Genomic Features and Clinical Implications of Intraductal Carcinoma of the Prostate

Intraductal carcinoma of the prostate (IDC-P) is a rare and unique form of aggressive prostate carcinoma, which is characterized by an expansile proliferation of malignant prostatic epithelial cells within prostatic ducts or acini and the preservation of basal cell layers around the involved glands. The vast majority of IDC-P tumors result from adjacent high-grade invasive cancer via the retrograde spreading of tumor cells into normal prostatic ducts or acini. A subset of IDC-P tumors is rarely derived from the de novo intraductal proliferation of premalignant cells. The presence of IDC-P in biopsy or surgical specimens is significantly associated with aggressive pathologic features, such as high Gleason grade, large tumor volume, and advanced tumor stage, and with poor clinical courses, including earlier biochemical recurrence, distant metastasis, and worse survival outcomes. These architectural and behavioral features of IDC-P may be driven by specific molecular properties. Notably, IDC-P possesses distinct genomic profiles, including higher rates of TMPRSS2–ERG gene fusions and PTEN loss, increased percentage of genomic instability, and higher prevalence of germline BRCA2 mutations. Considering that IDC-P tumors are usually resistant to conventional therapies for prostate cancer, further studies should be performed to develop optimal therapeutic strategies based on distinct genomic features, such as treatment with immune checkpoint blockades or poly (adenosine diphosphate–ribose) polymerase inhibitors for patients harboring increased genomic instability or BRCA2 mutations, as well as genetic counseling with genetic testing. Patient-derived xenografts and tumor organoid models can be the promising in vitro platforms for investigating the molecular features of IDC-P tumor.

TRANSFORMATION OF THE HUMAN PROSTATE GLAND IN INTERMEDIATE AND LATE FETAL PERIODS OF DEVELOPMENT

The purpose of the study was to determinate the morphometric parameters of epithelial cords, prostatic ducts, acini of the human prostate gland and their lining epithelium, the shape of prostate glands, and muscle tissue in fetal periods of development. Material and Method: The study was performed on 19 prostate glands of male sex fetuses of intermediate and late fetal periods. We used the morphometric method of verification of apoptotic cells on stained histoligical preps using the criteria of apoptosis. Morphometric research included measurements of acini and acinar lumen areas, epithelium height, assessment of shape factors. Results: In the late fetal period compared to the intermediate fetal period the acini area was not increased in 1.1 times (p =0,004), the area of acinar lumens increases by 3.8 times (p=0.0005). Changes in the shape of acinar lumens were detected. Conclusion: An insignificant increase of the specific area of the glandular parenchyma in the organ of transformation of the developing glands occurs mainly due to their canalization. The formation of prostatic ducts was not followed by the increase in their total area and was the result of differentiation epithelial cells and apoptosis. Transformation of prostate glands in the prenatal period occurs in a certain sequence: the formation of epithelial buds, their canalization by apoptosis with formation of epithelial ducts and prostatic ducts, and formation of end pieces of prostate glands from these ducts. Apoptotic bodies were removed from the lumen of the prostatic ducts by extrusion. The design and orientation of the smooth muscle bundles around prostatic ducts and acini do not ensure the evacuation of content of the prostate glands in the fetal period.

Urethral luminal epithelia are castration-insensitive progenitors of the proximal prostate

Castration-insensitive epithelial progenitors capable of regenerating the prostate are concentrated in the proximal region close to the urethra, but the identification of these cells has been limited to individual cell surface markers. Here, we use single cell RNA sequencing (scRNA-seq) to obtain a cellular anatomy of the mouse prostate and urethra and create a comparative map with the human. These data reveal that previously identified facultative progenitors marked by TROP2, Sca-1, KRT4, and PSCA are actually luminal epithelia of the urethra that extend into the proximal prostate. These mouse urethral cells are the human equivalent of previously identified club and hillock urethral cells. Castration decreases androgen-dependent prostate luminal epithelia as expected, but TROP2+ urethral luminal epithelia survive and expand into the prostate. Benign prostatic hyperplasia (BPH) has long been considered an ‘embryonic reawakening’, but the cellular origin of peri-urethral growth is unclear. We use scRNA-seq and flow cytometry to demonstrate an increase in urethral luminal epithelia within glandular nodules from patients with BPH, which are further enriched in patients treated with a 5 alpha reductase inhibitor. These data demonstrate that the putative prostate progenitors enriched by castration in the proximal prostate are an expansion of urethral luminal epithelia and that these cells may play an important role in the etiology of human BPH.Significance StatementThe prostate involutes after castration, but regrows to its original size with androgen replenishment. This observation prompted the search for a castration-insensitive prostate progenitor. Here, Joseph et al. produce a comparative cellular atlas of the prostate and urethra in the mouse vs. human, discovering an equivalent urethral luminal epithelial cell type that extends into the proximal prostatic ducts and expresses previously identified markers of facultative prostate progenitors. Urethral luminal epithelia are established before prostate budding in human and mouse development, and expand after castration in the mouse and after 5 alpha reductase inhibitor treatment in human BPH. These data suggest that luminal epithelia of the urethra are castration-insensitive cells of proximal ducts that may act as progenitors in human BPH.

Illuminating Clues of Cancer Buried in Prostate MR Image: Deep Learning and Expert Approaches

Deep learning algorithms have achieved great success in cancer image classification. However, it is imperative to understand the differences between the deep learning and human approaches. Using an explainable model, we aimed to compare the deep learning-focused regions of magnetic resonance (MR) images with cancerous locations identified by radiologists and pathologists. First, 307 prostate MR images were classified using a well-established deep neural network without locational information of cancers. Subsequently, we assessed whether the deep learning-focused regions overlapped the radiologist-identified targets. Furthermore, pathologists provided histopathological diagnoses on 896 pathological images, and we compared the deep learning-focused regions with the genuine cancer locations through 3D reconstruction of pathological images. The area under the curve (AUC) for MR images classification was sufficiently high (AUC = 0.90, 95% confidence interval 0.87–0.94). Deep learning-focused regions overlapped radiologist-identified targets by 70.5% and pathologist-identified cancer locations by 72.1%. Lymphocyte aggregation and dilated prostatic ducts were observed in non-cancerous regions focused by deep learning. Deep learning algorithms can achieve highly accurate image classification without necessarily identifying radiological targets or cancer locations. Deep learning may find clues that can help a clinical diagnosis even if the cancer is not visible.

Nine new species of the "aeruginosus"-group in Amynthas (Clitellata: Megascolecidae) from Nam Et-Phouley National protected Area, Laos

Nine new species of Amynthas (Clitellata: Megascolecidae) from Mt. Phouleoi, Lao PDR: Earthworm specimens were collected on the top of Mt. Phouleoi, Viengthong District, Houaphanh province, Lao PDR. The new species belonged to pheretimoid earthworms. They have spermathecal pores in 7/8 and 8/9, corresponding to the aeruginosus-group as characterized by Sims and Easton (1972). Their names are: Amynthas bouatongi sp. nov., Amynthas hoauykanangensis sp. nov., Amynthas phimpheti sp. nov., Amynthas nametensis sp. nov., Amynthas somechanae sp. nov., Amynthas wiggeri sp. nov., Amynthas fleischmani sp. nov., Amynthas antethecus sp. nov., and Amynthas elenabondae sp. nov. With the exception of A. nametensis sp. nov., all have the first dorsal pore in an unusually anterior location close to 5/6 and very large, often coiled, prostatic ducts. Several species have slight intraparietal invaginations of the primary male pores, but the similarity of other characters leads us to include them in Amynthas rather than in a polyphyletic Metaphire. Amynthas bouatongi sp. nov. has male pores 0.20–0.24 circumference apart on reniform male pads, pair genital papillae medial and lateral to male pores in XVIII. Amynthas hoauykanangensis sp. nov. has openings of copulatory pouches 0.19–0.25 circumference apart, and paired round genital papillae on postsetal XVII and presetal XIX in line with the male pores. Amynthas phimpheti sp. nov. has male pores 0.21–0.24 circumference apart, round thickened genital papillae paired on 17/18 and 18/19 in line with male pores. Amynthas nametensis sp. nov. has male pores superficial on thickened circular pads, 0.24–0.27 circumference apart. Amynthas somechanae sp. nov. has male pores 0.20–0.33 circumference apart, and paired equatorial papillae in XVIII. Amynthas wiggeri sp. nov. has male pores 0.22–0.30 circumference apart, paired genital papillae equatorial on XVIII medial to male pores and paired papillae equatorial in XVII and XIX. Amynthas fleischmani sp. nov. has openings of copulatory pouches 0.24 circumference apart, paired conical genital papillae equatorial on XVII and XIX; paired circular papillae in intersegmental furrows of 17/18 and 18/19. Amynthas antethecus sp. nov. has openings of copulatory pouches 0.31 circumference apart, paired circular papillae in intersegmental furrow of 17/18 and equatorial on XIX, slightly medial to secondary male pores. Amynthas elenabondae sp. nov. has openings of copulatory pouches 0.19 circumference apart, crescent, convex medially; primary male pore on tubercle on lateral wall of shallow parietal invagination.

The role of Cajal cells in chronic prostatitis

Types of prostatitis can be defined as groups of syndromes in adult men associated with infectious and noninfectious causes characterized frequently by lower abdominal and perineal signs and diverse clinical symptoms and complications. Etiopathogenesis of chronic prostatitis is not well defined. Moreover, its treatment outcomes are not satisfactory. Presence of c-kit positive interstitial cells in human prostate is already known. It has been demonstrated that these cells can be pacemaker cells which trigger spontaneous slow-wave electrical activity in the prostate and can be responsible for the transport of glandular secretion from acinar cells into major and minor prostatic ducts and finally into urethra. In the light of all these data, when presence of a possible inflammatory pathology is thought to involve prostate that secretes and has a reservoir which drains its secretion (for prostate, prostatic urethra), two points are worth mentioning. Impairment of secretion mechanism and collection of secretion within the organ with reflux of the microbial material from its reservoir back into prostate gland. Both of these potential conditions can be explained by ductal neuromuscular mechanism, which induces secretion. We think that in this neuromuscular mechanism interstitial Cajal cells have an important role in chronic prostatitis. Our hypothesis is that curability of prostatitis is correlated with the number of Cajal cells not subjected to apoptosis.

Lxrα Regulates the Androgen Response in Prostate Epithelium

Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-α knockout mice (lxrα−/−) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxrα−/− prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxrα−/− mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxrα is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxrα in the homeostasis of the ventral prostate and suggest lxrα−/− mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia.