are statistically significant (P < .001). Our study demonstrates the utility of immunohistochemical staining for CD44 in distinguishing prostatic small cell neuroendocrine carcinoma from its mimickers including prostatic adenocarcinoma of Gleason 5 pattern and small cell neuroendocrine carcinomas of other organs. CD44 is the first marker that shows a high degree of tissue/organ specificity for small cell neuroendocrine carcinomas. Because CD44 is a putative marker of prostate cancer stem cells, the strong and diffuse expression of CD44 and the lack of expression of prostate luminal differentiation markers androgen receptor and prostatic specific antigen in prostatic small cell neuroendocrine carcinomas suggest that the tumor cells may retain cancer stem cell features.

Molecular characterization of prostatic small-cell neuroendocrine carcinoma.

A subset of prostate carcinomas is composed predominantly, even exclusively, of neuroendocrine (NE) cells. In this report, we sought to characterize the gene expression profile of a prostate small cell NE carcinoma by assessing the diversity and abundance of transcripts in the LuCaP 49 prostate small cell carcinoma xenograft. We constructed a cDNA library (PRCA3) from the LuCap 49 prostate small cell xenograft. Single pass DNA sequencing of randomly selected cDNA clones followed by sequence assembly and annotation produced a library of Expressed Sequence Tags (ESTs) representing the LuCaP 49 transcriptome. Comparative sequence analysis with ESTs derived from prostate adenocarcinoma libraries was performed using statistical algorithms designed to identify differentially expressed sequences. Putative NE cell-specific genes were further examined by Northern analysis. Sequence assembly and analysis identified 1,447 distinct genes expressed in the LuCaP 49 cDNA library. These include cDNAs encoding the NE markers secretogranin (SCG2), CD24, and ENO2. Northern analysis revealed that three additional genes, ASCL1, INA, and SV2B are expressed in LuCaP 49 but not in various prostate cancer cell lines or xenografts. Fifteen genes were identified with a statistical probability (P > 0.9) of being up-regulated in LuCaP 49 small cell carcinoma relative to prostate adenocarcinoma (two primary prostate adenocarcinomas and the LNCaP prostate adenocarcinoma cell line). Prostate small cell carcinoma expresses a diverse repertoire of genes that reflect characteristics of their NE cell of origin. ASCL1, INA, and SV2B are potential molecular markers for small cell NE tumors and NE cells of the prostate. This small cell NE carcinoma gene expression profile may yield insights into the development, progression, and treatment of subtypes of prostate cancer.