-
Clinical Cancer Research : An Official... Feb 2021Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously...
PURPOSE
Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a promising NEPC cell surface antigen. Here we investigated the scope of CEACAM5 expression in end-stage prostate cancer, the basis for CEACAM5 enrichment in NEPC, and the therapeutic potential of the CEACAM5 antibody-drug conjugate labetuzumab govitecan in prostate cancer.
EXPERIMENTAL DESIGN
The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal metastatic CRPC (mCRPC) cases. A genetically defined neuroendocrine transdifferentiation assay of prostate cancer was developed to evaluate mechanisms of CEACAM5 regulation in NEPC. The specificity and efficacy of labetuzumab govitecan was determined in CEACAM5 prostate cancer cell lines and patient-derived xenografts models.
RESULTS
CEACAM5 expression was enriched in NEPC compared with other mCRPC subtypes and minimally overlapped with prostate-specific membrane antigen, prostate stem cell antigen, and trophoblast cell surface antigen 2 expression. We focused on a correlation between the expression of the pioneer transcription factor and to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5 prostate cancer cell lines and marked antitumor responses in CEACAM5 CRPC xenograft models including chemotherapy-resistant NEPC.
CONCLUSIONS
Our findings provide insights into the scope and regulation of CEACAM5 expression in prostate cancer and strong support for clinical studies of labetuzumab govitecan for NEPC.
Topics: Animals; Antibodies, Monoclonal, Humanized; Basic Helix-Loop-Helix Transcription Factors; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Cell Line, Tumor; DNA Damage; Drug Resistance, Neoplasm; GPI-Linked Proteins; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Promoter Regions, Genetic; Prostate; Prostatic Neoplasms, Castration-Resistant; RNA-Seq; Xenograft Model Antitumor Assays
PubMed: 33199493
DOI: 10.1158/1078-0432.CCR-20-3396 -
Virchows Archiv : An International... Mar 2023We report on the clinicopathologic features of 27 pleomorphic giant cell carcinoma (PGCC) cases of the prostate identified in 20 patients with an age range of 51 to...
We report on the clinicopathologic features of 27 pleomorphic giant cell carcinoma (PGCC) cases of the prostate identified in 20 patients with an age range of 51 to 84 years (68 ± 9; median 71 years). Charlson comorbidity index ranged from 3 to 12. Serum PSA ranged from 4.30 to 662 ng/mL (median 13 ng/mL). On histologic examination, bizarre giant cells with pleomorphic nuclei characterized pleomorphic giant cell carcinoma of the prostate. PGCC component was present in 5% to 100%, with half of the patients presenting with ≥ 20%. Half of the patients initially presented with T4 and 26% with T3 disease. All patients were considered Gleason scores of 9 to 10 (ISUP grade 5). A combination of hormone therapy with chemotherapy with or without radiation therapy was applied in 68% of patients. On follow-up, 14 patients (52%) were alive with disease (1-69 months) or dead of disease (1-38 months). Patients diagnosed earlier with lower TNM stage had longer survival than those diagnosed at a later T-stage or with metastatic disease (p = 0.02). The percentage of PGCC was not related to survival in the current study. Molecular alterations in 3 samples showed a microsatellite-stable disease with low tumor mutation burden and variable PTEN, PTCH1, KDM6A, ARv7, and PIK3CA loss/alteration, TP53 mutation, TMPRSS2-ERG fusion, and MYC, PIK3CB, RICTOR, or IRS2 amplification. Our findings suggest that PGCC is a rare and aggressive subtype of prostate carcinoma whose recognition may steer clinicians to adopt more aggressive treatments and investigate new therapeutic strategies.
Topics: Male; Humans; Middle Aged; Aged; Aged, 80 and over; Carcinoma, Giant Cell; Prostate; Prostatic Neoplasms; Giant Cells; Transcription Factors; Prostate-Specific Antigen
PubMed: 36600115
DOI: 10.1007/s00428-022-03481-7 -
Science Advances Apr 2023The mechanisms underlying -driven prostate cancer initiation and progression remain poorly understood due to a lack of model systems that recapitulate this phenotype. We...
The mechanisms underlying -driven prostate cancer initiation and progression remain poorly understood due to a lack of model systems that recapitulate this phenotype. We generated a genetically engineered mouse with prostate-specific expression of the factor, ETV4, at lower and higher protein dosage through mutation of its degron. Lower-level expression of ETV4 caused mild luminal cell expansion without histologic abnormalities, and higher-level expression of stabilized ETV4 caused prostatic intraepithelial neoplasia (mPIN) with 100% penetrance within 1 week. Tumor progression was limited by p53-mediated senescence and deletion cooperated with stabilized ETV4. The neoplastic cells expressed differentiation markers such as Nkx3.1 recapitulating luminal gene expression features of untreated human prostate cancer. Single-cell and bulk RNA sequencing showed that stabilized ETV4 induced a previously unidentified luminal-derived expression cluster with signatures of cell cycle, senescence, and epithelial-to-mesenchymal transition. These data suggest that overexpression alone, at sufficient dosage, can initiate prostate neoplasia.
Topics: Male; Mice; Animals; Humans; Prostate; Tumor Suppressor Protein p53; Prostatic Neoplasms; Transcription Factors; Prostatic Intraepithelial Neoplasia; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Proto-Oncogene Proteins c-ets
PubMed: 37018402
DOI: 10.1126/sciadv.adc9446 -
Journal For Immunotherapy of Cancer Sep 2023Enzalutamide, a next-generation antiandrogen agent, is approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). While enzalutamide has been...
BACKGROUND
Enzalutamide, a next-generation antiandrogen agent, is approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). While enzalutamide has been shown to improve time to progression and extend overall survival in men with CRPC, the majority of patients ultimately develop resistance to treatment. Immunotherapy approaches have shown limited clinical benefit in this patient population; understanding resistance mechanisms could help develop novel and more effective treatments for CRPC. One of the mechanisms involved in tumor resistance to various therapeutics is tumor phenotypic plasticity, whereby carcinoma cells acquire mesenchymal features with or without the loss of classical epithelial characteristics. This work investigated a potential link between enzalutamide resistance, tumor phenotypic plasticity, and resistance to immune-mediated lysis in prostate cancer.
METHODS
Models of prostate cancer resistant to enzalutamide were established by long-term exposure of human prostate cancer cell lines to the drug in culture. Tumor cells were evaluated for phenotypic features in vitro and in vivo, as well as for sensitivity to immune effector cell-mediated cytotoxicity.
RESULTS
Resistance to enzalutamide was associated with gain of mesenchymal tumor features, upregulation of estrogen receptor expression, and significantly reduced tumor susceptibility to natural killer (NK)-mediated lysis, an effect that was associated with decreased tumor/NK cell conjugate formation with enzalutamide-resistant cells. Fulvestrant, a selective estrogen receptor degrader, restored the formation of target/NK cell conjugates and increased susceptibility to NK cell lysis in vitro. In vivo, fulvestrant demonstrated antitumor activity against enzalutamide-resistant cells, an effect that was associated with activation of NK cells.
CONCLUSION
NK cells are emerging as a promising therapeutic approach in prostate cancer. Modifying tumor plasticity via blockade of estrogen receptor with fulvestrant may offer an opportunity for immune intervention via NK cell-based approaches in enzalutamide-resistant CRPC.
Topics: Male; Humans; Fulvestrant; Prostatic Neoplasms, Castration-Resistant; Receptors, Estrogen; Prostate
PubMed: 37678915
DOI: 10.1136/jitc-2023-007386 -
Radiographics : a Review Publication of... 2016Multiparametric magnetic resonance (MR) imaging combines anatomic and functional imaging techniques for evaluating the prostate and is increasingly being used in... (Comparative Study)
Comparative Study Review
Multiparametric magnetic resonance (MR) imaging combines anatomic and functional imaging techniques for evaluating the prostate and is increasingly being used in diagnosis and management of prostate cancer. A wide spectrum of anatomic and pathologic processes in the prostate may masquerade as prostate cancer, complicating the imaging interpretation. The histopathologic and imaging findings of these potential mimics are reviewed. These entities include the anterior fibromuscular stroma, surgical capsule, central zone, periprostatic vein, periprostatic lymph nodes, benign prostatic hyperplasia (BPH), atrophy, necrosis, calcification, hemorrhage, and prostatitis. An understanding of the prostate zonal anatomy is helpful in distinguishing the anatomic entities from prostate cancer. The anterior fibromuscular stroma, surgical capsule, and central zone are characteristic anatomic features of the prostate with associated low T2 signal intensity due to dense fibromuscular tissue or complex crowded glandular tissue. BPH, atrophy, necrosis, calcification, and hemorrhage all have characteristic features with one or more individual multiparametric MR imaging modalities. Prostatitis constitutes a heterogeneous group of infective and inflammatory conditions including acute and chronic bacterial prostatitis, infective and noninfective granulomatous prostatitis, and malacoplakia. These entities are associated with variable clinical manifestations and are characterized by the histologic hallmark of marked inflammatory cellular infiltration. In some cases, these entities are indistinguishable from prostate cancer at multiparametric MR imaging and may even exhibit extraprostatic extension and lymphadenopathy, mimicking locally advanced prostate cancer. It is important for the radiologists interpreting prostate MR images to be aware of these pitfalls for accurate interpretation. Online supplemental material is available for this article.
Topics: Atrophy; Calcinosis; Humans; Image Enhancement; Magnetic Resonance Imaging; Male; Pathology; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatitis; Statistics as Topic
PubMed: 26587887
DOI: 10.1148/rg.2016150030 -
Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation.Asian Journal of Andrology 2014Most prostate cancers (PCas) are classified as acinar type (conventional) adenocarcinoma which are composed of tumor cells with luminal differentiation including the... (Review)
Review
Most prostate cancers (PCas) are classified as acinar type (conventional) adenocarcinoma which are composed of tumor cells with luminal differentiation including the expression of androgen receptor (AR) and prostate-specific antigen (PSA). There are also scattered neuroendocrine (NE) cells in every case of adenocarcinoma. The NE cells are quiesecent, do not express AR or PSA, and their function remains unclear. We have demonstrated that IL8-CXCR2-P53 pathway provides a growth-inhibitory signal and keeps the NE cells in benign prostate and adenocarcinoma quiescent. Interestingly, some patients with a history of adenocarcinoma recur with small cell neuroendocrine carcinoma (SCNC) after hormonal therapy, and such tumors are composed of pure NE cells that are highly proliferative and aggressive, due to P53 mutation and inactivation of the IL8-CXCR2-P53 pathway. The incidence of SCNC will likely increase due to the widespread use of novel drugs that further inhibit AR function or intratumoral androgen synthesis. A phase II trial has demonstrated that platinum-based chemotherapy may be useful for such therapy-induced tumors.
Topics: Adenocarcinoma; Androgen Antagonists; Cell Differentiation; Humans; Male; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Prostate; Prostatic Neoplasms
PubMed: 24589459
DOI: 10.4103/1008-682X.123669 -
BMC Cancer Dec 2022Prostate-specific membrane antigen (PSMA) overexpression has been observed in the endothelial neovasculature of several solid malignancies. This study aimed to identify... (Review)
Review
BACKGROUND
Prostate-specific membrane antigen (PSMA) overexpression has been observed in the endothelial neovasculature of several solid malignancies. This study aimed to identify PSMA expression in the primary tumor of classical papillary thyroid carcinoma (PTC) and assess the correlation between the degree of PSMA expression and recurrence.
METHODS
We reviewed the electronic medical records of patients who underwent total thyroidectomy and central neck dissection, with or without lateral neck dissection, for classical PTC between 2009 and 2014 at our institution. Recurrence was defined as a structural disease based on histological confirmation on follow-up. Fifty-one patients with the recurrent structural disease were matched, using a propensity score matching method, to patients with no disease evidence during follow-up. Clinicopathological and follow-up data were collected for 102 patients. The monoclonal mouse anti-human PSMA/FOLH1/NAALADase I antibody was used for staining the primary tumor. The score of PSMA expression was classified as negative (< 5% positivity), weak (5-10 % positivity), moderate (11-49% positivity), and strong (more than 50% positivity). Clinicopathological factors were compared between patients with low and high PSMA expression. Moreover, whether the degree of PSMA expression and clinicopathological factors could predict recurrence was investigated. Cox proportional hazard regression models were used to evaluate the risk of recurrence.
RESULTS
There was no significant difference in clinicopathological factors between low (negative or weak) and high (moderate or strong) PSMA expression. Gross extrathyroidal extension (ETE), absence of chronic lymphocytic thyroiditis, and high PSMA expression were all associated with lower recurrence-free survival (RFS) rate in a univariate analysis. In multivariate analysis, gross ETE (hazard ratio [HR], 2.279; 95% confidence interval [CI], 1.257-4.132; p = 0.007) and high PSMA expression (HR, 1.895; 95% CI, 1.073-3.348; p = 0.028) were associated with poor RFS.
CONCLUSIONS
High PSMA expression in the primary tumor was a significant factor in predicting recurrence in classic PTC. PSMA could be a potential biomarker for personalized management for PTC.
Topics: Male; Animals; Mice; Thyroid Cancer, Papillary; Prostate; Research Design; Thyroid Neoplasms
PubMed: 36476583
DOI: 10.1186/s12885-022-10375-z -
Veterinary and Comparative Oncology Mar 2022A limited number of species, including men and dogs, spontaneously develop prostate cancer (PC). The histological and molecular relevance of canine PC as a model for the...
A limited number of species, including men and dogs, spontaneously develop prostate cancer (PC). The histological and molecular relevance of canine PC as a model for the disease in men remains controversial. To address this challenge, this study aimed to assess the histomorphology and expression of basal cell, urothelial and neuroendocrine markers [p63, high molecular weight cytokeratin (HMWCK), Uroplakin 3 (UPIII), neuron-specific enolase (NSE)] in canine PC (n = 41). Based on histomorphology, 10/41 (24%), 21/41 (51%) and 9/41 (22%) were classified as adenocarcinoma (AC), urothelial carcinoma (UC), and mixed carcinoma, respectively. Tumour inflammation was common, frequently severe [20/41 (49%)], and associated with neutering (p < .02) and urothelial differentiation (p < .02). Most (36/40, 90%) cancers contained only rare cells with basal cell marker expression or were negative. The expression of UPIII was absent or weak in the majority (33/38, 87%) of tumours, with moderate to strong staining in the remaining cases. NSE expression in PC was rare and limited to 2/14 (14%) cases. Tumour extension into benign ducts and glands was a common finding with presence in 17/39 (44%) of carcinomas with and without urothelial differentiation. In conclusion, we confirm that canine PC is characterized by absent or weak expression of basal cell and urothelial markers. Although rare, NSE expression, potentially indicating neuroendocrine differentiation, is reported for the first time in canine PCa. Intraductal carcinoma of the prostate with concurrent invasive PCa (IDCP-inv) is a frequent, not previously described, finding in dogs with PC.
Topics: Animals; Biomarkers, Tumor; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Transitional Cell; Dog Diseases; Dogs; Immunohistochemistry; Male; Prostate; Prostatic Neoplasms; Urinary Bladder Neoplasms
PubMed: 33963663
DOI: 10.1111/vco.12704 -
Modern Pathology : An Official Journal... Jan 2018Many prostate lesions have 'large gland' morphology with gland size similar to or larger than benign glands, complex glandular architecture including papillary,... (Review)
Review
Many prostate lesions have 'large gland' morphology with gland size similar to or larger than benign glands, complex glandular architecture including papillary, cribriform, and solid, and significant cytological atypia in glandular epithelium with nucleomegaly, prominent nucleoli, or anisonucleosis. The most common and clinically important lesions with 'large gland' morphology include high-grade prostatic intraepithelial neoplasia (HGPIN), PIN-like carcinoma, ductal adenocarcinoma, and intraductal carcinoma. These lesions have diverse clinical significance and management implications. HGPIN refers to proliferation of glandular epithelium that displays severe cytological atypia within the confines of prostatic ducts and acini. A HGPIN diagnosis in biopsies connotes ~25% risk of detection of cancer in repeat biopsies. It has been accepted as the main precursor lesion to invasive carcinoma. PIN-like carcinoma is a variant of acinar carcinoma that is morphologically reminiscent of HGPIN and is composed of large cancer glands lined with pseudostratified epithelium. Its clinical outcome is similar to that of usual acinar carcinomas and is graded as Gleason score 3+3=6. Ductal adenocarcinoma comprises large glands lined with tall columnar and pseudostratified epithelium. It is more aggressive than acinar carcinomas and is associated with higher stage disease and greater risk of PSA recurrence and mortality. Intraductal carcinoma is an intraglandular/ductal neoplastic proliferation of glandular epithelial cells that results in marked expansion of glandular architecture and nuclear atypia that often exceeds that in invasive carcinomas. In majority of cases, it is thought to represent retrograde extension of invasive carcinoma into pre-existing ducts and acini. Rarely it may represent a peculiar form of carcinoma with predilection for intraductal location. It is considered an adverse pathological feature and is seen almost always in high-grade and volume carcinoma and harbingers worse clinical outcomes. This article reviews 'new' information on the clinical and pathological features of HGPIN, PIN-like carcinoma, ductal carcinoma, and intraductal carcinoma, and focuses morphological features that aid the differential diagnosis.
Topics: Biopsy, Large-Core Needle; Carcinoma, Acinar Cell; Carcinoma, Ductal; Diagnosis, Differential; Humans; Male; Membrane Proteins; Neoplasm Grading; PTEN Phosphohydrolase; Prostate; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Transcriptional Regulator ERG
PubMed: 29297491
DOI: 10.1038/modpathol.2017.138 -
Cancer Medicine Jan 2024Intraductal carcinoma of the prostate (IDC-P) is an aggressive subtype of prostate cancer characterized by the growth of tumor cells within the prostate ducts. It is... (Review)
Review
Intraductal carcinoma of the prostate (IDC-P) is an aggressive subtype of prostate cancer characterized by the growth of tumor cells within the prostate ducts. It is often found alongside invasive carcinoma and is associated with poor prognosis. Understanding the molecular mechanisms driving IDC-P is crucial for improved diagnosis, prognosis, and treatment strategies. This review summarizes the molecular characteristics of IDC-P and their prognostic indications, comparing them to conventional prostate acinar adenocarcinoma, to gain insights into its unique behavior and identify potential therapeutic targets.
Topics: Male; Humans; Carcinoma, Intraductal, Noninfiltrating; Prostate; Prostatic Neoplasms; Prognosis
PubMed: 38379333
DOI: 10.1002/cam4.6939