Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Since early studies on the role of the androgen receptor that led ...to the advent of androgen deprivation therapy in the 1940s, there has long been intensive interest in the basic mechanisms underlying prostate cancer initiation and progression, as well as the potential to target these processes for therapeutic intervention. Here, we present an overview of major themes in prostate cancer research, focusing on current knowledge of principal events in cancer initiation and progression. We discuss recent advances, including new insights into the mechanisms of castration resistance, identification of stem cells and tumor-initiating cells, and development of mouse models for preclinical evaluation of novel therapuetics. Overall, we highlight the tremendous research progress made in recent years, and underscore the challenges that lie ahead.
Prostate organogenesis is a complex process that is primarily mediated by the presence of androgens and subsequent mesenchyme-epithelial interactions. The investigation of prostate development is ...partly driven by its potential relevance to prostate cancer, in particular the apparent re-awakening of key developmental programs that occur during tumorigenesis. However, our current knowledge of the mechanisms that drive prostate organogenesis is far from complete. Here, we provide a comprehensive overview of prostate development, focusing on recent findings regarding sexual dimorphism, bud induction, branching morphogenesis and cellular differentiation.
Pulmonary delivery of lipid-based nanotherapeutics by inhalation presents an advantageous alternative to oral and intravenous routes of administration that avoids enzymatic degradation in ...gastrointestinal tract and hepatic first pass metabolism and also limits off-target adverse side effects upon heathy tissues. For lung-related indications, inhalation provides localized delivery in order to enhance therapeutic efficacy at the site of action. Optimization of physicochemical properties, selected drug and inhalation format can greatly influence the pharmacokinetic behavior of inhaled nanoparticle systems and their payloads. The present review analyzes a wide range of nanoparticle systems, their formulations and consequent effect on pharmacokinetic distribution of delivered active components after inhalation.
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Nodal-related ligands of the transforming growth factor-beta (TGFβ) superfamily play central roles in patterning the early embryo during the induction of mesoderm and endoderm and the specification ...of left-right asymmetry. Additional roles for this pathway in the maintenance of embryonic stem cell pluripotency and in carcinogenesis have been uncovered more recently. Consistent with its crucial developmental functions, Nodal signaling is tightly regulated by diverse mechanisms including the control of ligand processing, utilization of co-receptors, expression of soluble antagonists, as well as positive- and negative-feedback activities.
Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of ...patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.
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•Efficient generation of a biobank of patient-derived bladder cancer organoids•Organoids recapitulate the histological and molecular spectrum of human bladder cancer•Bladder tumor organoids display clonal evolution in culture and as xenografts•Drug response of organoids can be validated in xenografts
A biobank of patient-derived bladder tumor organoids faithfully recapitulates features of human cancer and enables analysis of clonal evolution and drug responses.
Widespread structural alterations of cancer genomes are increasingly observed in a broad spectrum of tumors. In a recent issue of Cell, Baca and colleagues describe large chains of rearrangements ...that coordinately affect multiple chromosomes in prostate cancer. This phenomenon of chromoplexy may define cancer subtypes and drive punctuated tumor evolution.
The cancer stem cell (CSC) model proposes that cells within a tumor are organized in a hierarchical lineage relationship and display different tumorigenic potential, suggesting that effective ...therapeutics should target rare CSCs that sustain tumor malignancy. Here we review the current status of studies to identify CSCs in human prostate cancer as well as mouse models, with an emphasis on discussing different functional assays and their advantages and limitations. We also describe current controversies regarding the identification of prostate epithelial stem cells and cell types of origin for prostate cancer, and present potential resolutions of these issues. Although definitive evidence for the existence of CSCs in prostate cancer is still lacking, future directions pursuing the identification of tumor-initiating stem cells in the mouse may provide important advances in evaluating the CSC model for prostate cancer.
Current treatments for castration-resistant prostate cancer (CRPC) that target androgen receptor (AR) signaling improve patient survival, yet ultimately fail. Here, we provide novel insights into ...treatment response for the antiandrogen abiraterone by analyses of a genetically engineered mouse (GEM) model with combined inactivation of
and
, which are frequently comutated in human CRPC. These NPp53 mice fail to respond to abiraterone and display accelerated progression to tumors resembling treatment-related CRPC with neuroendocrine differentiation (CRPC-NE) in humans. Cross-species computational analyses identify master regulators of adverse response that are conserved with human CRPC-NE, including the neural differentiation factor
, which promotes neuroendocrine differentiation in cells derived from NPp53 tumors. Furthermore, abiraterone-treated NPp53 prostate tumors contain regions of focal and/or overt neuroendocrine differentiation, distinguished by their proliferative potential. Notably, lineage tracing
provides definitive and quantitative evidence that focal and overt neuroendocrine regions arise by transdifferentiation of luminal adenocarcinoma cells. These findings underscore principal roles for
and
inactivation in abiraterone resistance and progression from adenocarcinoma to CRPC-NE by transdifferentiation.
Understanding adverse treatment response and identifying patients likely to fail treatment represent fundamental clinical challenges. By integrating analyses of GEM models and human clinical data, we provide direct genetic evidence for transdifferentiation as a mechanism of drug resistance as well as for stratifying patients for treatment with antiandrogens.
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We report spin-torque ferromagnetic resonance studies of the efficiency of the damping-like (ξDL) spin–orbit torque exerted on an adjacent ferromagnet film by current flowing in epitaxial (001) and ...(110) IrO2 thin films. IrO2 possesses Dirac nodal lines (DNLs) in the band structure that are gapped by spin–orbit coupling, which could enable a very high spin Hall conductivity, σSH. We find that the (001) films do exhibit exceptionally high ξDL ranging from 0.45 at 293 K to 0.65 at 30 K, which sets the lower bounds of σSH to be 1.9 × 105 and 3.75 × 105 Ω–1 m–1, respectively, 10 times higher and of opposite sign than the theoretical prediction. Furthermore, ξDL and σSH are substantially reduced in anisotropically strained (110) films. We suggest that this high sensitivity to anisotropic strain is because of changes in contributions to σSH near the DNLs.
In this issue of Cancer Cell, Su et al. demonstrate that epigenetic reprogramming by Polycomb Repressive Complex 1 (PRC1) promotes an inflammatory tumor microenvironment in a subtype of metastatic ...prostate cancer, and show that a PRC1 inhibitor can synergize with immune checkpoint inhibitors to suppress metastasis in mouse models.
In this issue of Cancer Cell, Su et al. demonstrate that epigenetic reprogramming by Polycomb Repressive Complex 1 (PRC1) promotes an inflammatory tumor microenvironment in a subtype of metastatic prostate cancer, and show that a PRC1 inhibitor can synergize with immune checkpoint inhibitors to suppress metastasis in mouse models.
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