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We report a patient with adenocarcinoma of the prostate, who eventually developed Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion from the tumor. At first, maximal androgen blockade (MAB) therapy was effective for the prostate carcinoma, which was positive for prostate-specific antigen (PSA) and negative for ACTH on the biopsy specimen. However, 3 years later, the patient complained of bilateral leg edema. A chest computed tomographic (CT) scan showed bilateral pleural effusion and inflammatory changes, focused on the right upper-lobe. While his PSA was not elevated, and there were no obvious tumor metastases, his serum cortisol and ACTH levels were elevated, without any evidence of lesions that could release ectopic ACTH. Two weeks later, the patient complained of dyspnea and bilateral pleural effusion, and inflammatory changes were worse. Although the patient was administered inhibitors of adrenocorticoid synthesis-metyrapone, they did not have enough clinical efficiency. Steroid pulse therapy was also administered but the patient's severe pneumonia and pleural effusion did not improve and he finally died of respiratory failure. In contrast to the initial biopsy specimen findings, on autopsy, the tumor was negative for PSA but positive for ACTH. Thus, it would appear that the tumor began to produce and release ectopic ACTH after therapy, which resulted in the development of Cushing syndrome in this patient with prostate carcinoma. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) is a cornerstone of prostate cancer (PCa) management. Although tumors initially regress, many progress to a hormone‐independent state termed castration‐resistant PCa (CRPC), for which treatment options are limited. We here report that the major luminal cell population in tumors of Pten(i)pe−/− mice, generated by luminal epithelial cell‐specific deletion of the tumor suppressor PTEN after puberty, is castration‐resistant and that the expression of inflammation and stemness markers is enhanced in persistent luminal cells. In addition, hypoxia‐inducible factor 1 (HIF1) signaling, which we have previously demonstrated to be induced in luminal cells of Pten(i)pe−/− mice and to promote malignant progression, is further activated. Importantly, we show that genetic and pharmacological inhibition of HIF1A sensitizes Pten‐deficient prostatic tumors to castration and provides durable therapeutic responses. Furthermore, HIF1A inhibition induces apoptotic signaling in human CRPC cell lines. Therefore, our data demonstrate that HIF1A in prostatic tumor cells is a critical factor that enables their survival after ADT, and identify it as a target for CRPC management. Synopsis: Resistance development to androgen deprivation therapy (ADT) in prostate cancer (PCa) patients is a major clinical issue. By analysing PCa mouse models, we found that HIF1A promotes androgen deprivation‐induced luminal cell plasticity and that its inhibition overcomes ADT resistance. Luminal‐C cells, the major epithelial subset in Pten‐deficient tumors, are intrinsically castration‐resistant.Single‐cell analyses revealed that HIF1 signaling is further activated in luminal‐C cells by castration, mediates a high plasticity state and induces resistance to ADT.HIF1A inhibition sensitizes castration‐resistant prostatic tumors to androgen deprivation and leads to long‐term therapeutic responses.ADT combined with HIF1A inhibition is a promising approach to treat castration‐resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract: Prostate cancer (PCa) progression mechanism has been linked to epithelial proliferation, tumor invasion ability, and growth factors. Nintedanib (BIBF 1120) has been reported as being FGF and VEGF pathway inhibitors, exhibiting antitumor activity. Thus, the objective herein was to characterize the early Nintedanib treatment effects on the structure and molecules involved in the basal membrane, the extracellular matrix (ECM) maintenance, in addition to the angiogenesis and mitogenic processes at different grades of prostatic tumor development in TRAMP mice. Therefore, 45 male TRAMP mice were divided into control groups: 8‐week‐old mice (TC8), 12‐week‐old mice (TC12), and 16‐week‐old mice (TC16); and treated groups with 10 mg/kg/day Nintedanib dose for 4 weeks. The treated groups were euthanized at 12 (TN12) and 16 (TN16) weeks of age. Samples from the dorsolateral lobe were collected and processed for light microscopy, immunohistochemistry, Western blotting, and microvessel density analysis. The results showed that early Nintedanib treatment led to an increase of healthy epithelium frequency and a reduction of LGPIN and a maximum vascularization density in the TN12 group. Also, treatment led to a well‐differentiated adenocarcinoma decrease and an α and β dystroglycan and also laminin 1 increase in the TN16 group. IGFR1 decreased in the TN16 group. To conclude, early Nintedanib treatment led to a reduction in cancer severity, interfering in both ECM compounds and angiogenesis process to then contribute to a balance, not only in the prostatic epithelium and stroma, but also in the epithelial‐stromal interaction during PCa progression. [ABSTRACT FROM AUTHOR]

The crosstalk between tumor microenvironment and cancer cells is emerging as a critical determinant in tumor progression. However, the underlying mechanism of tumor microenvironment‐induced cancer development remains controversial. Here, our study provides evidence to suggest that tumor‐associated macrophage (TAM) enrichment is found in chemoresistant prostatic tumor tissues. Those TAMs are demonstrated to promote chemoresistance and distant metastasis in prostatic cancer through secretion of CCL5. Mechanistically, TAM coculture or additional CCL5 can mediate the STAT3‐dependent epithelial–mesenchymal transition process, resulting in distant metastasis in prostatic cancer. Meanwhile, activation of STAT3 induced by CCL5 can mediate upregulation of the transcription factor Nanog, leading to drug resistance. In vivo study further demonstrated that blockade of STAT3 signals significantly reverses chemoresistance and suppresses lung metastasis in colorectal tumor‐bearing mice, suggesting a novel strategy for clinical prostatic cancer treatment. [ABSTRACT FROM AUTHOR]

In the current issue of Cancer, Pasqualini and colleagues report on a study in which they target prostatic tumor vasculature signatures with an apoptosis‐inducing, peptidomimetic drug. The authors of this editorial place this vascular‐targeting discovery into a broader clinical context while focusing on opportunities and challenges in implementing it further. [ABSTRACT FROM AUTHOR]

Tumor‐associated macrophages (TAMs) play an essential role in tumor therapeutic resistance. Although the lethal effect of ferroptosis on tumor cells is well reported, how TAMs inhibit the effect of ferroptosis in tumors has not been clearly defined. In this study, it is demonstrated that TAM‐secreted taurine suppresses ferroptosis in prostate cancer (PCa) by activating the Liver X receptor alpha/Stearoyl‐Coenzyme A desaturase 1 (LXRα/SCD1) pathway. Blocking taurine intake via inhibition of taurine transporter TauT restores the sensitivity to ferroptosis in tumors. Furthermore, LXRα activates the transcription of both miR‐181a‐5p and its binding protein FUS to increase the recruitment of miR‐181a‐5p in tumor‐derived extracellular vesicles (EVs). It is observed that macrophages appear to be recipient cells of the miR‐181a‐5p‐enriched EVs. Intake of miR‐181a‐5p in macrophages promotes their M2 polarization and enhances the taurine export by inhibiting expression of its target gene lats1, which in turn inactivates the hippo pathway and results in a Yes‐associated protein (YAP) nuclear translocation for transcriptional activation of both M2 polarization‐related genes such as ARG1 and CD163 and the taurine transport gene TauT. Taken together, the findings indicate a reciprocal interaction between PCa cells and TAMs as a positive feedback‐loop to repress ferroptosis in PCa, mediated by TAM‐secreted taurine and tumor EV‐delivered miR‐181a‐5p. [ABSTRACT FROM AUTHOR]

Cancer is one of the most prevailing causes of mortality worldwide. Standard therapies for cancer patients include surgical intervention, chemotherapy, and radiotherapy. Nevertheless, chemoresistance and toxicity are clinical implications of advanced disease. New treatments are obliged to overcome these challenges. According to clinical investigations, melatonin (MLT) has the potential to prevent and cure cancer. It is nontoxic and has a plethora of anticancer properties including apoptosis, antiangiogenic, antiproliferative, and metastasis‐inhibitory mechanisms. It enhances the therapeutic sensitivity of malignancies when coupled with conventional medications. The investigations that demonstrate how MLT possesses antitumor characteristics are reviewed in this manuscript. We provided an overview of recent research on the etiology, factors associated, therapeutic property of MLT on various cancer types. We discussed the clinical implications of MLT alone or in conjunction with chemotherapeutic drugs or radiation therapy. Furthermore, we have addressed the mechanisms of its anticancer activities against several types of cancers along with research findings of various investigations done by researchers and advancements in the field of nanotechnology for efficient delivery of MLT. The recent clinical investigations of MLT in various cancer types are reported in this review. [ABSTRACT FROM AUTHOR]

The purpose of this work was to compare the performance of 7 meta‐heuristics algorithms namely: Dragonfly (DA), Ant Lion (ALO), Grey Wolf (GWO), Artificial Bee Colony (ABC), Particle Swarm (PSO), Whale (WAO), and a hybrid Particle Swarm with Grey Wolf (HPSOGWO) optimizers in terms of fine‐tuning hyper‐parameters of a hybrid quantitative structure property relationships (QSPR)‐support vector regression (SVR) for the prediction of molar fraction solubilities of drug compounds in supercritical carbon dioxide (SC‐CO2). A dataset of 168 drug compounds, 13 inputs, and 4490 experimental data points was used to achieve the goal. All 7 models were statistically and graphically approved while the HPSOGWO‐SVR was found to over‐perform with an average absolute relative deviation (AARD) of 0.706% and an AIC of −14,434,249. The model was subjected to an external test (validation) using 160 experimental data points that were not used in the training and the test set. The overall results proved that the obtained model has good predictivity ability and robustness. [ABSTRACT FROM AUTHOR]

Toll‐like receptors (TLRs) and inflammasomes belong to the pattern recognition receptors (PRRs) of innate immunity identifying conserved compounds produced by pathogens or discharged by injured cells. Different cell subsets in the human urogenital system, such as epithelial cells and infiltrating leukocytes, express different kinds of TLRs (such as TLR2, TLR3, TLR4, TLR5 and TLR9) as well as inflammasomes (such as NLRP3, NLRC4 and AIM2). Various types of the Trichomonas vaginalis‐derived components such as glycosyl‐phosphatidylinositol (GPI), T. vaginalis virus (TVV), Lipophosphoglycan (LPG) and flagellin can be recognized by TLR2, TLR3, TLR4 and TLR5, respectively, leading to the production of proinflammatory cytokines and chemokines in the cervicovaginal mucosa. The T. vaginalis‐induced inflammasomes can lead to pyroptosis as well as the release of IL‐1β and IL‐18 promoting innate and adaptive immune responses. The PRR‐mediated responses to T. vaginalis may contribute to the induction of protective immune responses, local inflammation, promotion of co‐infections, or even the development of malignancies, for example, prostate cancer. The protective or pathogenic roles of the TLRs and inflammasomes during trichomoniasis are highlighted in this review. A better understanding of PRR‐mediated responses provides invaluable insights to develop effective immunotherapeutic strategies against T. vaginalis infection. [ABSTRACT FROM AUTHOR]

A review of the current treatment options for prostate cancer and the formation of resistance to these regimens has been compiled including primary, acquired, and cross‐resistance. The diversification of the pathways involved and the escape routes the tumor is utilizing have been addressed. Whereas early stages of tumor can be cured, there is no treatment available after a point of no return has been reached, leaving palliative treatment as the only option. The major reasons for this outcome are the heterogeneity of tumors, both inter‐ and intra‐individually and the nearly endless number of escape routes, which the tumor can select to overcome the effects of treatment. This means that more focus should be applied to the individualization of both diagnosis and therapy of prostate cancer. In addition to current treatment options, novel drugs and ongoing clinical trials have been addressed in this review. [ABSTRACT FROM AUTHOR]

Cancers of epithelial origin such as breast, prostate, cervical, gastric, colon and lung cancer account for a large proportion of deaths worldwide. Better treatment of metastasis, the main cause of cancer deaths, is therefore urgently required. Several of these tumours have been shown to have an abnormally high concentration of Na+ ([Na+]) and emerging evidence points to this accumulation being due to elevated intracellular [Na+]. This poses intriguing questions about the cellular mechanisms underlying Na+ dysregulation in cancer, and its pathophysiological significance. Elevated intracellular [Na+] may be due to alterations in activity of the Na+/K+‐ATPase, and/or increased influx via Na+ channels and Na+‐linked transporters. Maintenance of the electrochemical Na+ gradient across the plasma membrane is vital to power many cellular processes that are highly active in cancer cells, including glucose and glutamine import. Na+ channels are also upregulated in cancer cells, which in turn promotes tumour growth and metastasis. For example, ENaC and ASICs are overexpressed in cancers, increasing invasion and proliferation. In addition, voltage‐gated Na+ channels are also upregulated in a range of tumour types, where they promote metastatic cell behaviours via various mechanisms, including membrane potential depolarisation and altered pH regulation. Together, recent findings relating to elevated Na+ in the tumour microenvironment and how this may be regulated by several classes of Na+ channels provide a link between altered Na+ handling and poor clinical outcome. There are new opportunities to leverage this altered Na+ microenvironment for therapeutic benefit, as exemplified by several ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Vasculogenic mimicry (VM) is the formation of microvascular channels by cancer cells. VM requires cellular processes that are regulated by changes in cellular migration and morphology. Cofilin (CFL), a key regulator of actin depolymerization, has been reported to affect malignant phenotypes of cancer. We show that treatment with inhibitors of actin dynamics suppresses VM in MDA‐MB‐231 human breast cancer cells. We established CFL‐knockout (KO) MDA‐MB‐231 cells and found that VM was attenuated in CFL‐KO cells. Although the re‐expression of wild‐type CFL restored VM in CFL‐KO cells, inactive phosphomimetic CFL failed to do so. Collectively, our results demonstrate that CFL is a critical regulator of VM and implicate CFL as a novel therapeutic target for breast cancer. [ABSTRACT FROM AUTHOR]

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is overexpressed in a variety of malignancies including prostate cancer (PCa) and may play important roles in tumor progression. Gene copy number gains, enhanced transcription, and a few circRNAs have been reported to upregulate EZH2. It was not known whether EZH2 itself generates circRNAs that promote its own expression. We here report the identification of circEZH2E2/E3 that is derived from exons 2 and 3 of the EZH2 gene and overexpressed in PCa. We show that circEZH2E2/E3 functions as a dual inhibitor for both miR363 and miR708 that target the EZH2 3′UTR and CDS, respectively, resulting in the upregulation of EZH2 expression and hence the downregulation of EZH2‐repressed genes (e.g., CDH1 and DAB2IP), and enhancement of PCa cell proliferation, migration, invasion, and xenograft PCa growth. Overexpression of circEZH2E2/E3 is significantly correlated with higher tumor grade, tumor progression, and unfavorable progression‐free and disease‐specific survival in PCa patients. These findings show a novel autoenhancing EZH2–circEZH2E2/E3‐miR363/miR708–EZH2 regulatory loop, by which circEZH2E2/E3 plays important roles in PCa tumorigenesis and progression by upregulating EZH2, and may have potential diagnostic, prognostic, and therapeutic uses in PCa management. [ABSTRACT FROM AUTHOR]