Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor.

Prostate inflammation has been suggested as an etiology for benign prostatic hyperplasia (BPH). We show that decreased expression of the androgen receptor (AR) in luminal cells of human BPH specimens correlates with a higher degree of regional prostatic inflammation. However, the cause-and-effect relationship between the two events remains unclear. We investigated specifically whether attenuating AR activity in prostate luminal cells induces inflammation. Disrupting luminal cell AR signaling in mouse models promotes cytokine production cell-autonomously, impairs epithelial barrier function, and induces immune cell infiltration, which further augments local production of cytokines and chemokines including Il-1 and Ccl2. This inflammatory microenvironment promotes AR-independent prostatic epithelial proliferation, which can be abolished by ablating IL-1 signaling or depleting its major cellular source, the macrophages. This study demonstrates that disrupting luminal AR signaling promotes prostate inflammation, which may serve as a mechanism for resistance to androgen-targeted therapy for prostate-related diseases.

Near-Quantum-Noise Axion Dark Matter Search at CAPP around 9.5 µeV.

We report the results of an axion dark matter search over an axion mass range of 9.39-9.51 µeV. A flux-driven Josephson parametric amplifier (JPA) was added to the cryogenic receiver chain. A system noise temperature of as low as 200 mK was achieved, which is the lowest recorded noise among published axion cavity experiments with phase-insensitive JPA operation. In addition, we developed a two-stage scanning method which boosted the scan speed by 26%. As a result, a range of two-photon coupling in a plausible model for the QCD axion was excluded with an order of magnitude higher in sensitivity than existing limits.

Axion Dark Matter Search around 4.55 µeV with Dine-Fischler-Srednicki-Zhitnitskii Sensitivity.

We report an axion dark matter search at Dine-Fischler-Srednicki-Zhitnitskii sensitivity with the CAPP-12TB haloscope, assuming axions contribute 100% of the local dark matter density. The search excluded the axion-photon coupling g_{aγγ} down to about 6.2×10^{-16} GeV^{-1} over the axion mass range between 4.51 and 4.59 µeV at a 90% confidence level. The achieved experimental sensitivity can also exclude Kim-Shifman-Vainshtein-Zakharov axion dark matter that makes up just 13% of the local dark matter density. The CAPP-12TB haloscope will continue the search over a wide range of axion masses.

Paracrine Wnt signaling is necessary for prostate epithelial proliferation.

INTRODUCTION: The Wnt proteins play key roles in the development, homeostasis, and disease progression of many organs including the prostate. However, the spatiotemporal expression patterns of Wnt proteins in prostate cell lineages at different developmental stages and in prostate cancer remain inadequately characterized. METHODS: We isolated the epithelial and stromal cells in the developing and mature mouse prostate by flow cytometry and determined the expression levels of Wnt ligands. We used Visium spatial gene expression analysis to determine the spatial distribution of Wnt ligands in the mouse prostatic glands. Using laser-capture microscopy in combination with gene expression analysis, we also determined the expression patterns of Wnt signaling components in stromal and cancer cells in advanced human prostate cancer specimens. To investigate how the stroma-derived Wnt ligands affect prostate development and homeostasis, we used a Col1a2-CreERT2 mouse model to disrupt the Wnt transporter Wntless specifically in prostate stromal cells. RESULTS: We showed that the prostate stromal cells are a major source of several Wnt ligands. Visium spatial gene expression analysis revealed a distinct spatial distribution of Wnt ligands in the prostatic glands. We also showed that Wnt signaling components are highly expressed in the stromal compartment of primary and advanced human prostate cancer. Blocking stromal Wnt secretion attenuated prostate epithelial proliferation and regeneration but did not affect cell survival and lineage maintenance. DISCUSSION: Our study demonstrates a critical role of stroma-derived Wnt ligands in prostate development and homeostasis.

Thyroid Isthmusectomy with Prophylactic Central Compartment Neck Dissection is a Feasible Approach for Papillary Thyroid Cancer on the Isthmus.

BACKGROUND: The treatment for papillary thyroid cancer (PTC) has become more conservative, but still no specific guidelines exist for managing isthmic PTC. This study analyzed the outcomes from isthmusectomy in single isthmic PTC and compared it with those for patients who previously had undergone a total thyroidectomy. METHODS: An isthmusectomy with prophylactic central compartment neck dissection (pCCND) was planned for a single isthmic PTC between 2014 and 2018 (isthmusectomy group). For cases with gross extrathyroidal extension (ETE) or multiple nodal metastasis, the procedure was converted to a total thyroidectomy. The study analyzed the characteristics and outcomes of the isthmusectomy group. Additionally, the results were compared with those of the isthmusectomy-feasible group who met the eligibility criteria for isthmusectomy among total thyroidectomies performed between 2009 and 2013. RESULTS: Of the 90 patients in the isthmusectomy group, 81 received isthmusectomy and 9 had conversion to a total thyroidectomy. Microcarcinoma occurred in 72 cases and gross ETE in 3 cases. One patient showed occult satellite cancer, and seven patients showed more than five metastatic nodes. Transient hypocalcemia developed in five and patients and permanent hypocalcemia in one patient with total thyroidectomy. Of 46 patients who began hormone replacement postoperatively, 13 completely stopped taking medication during the follow-up period. Metachronous PTC was diagnosed for one patient 12 months after isthmusectomy. The isthmusectomy group and the isthmusectomy-feasible group showed similar clinicopathologic properties including multifocality, ETE, and nodal metastasis. However, the isthmusectomy group showed significantly less transient or permanent hypocalcemia and thyroid hormone dependency. CONCLUSIONS: Isthmusectomy with pCCND may be a feasible alternative for properly selected isthmic PTC, resulting in a better quality of life than total thyroidectomy.

The Sca-1+ and Sca-1- mouse prostatic luminal cell lineages are independently sustained.

The phenotypic and functional heterogeneity of the mouse prostate epithelial cell lineages remains incompletely characterized. We show that the Sca-1+ luminal cells at the mouse proximal prostate express Sox2. These cells are replicative quiescent, castration resistant, and do not possess secretory function. We use the Probasin-CreERT2 and Sox2-CreERT2 models in concert with a fluorescent reporter line to label the Sca-1- and Sca-1+ luminal cells, respectively. By a lineage tracing approach, we show that the two luminal cell populations are independently sustained. Sox2 is dispensable for the maintenance of the Sca-1+ luminal cells but is essential for their facultative bipotent differentiation capacity. The Sca-1+ luminal cells share molecular features with the human TACSTD2+ luminal cells. This study corroborates the heterogeneity of the mouse prostate luminal cell lineage and shows that the adult mouse prostate luminal cell lineage is maintained by distinct cellular entities rather than a single progenitor population.

First Results from an Axion Haloscope at CAPP around 10.7 µeV.

The Center for Axion and Precision Physics Research at the Institute for Basic Science is searching for axion dark matter using ultralow temperature microwave resonators. We report the exclusion of the axion mass range 10.7126-10.7186 µeV with near Kim-Shifman-Vainshtein-Zakharov (KSVZ) coupling sensitivity and the range 10.16-11.37 µeV with about 9 times larger coupling at 90% confidence level. This is the first axion search result in these ranges. It is also the first with a resonator physical temperature of less than 40 mK.

PTEN is required to maintain luminal epithelial homeostasis and integrity in the adult mammary gland.

In the mammary gland, PTEN loss in luminal and basal epithelial cells results in differentiation defects and enhanced proliferation, leading to the formation of tumors with basal epithelial characteristics. In breast cancer, PTEN loss is associated with a hormone receptor-negative, basal-like subtype that is thought to originate in a luminal epithelial cell. Here, we show that luminal-specific PTEN loss results in distinct effects on epithelial homeostasis and mammary tumor formation. Luminal PTEN loss increased proliferation of hormone receptor-negative cells, thereby decreasing the percentage of hormone receptor-positive cells. Moreover, luminal PTEN loss led to misoriented cell divisions and mislocalization of cells to the intraluminal space of mammary ducts. Despite their elevated levels of activated AKT, Pten-null intraluminal cells showed increased levels of apoptosis. One year after Pten deletion, the ducts had cleared and no palpable mammary tumors were detected. These data establish PTEN as a critical regulator of luminal epithelial homeostasis and integrity in the adult mammary gland, and further show that luminal PTEN loss alone is not sufficient to promote the progression of mammary tumorigenesis.

Stem Cell Antigen-1 Identifies a Distinct Androgen-Independent Murine Prostatic Luminal Cell Lineage with Bipotent Potential.

Recent lineage tracing studies support the existence of prostate luminal progenitors that possess extensive regenerative capacity, but their identity remains unknown. We show that Sca-1 (stem cell antigen-1) identifies a small population of murine prostate luminal cells that reside in the proximal prostatic ducts adjacent to the urethra. Sca-1(+) luminal cells do not express Nkx3.1. They do not carry the secretory function, although they express the androgen receptor. These cells are enriched in the prostates of castrated mice. In the in vitro prostate organoid assay, a small fraction of the Sca-1(+) luminal cells are capable of generating budding organoids that are morphologically distinct from those derived from other cell lineages. Histologically, this type of organoid is composed of multiple inner layers of luminal cells surrounded by multiple outer layers of basal cells. When passaged, these organoids retain their morphological and histological features. Finally, the Sca-1(+) luminal cells are capable of forming small prostate glands containing both basal and luminal cells in an in vivo prostate regeneration assay. Collectively, our study establishes the androgen-independent and bipotent organoid-forming Sca-1(+) luminal cells as a functionally distinct cellular entity. These cells may represent a putative luminal progenitor population and serve as a cellular origin for castration resistant prostate cancer.

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin.

Chronic inflammation has been shown to promote the initiation and progression of diverse malignancies by inducing genetic and epigenetic alterations. In this study, we investigate an alternative mechanism through which inflammation promotes the initiation of prostate cancer. Adult murine prostate epithelia are composed predominantly of basal and luminal cells. Previous studies revealed that the two lineages are largely self-sustained when residing in their native microenvironment. To interrogate whether tissue inflammation alters the differentiation program of basal cells, we conducted lineage tracing of basal cells using a K14-CreER;mTmG model in concert with a murine model of prostatitis induced by infection from the uropathogenic bacteria CP9. We show that acute prostatitis causes tissue damage and creates a tissue microenvironment that induces the differentiation of basal cells into luminal cells, an alteration that rarely occurs under normal physiological conditions. Previously we showed that a mouse model with prostate basal cell-specific deletion of Phosphatase and tensin homolog (K14-CreER;Pten(fl/fl)) develops prostate cancer with a long latency, because disease initiation in this model requires and is limited by the differentiation of transformation-resistant basal cells into transformation-competent luminal cells. Here, we show that CP9-induced prostatitis significantly accelerates the initiation of prostatic intraepithelial neoplasia in this model. Our results demonstrate that inflammation results in a tissue microenvironment that alters the normal prostate epithelial cell differentiation program and that through this cellular process inflammation accelerates the initiation of prostate cancer with a basal cell origin.

Biodegradable Inorganic Nanovector: Passive versus Active Tumor Targeting in siRNA Transportation.

The biodegradable inorganic nanovector based on a layered double hydroxide (LDH) holds great promise for gene and drug delivery systems. However, in vivo targeted delivery of genes through LDH still remains a key challenge in the development of RNA interference therapeutics. Here, we describe in vivo and in vitro delivery system for Survivin siRNA (siSurvivin) assembled with passive LDH with a particle size of 100 nm or active LDH conjugated with a cancer overexpressing receptor targeting ligand, folic acid (LDHFA), conferring them an ability to target the tumor by either EPR-based clathrin-mediated or folate receptor-mediated endocytosis. When not only transfected into KB cells but also injected into xenograft mice, LDHFA/siSurvivin induced potent gene silencing at mRNA and protein levels in vitro, and consequently achieved a 3.0-fold higher suppression of tumor volume than LDH/siSurvivin in vivo. This anti-tumor effect was attributed to a selectively 1.2-fold higher accumulation of siSurvivin in tumor tissue compared with other organs. Targeting to the tumor with inorganic nanovector can guide and accelerate an evolution of next-generation theranosis system.

Surface-coupling of Cerenkov radiation from a modified metallic metamaterial slab via Brillouin-band folding.

Metallic metamaterials with positive dielectric responses are promising as an alternative to dielectrics for the generation of Cerenkov radiation [J.-K. So et al., Appl. Phys. Lett. 97(15), 151107 (2010)]. We propose here by theoretical analysis a mechanism to couple out Cerenkov radiation from the slab surfaces in the transverse direction. The proposed method based on Brillouin-zone folding is to periodically modify the thickness of the metamaterial slab in the axial direction. Moreover, the intensity of the surface-coupled radiation by this mechanism shows an order-of-magnitude enhancement compared to that of ordinary Smith-Purcell radiation.

Inhibition of tumour angiogenesis and growth by small hairpin HIF-1α and IL-8 in hepatocellular carcinoma.

BACKGROUND & AIMS: Hypoxia-inducible factor-1α (HIF-1α), a key transcription factor in the cellular response to hypoxia, and interleukin 8 (IL-8), a key mediator of angiogenesis, are important in cancerous tumour growth. In this study, we evaluated the effects of HIF-1α and IL-8 knockdown on angiogenesis and tumour growth in hepatocellular carcinoma (HCC). METHODS: Hepatocellular carcinoma cell lines were infected with adenoviruses expressing small-hairpin RNA (shRNA) specific for HIF-1α or IL-8, cultured under hypoxic conditions (1% O2), and examined for their levels of HIF-1α, IL-8, and angiogenesis factors using immunoblot. The effects of adenovirus-mediated shRNA-induced HIF-1α and IL-8 knockdown on tumour growth and angiogenesis were also investigated in a subcutaneous Hep3B-tumour mouse model. RESULTS: Hypoxia-inducible factor-1α knockdown directly repressed tumour growth, whereas IL-8 knockdown indirectly repressed tumour growth. Combined knockdown of HIF-1α and IL-8 increased survival rates of mice. HIF-1α and IL-8 knockdown also decreased microvessel density and tumour volume in vivo. Similarly, HIF-1α and IL-8 knockdown inhibited the angiogenic effects of HCC cell-conditioned media on tube formation and invasion by endothelial cells in vitro. CONCLUSION: These findings indicate that shRNA-induced HIF-1α and IL-8 knockdown inhibit angiogenesis and tumour growth in HCC. Further development of HIF-1α and IL-8 shRNA technologies could lead to effective therapies for HCC.

Risk factors associated with high-risk nodal disease in patients considered for active surveillance of papillary thyroid microcarcinoma without extrathyroidal extension.

Background: Active surveillance (AS) has become an alternative treatment approach for papillary thyroid microcarcinoma (PTMC). The purpose of this study is to uncover the clinicopathological factors associated with high-risk nodal disease in order to select proper candidates for AS of PTMC. Methods: We retrospectively reviewed 5,329 patients with PTMC without extrathyroidal extension (ETE) who underwent thyroidectomy with central compartment neck dissection (CCND) between 2007 and 2021 at Seoul St. Mary's Hospital. Patients with more than five metastatic lymph nodes (MLNs) (higher-risk N1 disease) and/or lateral neck node metastases (N1b disease) were defined as having high-risk nodal disease. The clinicopathological factors associated with high-risk nodal disease were analyzed. Results: A total of 415 (7.8%) patients had higher-risk N1 disease. These patients were younger on average, included a higher proportion of males, and had a larger tumor size and more frequent capsular invasion and multifocality compared with other patients. For the tumor size, a cutoff value of 0.65 cm was the best predictor of nodal risk groups. In a multivariate analysis, the independent risk factors associated with higher-risk N1 disease were younger age, male sex, tumor size >0.65 cm, and the presence of capsular invasion and/or multifocality. A total of 246 (4.6%) patients had N1b disease at initial diagnosis. In a multivariate analysis, the independent risk factors associated with N1b disease were younger age, male sex, tumor size >0.65 cm, and the presence of capsular invasion and/or multifocality. Conclusions: Young age, male sex, tumor size >0.65 cm, and presence of capsular invasion and/or multifocality can be considered risk factors for high-risk nodal disease in PTMC. Therefore, cautious observation is necessary for AS of patients with these characteristics.

The role of prophylactic central compartment neck dissection in patients with T1-T2 cN0 papillary thyroid carcinoma.

Background: It remains controversial whether prophylactic central compartment neck dissection (pCCND) is necessary in cases of stage T1-T2 cN0 papillary thyroid carcinoma (PTC). Some studies have demonstrated the benefits of pCCND on oncologic outcomes, whereas others reported that any advantages were insignificant. The purpose of this study was to investigate the effects of pCCND on cancer recurrence and its pattern in patients with T1-T2 cN0 PTC. Methods: We retrospectively reviewed 2,902 patients with PTC who had undergone thyroidectomy between 2006 and 2012 at Seoul St. Mary's Hospital: 2,099 patients had undergone pCCND and thyroidectomy (pCCND group), whereas 803 did not undergo pCCND (non-pCCND group). We investigated the effects of pCCND on cancer recurrence by comparing these two groups. Recurrence was classified according to the location of the recurrence. Results: The mean follow-up period was 112 months. The mean patient age was significantly younger in the pCCND group than in the non-pCCND group. There were no statistically significant differences in the distribution of sex, tumor size, or thyroidectomy extension between the groups. In the pCCND group, 883 (42%) patients showed evidence of N1a disease, and the mean number of metastatic lymph nodes was 1.26±2.2. Recurrence occurred in 67 (2.3%) patients in the total cohort. Recurrence was observed in 20 (2.5%) and 47 (2.2%) patients in the non-pCCND and pCCND groups, respectively, but there were no significant differences between the groups (P=0.687). When analyzed by the site of recurrence, 50% and 4.3% of recurrent disease in the non-pCCND and pCCND groups, respectively, occurred in the central compartment (P<0.001). There were no differences between the two groups in recurrent disease at other sites. The 15-year cumulative central compartment recurrence-free survival (RFS) rates of patients in the non-pCCND and pCCND groups were 99% and 100%, respectively (P<0.001). In the multivariate analysis, not performing pCCND was the only independent risk factor related to central compartment RFS, and the hazard ratio was 13.362 [95% confidence interval (CI): 2.928-60.986; P<0.001]. Conclusions: The omission of pCCND was found to be an independent risk factor for recurrence in the central compartment in patients with T1-T2 cN0 PTC.

Implications of isthmic location as a risk factor in papillary thyroid carcinoma.

Background: Papillary thyroid carcinoma (PTC) located in the isthmus generally has been known to have more extrathyroidal extension (ETE), lymph node involvement, and multifocality. The purpose of this study was to determine the clinical significance of an isthmic location of PTC. Methods: The records of 160 patients who underwent a total thyroidectomy due to a single, dominant isthmic PTC were retrospectively reviewed. The characteristics of isthmic cancer were compared with those of unilateral-lobar cancer in a PTC cohort at Seoul St. Mary's hospital. After propensity score matching for age, sex, and tumor size, 160 isthmic PTCs and 800 unilateral-lobar PTCs were compared. The clinicopathologic characteristics were analyzed to evaluate the prognostic significance of an isthmic tumor location. Results: The isthmic group was significantly older (49.6 vs. 46.8 years, P=0.007) and had a smaller mean tumor size (0.8±0.4 vs. 1.0±0.7 cm, P<0.001) than the unilateral-lobar group. After propensity score matching, tumor size categories, ETE, multifocality, nodal metastasis and proportion of patients with more than five metastatic lymph nodes were similar in both groups. However, N1b cases were more frequent in the unilateral-lobar group both before and after propensity score matching. In multivariate analysis, isthmic location was not correlated with gross ETE, multifocality, and higher-risk N1 disease. Younger age and more than five metastatic nodes increased the risk of PTC recurrence. However, isthmic tumor location was not significantly correlated with recurrence-free survival. Conclusions: Isthmic location is not an independent risk factor for aggressive clinicopathologic features and is not related to PTC recurrence.

A Rare Case of Hyperfunctioning Lipoadenoma Presenting as a Cystic Pararthyroid Lesion.

A 58-year-old woman visited the hospital complaining of fatigue and indigestion lasting for more than 3 months. She had no medical history other than taking a calcium plus vitamin D supplement for osteopenia. The initial blood test showed a high calcium level of 14.0 mg/dL. Additional tests were performed to differentially diagnose hypercalcemia. The blood test results were as follows: serum parathyroid hormone (PTH)=247.0 pg/mL, PTH-related peptide <1.0 pg/mL, phosphorous=2.6 mg/dL, 25-hydroxy-vitamin D=14.5 pg/mL, creatinine=1.09 mg/dL, and 24 hr urine calcium=215 mg/dL. A 4.5 cm sized cystic lesion on the intra-thyroidal space was confirmed on neck sonography and 4-dimensional parathyroid computed tomography, but technetium-99m methoxyisobutylisonitrile parathyroid scintigraphy showed equivocal results. After removal of the cystic lesion, serum calcium and PTH were normalized, and parathyroid lipoadenoma was confirmed in the postoperative pathology. Clinical features of parathyroid lipoadenoma are known to be similar to common parathyroid adenoma, but imaging studies often report negative findings. Therefore, it is necessary to better understand this rare disease for the differential diagnosis. For the final diagnosis and treatment of this disease, parathyroidectomy with intraoperative PTH measurement may be required.

Androgen-regulated stromal complement component 7 (C7) suppresses prostate cancer growth.

The complement system is a major component of the innate immune system that works through the cytolytic effect of the membrane attack complex (MAC). Complement component 7 (C7) is essential for MAC assembly and its precisely regulated expression level is crucial for the cytolytic activity of MAC. We show that C7 is specifically expressed by the stromal cells in both mouse and human prostates. The expression level of C7 inversely correlates with clinical outcomes in prostate cancer. C7 is positively regulated by androgen signaling in the mouse prostate stromal cells. The androgen receptor directly transcriptionally regulates the mouse and human C7. Increasing C7 expression in the C57Bl/6 syngeneic RM-1 and Pten-Kras allografts suppresses tumor growth in vivo. Conversely, C7 haploinsufficiency promotes tumor growth in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Interestingly, replenishing C7 in androgen-sensitive Pten-Kras tumors during androgen depletion only slightly enhances cellular apoptosis, highlighting the diverse mechanisms employed by tumors to counteract complement activity. Collectively, our research indicates that augmenting complement activity could be a promising therapeutic approach to impede the development of castration resistance in prostate cancer.

Elevated expression of the colony-stimulating factor 1 (CSF1) induces prostatic intraepithelial neoplasia dependent of epithelial-Gp130.

Macrophages are increased in human benign prostatic hyperplasia and prostate cancer. We generate a Pb-Csf1 mouse model with prostate-specific overexpression of macrophage colony-stimulating factor (M-Csf/Csf1). Csf1 overexpression promotes immune cell infiltration into the prostate, modulates the macrophage polarity in a lobe-specific manner, and induces senescence and low-grade prostatic intraepithelial neoplasia (PIN). The Pb-Csf1 prostate luminal cells exhibit increased stem cell features and undergo an epithelial-to-mesenchymal transition. Human prostate cancer patients with high CSF-1 expression display similar transcriptional alterations with the Pb-Csf1 model. P53 knockout alleviates senescence but fails to progress PIN lesions. Ablating epithelial Gp130 but not Il1r1 substantially blocks PIN lesion formation. The androgen receptor (AR) is downregulated in Pb-Csf1 mice. ChIP-Seq analysis reveals altered AR binding in 2482 genes although there is no significant widespread change in global AR transcriptional activity. Collectively, our study demonstrates that increased macrophage infiltration causes PIN formation but fails to transform prostate cells.

Stromal FOXF2 suppresses prostate cancer progression and metastasis by enhancing antitumor immunity.

Cancer-associated fibroblasts (CAFs) mediate an immunosuppressive effect, but the underlying mechanism remains incompletely defined. Here we show that increasing prostatic stromal Foxf2 suppresses the growth and progression of both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context. Mechanistically, Foxf2 moderately attenuates the CAF phenotype and transcriptionally downregulates Cxcl5, which diminish the immunosuppressive myeloid cells and enhance T cell cytotoxicity. Increasing prostatic stromal Foxf2 sensitizes prostate cancer to the immune checkpoint blockade therapies. Augmenting lung stromal Foxf2 also mediates an immunosuppressive milieu and inhibits lung colonization of prostate cancer. FOXF2 is expressed higher in the stroma of human transition zone (TZ) than peripheral zone (PZ) prostate. The stromal FOXF2 expression level in primary prostate cancers inversely correlates with the Gleason grade. Our study establishes Foxf2 as a stromal transcription factor modulating the tumor immune microenvironment and potentially explains why cancers are relatively rare and indolent in the TZ prostate.