Abstract\n\nBackground\nMulti-Cancer tests (MCTs) hold potential to detect cancer across multiple sites and some predict the origin of the cancer signal. Understanding stakeholder preferences for MCTs could help to develop appealing MCTs, encouraging their adoption.\n\n\nMethods\nDiscrete Choice Experiments (DCEs) conducted online in England.\n\n\nResults\nGPs (n\u2009=\u2009251) and the general public (n\u2009=\u20091005) preferred MCTs that maximised negative predictive value, positive predictive value, and could test for a larger number of cancer sites. A reduction of the NPV of 4.0% was balanced by a 12.5% increase in the PPV for people and a 32.5% increase in PPV for GPs. People from ethnic minority backgrounds placed less importance on whether MCTs can detect multiple cancers. People with more knowledge and experience of cancer placed substantial importance on the MCT being able to detect cancer at an early stage. Both GPs and members of the public preferred the MCT reported in the SYMPLIFY study to FIT, PSA, and CA125, and preferred the SYMPLIFY MCT to 91% (GPs) and 95% (people) of 2048 simulated MCTs.\n\n\nConclusions\nThese findings provide a basis for designing clinical implementation strategies for MCTs, according to their performance characteristics.\n
\n \n\n \n \nPURPOSE: The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, because in colorectal cancer, the degree of differentiation of a tumor is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer, there is marked downregulation of SGK1 compared with normal tissue.Experimental Design: An inducible SGK1 viral overexpression system was utilized to induce reexpression of SGK1 in colorectal cancer cell lines. Transcriptomic and phenotypic analyses of these colorectal cancer lines was performed and validation in mouse and human cohorts was performed. RESULTS: We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Reexpression of SGK1 in colorectal cancer cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated, in part, by SGK1-induced PKP3 expression and increased degradation of MYC. CONCLUSIONS: Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit colorectal cancer metastasis.
\n \n\n \n \nThe conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies.
\n \n\n \n \nThe conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies.
\n \n\n \n \nMany newly diagnosed prostate cancers present as low Gleason score tumors that require no treatment intervention. Distinguishing the many indolent tumors from the minority of lethal ones remains a major clinical challenge. We now show that low Gleason score prostate tumors can be distinguished as indolent and aggressive subgroups on the basis of their expression of genes associated with aging and senescence. Using gene set enrichment analysis, we identified a 19-gene signature enriched in indolent prostate tumors. We then further classified this signature with a decision tree learning model to identify three genes--FGFR1, PMP22, and CDKN1A--that together accurately predicted outcome of low Gleason score tumors. Validation of this three-gene panel on independent cohorts confirmed its independent prognostic value as well as its ability to improve prognosis with currently used clinical nomograms. Furthermore, protein expression of this three-gene panel in biopsy samples distinguished Gleason 6 patients who failed surveillance over a 10-year period. We propose that this signature may be incorporated into prognostic assays for monitoring patients on active surveillance to facilitate appropriate courses of treatment.
\n \n\n \n \nMED1 is a key coactivator of the androgen receptor (AR) and other signal-activated transcription factors. Whereas MED1 is overexpressed in prostate cancer cell lines and is thought to coactivate distinct target genes involved in cell-cycle progression and castration-resistant growth, the underlying mechanisms by which MED1 becomes overexpressed and its oncogenic role in clinical prostate cancer have remained unclear. Here, we report that MED1 is overexpressed in the epithelium of clinically localized human prostate cancer patients, which correlated with elevated cellular proliferation. In a Nkx3.1:Pten mutant mouse model of prostate cancer that recapitulates the human disease, MED1 protein levels were markedly elevated in the epithelium of both invasive and castration-resistant adenocarcinoma prostate tissues. Mechanistic evidence showed that hyperactivated ERK and/or AKT signaling pathways promoted MED1 overexpression in prostate cancer cells. Notably, ectopic MED1 overexpression in prostate cancer xenografts significantly promoted tumor growth in nude mice. Furthermore, MED1 expression in prostate cancer cells promoted the expression of a number of novel genes involved in inflammation, cell proliferation, and survival. Together, these findings suggest that elevated MED1 is a critical molecular event associated with prostate oncogenesis.
\n \n\n \n \nMore than 15 years ago, the first generation of genetically engineered mouse (GEM) models of prostate cancer was introduced. These transgenic models utilized prostate-specific promoters to express SV40 oncogenes specifically in prostate epithelium. Since the description of these initial models, there have been a plethora of GEM models of prostate cancer representing various perturbations of oncogenes or tumor suppressors, either alone or in combination. This review describes these GEM models, focusing on their relevance for human prostate cancer and highlighting their strengths and limitations, as well as opportunities for the future.
\n \n\n \n \nWe have established a systematic high-throughput screen for genes that cause cell death specifically in transformed tumor cells. In a first round of screening, cDNAs that induce apoptosis in a transformed human cell line are detected. Positive genes are subsequently tested in a synthetic lethal screen in normal cells versus their isogenic counterparts that have been transformed by a particular oncogene. In this way, the organic cation transporter-like 3 (ORCTL3) gene was found to be inactive in normal rat kidney (NRK) cells, but to induce apoptosis in NRK cells transformed by oncogenic H-ras. ORCTL3 also causes cell death in v-src-transformed cells and in various human tumor cell lines but not in normal cells or untransformed cell lines. Although ORCTL3 is a member of the organic cation transporter gene family, our data indicate that this gene induces apoptosis independently of its putative transporter activity. Rather, various lines of evidence suggest that ORCTL3 brings about apoptosis by an endoplasmic reticulum stress-mediated mechanism. Finally, we detected ORCTL3 to be downregulated in human kidney tumors.
\n \n\n \n \nBrn-3b transcription factor enhances proliferation of neuroblastoma (NB) and breast cancer cell lines in vitro and increases the rate and size of in vivo tumour growth, whereas reducing Brn-3b slows growth, both in vitro and in vivo. Brn-3b is elevated in >65% of breast cancer biopsies, and here we demonstrate that Brn-3b is also elevated in NB tumours. We show a significant correlation between Brn-3b and cyclin D1 (CD1) in breast cancers and NB tumours and cell lines. Brn-3b directly transactivates the CD1 promoter in co-transfection experiments, whereas electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrate that Brn-3b protein binds to an octamer sequence located in the proximal CD1 promoter. Site-directed mutagenesis of this sequence resulted in loss of transactivation of the CD1 promoter by Brn-3b. Thus, Brn-3b may act to alter growth properties of breast cancer and NB cells by enhancing CD1 expression in these cells.
\n \n\n \n \nNeuroblastomas are the second most common solid tumor in children but the molecular mechanisms underlying the initiation and progression of this disease are poorly understood. We previously showed that the Brn-3b transcription factor is highly expressed in actively proliferating neuroblastoma cells but is significantly decreased when these cells are induced to differentiate. In this study, we analyzed the effects of manipulating Brn-3b levels in the human neuroblastoma cell line, IMR-32 and showed that constitutive overexpression of Brn-3b consistently increased cellular growth and proliferation in monolayer as well as in an anchorage-independent manner compared with controls whereas stably decreasing Brn-3b can reduce the rate of growth of these cells. Cells with high Brn-3b also fail to respond to growth inhibitory retinoic acid, as they continue to proliferate. Moreover, Brn-3b levels significantly modified tumor growth in vivo with elevated Brn-3b resulting in faster tumor growth in xenograft models whereas decreasing Brn-3b resulted in slower growth compared with controls. Interestingly, elevated Brn-3b levels also enhances the invasive capacity of these neuroblastoma cells with significantly larger numbers of migrating cells observed in overexpressing clones compared with controls. Because invasion and metastasis influence morbidity and mortality in neuroblastoma and so significantly affect the course and outcome of neuroblastomas, this finding is very important. Our results therefore suggest that Brn-3b transcription factor contributes to proliferation of neuroblastoma cells in vivo and in vitro but may also influence progression and/or invasion during tumorigenesis. It is possible that decreasing Brn-3b levels may reverse some effects on growth and proliferation of these cells.
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