New tools to prevent cancer growth and spread: a ‘Clever’ approach

Hollmén, Maija; Figueiredo, Carlos R.; Jalkanen, Sirpa

doi:10.1038/s41416-020-0953-0

Cited by 46 publications

(44 citation statements)

References 68 publications

(124 reference statements)

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“…This is consistent with the observation that mouse bladder wall injection with S. haematobium eggs leads to urothelial hyperplasia, a potentially be pre-cancerous state [17]. Proteins including metalloreductase (STEAP4) [40], platelet-activating factor acetylhydrolase (Pla2g7) [41], disabled homolog 2 (Dab2) [42], peptidyl-prolyl cis-trans isomerase (Fkbp14) [43], stabilin-1 (Stab1) [44,45], lysyl oxidase homolog 2 (Loxl2) [46], U4/U6 small nuclear ribonucleoprotein (Prpf3) [47], latent-transforming growth factor beta-binding protein (Ltbp3) [48], RNA-binding protein (Nob1) [49], isoform 1 of RNA-binding protein (Raly) [50], and probable glutathione peroxidase 8 (Gpx8) [51] are all expressed in many different malignant tissues, including bladder tissue, and are linked with increased cell proliferation, oncogenic properties, and poor cancer prognosis. This is in line with our observations, as all these proteins were more highly expressed in egg-injected mice bladder tissue.…”

Section: Discussionsupporting

confidence: 88%

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

Osakunor

Ishida

Lamanna

et al. 2021

Preprint

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BackgroundUrogenital schistosomiasis remains a major public health concern worldwide. In response to egg deposition, the host bladder undergoes gross and molecular morphological changes relevant for disease manifestation. However, limited mechanistic studies to date imply that the molecular mechanisms underlying pathology have not been well-defined. We leveraged a mouse model of urogenital schistosomiasis to perform for the first time, proteome profiling of the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to elucidate the protein pathways involved in urogenital schistosomiasis-induced pathology.MethodsPurified S. haematobium eggs or control vehicle were microinjected into the bladder walls of mice. Mice were sacrificed seven days post-injection and bladder proteins isolated and processed for proteome profiling using mass spectrometry.ResultsWe demonstrate that biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism were significantly enriched in S. haematobium infection.ConclusionS. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Our findings highlight the potential bladder protein indicators for host-parasite interplay and provide new insights into the complex dynamics of pathology and characteristic bladder tissue changes in urogenital schistosomiasis. The findings will be relevant for development of improved interventions for disease control.Author summaryThe molecular mechanisms underlying the urinary and genital pathology from urogenital schistosomiasis have not been well-defined. This has mainly been due to limited mechanistic studies and the lack of a suitable animal model for S. haematobium infection. We leveraged a mouse model of urogenital schistosomiasis, along with proteomics analysis, to determine the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to define protein pathways that may be involved in morbidity from urogenital schistosomiasis infection. Our results show that S. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism are significantly enriched in S. haematobium infection. Our findings highlight important protein indicators of host-parasite interactions in the bladder and their association with tissue changes in urogenital schistosomiasis. The findings presented here will be relevant for development of improved interventions for disease control, and contribute to realizing the 2021-2030 NTD goals by demonstrating evidence on the early events that occur during schistosome infection..

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Section: Discussionsupporting

confidence: 88%

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

Osakunor

Ishida

Lamanna

et al. 2021

Preprint

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“…However, if the expression difference we observed for GPR162 is partially attributable to a global change in methylation, this could suggest an altered reception of adrenergic signaling [61][62][63]. STAB1 (Stabilin 1; log 2 FC = -0.05) from the study of Koestler et al [7] encodes a scavenger receptor suggested to mark immunosuppressive monocytes and macrophages, where decreased expression appears to increase T cell antitumor cytotoxicity [64]. SKAP1 (Src kinase-associated phosphoprotein 1; log 2 FC = 0.07) from the gene set of Yang et al [8] encodes a T cell receptor adaptor protein and is a known EOC risk locus with a possible cell-autonomous role in EOC tumorigenesis [65].…”

Section: Plos Onementioning

confidence: 99%

The blood transcriptome prior to ovarian cancer diagnosis: A case-control study in the NOWAC postgenome cohort

et al. 2021

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Epithelial ovarian cancer (EOC) has a 5-year relative survival of 50%, partly because markers of early-stage disease are not available in current clinical diagnostics. The aim of the present study was to investigate whether EOC is associated with transcriptional profiles in blood collected up to 7 years before diagnosis. For this, we used RNA-stabilized whole blood, which contains circulating immune cells, from a sample of EOC cases from the population-based Norwegian Women and Cancer (NOWAC) postgenome cohort. We explored case-control differences in gene expression in all EOC (66 case-control pairs), as well as associations between gene expression and metastatic EOC (56 pairs), serous EOC (45 pairs, 44 of which were metastatic), and interval from blood sample collection to diagnosis (≤3 or >3 years; 34 and 31 pairs, respectively). Lastly, we assessed differential expression of genes associated with EOC in published functional genomics studies that used blood samples collected from newly diagnosed women. After adjustment for multiple testing, this nested case-control study revealed no significant case-control differences in gene expression in all EOC (false discovery rate q>0.96). With the exception of a few probes, the log2 fold change values obtained in gene-wise linear models were below ±0.2. P-values were lowest in analyses of metastatic EOC (80% of which were serous EOC). No common transcriptional profile was indicated by interval to diagnosis; when comparing the 100 genes with the lowest p-values in gene-wise tests in samples collected ≤3 and >3 years before EOC diagnosis, no overlap in these genes was observed. Among 86 genes linked to ovarian cancer in previous publications, our data contained expression values for 42, and of these, tests of LIME1, GPR162, STAB1, and SKAP1, resulted in unadjusted p<0.05. Although limited by sample size, our findings indicated less variation in blood gene expression between women with similar tumor characteristics.

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“…Additionally, TECs were shown to promote regulatory T cell (Treg) accumulation via up-regulation of the lymphatic and vasculature endothelial receptor 1 (CLEVER-1); an abundance of CLEVER-1-positive macrophages support immunosuppression. It has been reported that tumor-induced CLEVER-1 expression in both macrophages and endothelial cell populations was required to support the growth of melanoma, and that the chief driver was the diminished expression of vascular E- and P-selectin, and accumulation of Tregs and M2 macrophages in the tumors induced by CLEVER-1 ( 27 , 28 ).…”

Section: Cells and Components Of The Tme Involved In Suppression Of The Anti-tumor Responsementioning

confidence: 99%

Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance

et al. 2021

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The tumor microenvironment (TME) is a complex and ever-changing “rogue organ” composed of its own blood supply, lymphatic and nervous systems, stroma, immune cells and extracellular matrix (ECM). These complex components, utilizing both benign and malignant cells, nurture the harsh, immunosuppressive and nutrient-deficient environment necessary for tumor cell growth, proliferation and phenotypic flexibility and variation. An important aspect of the TME is cellular crosstalk and cell-to-ECM communication. This interaction induces the release of soluble factors responsible for immune evasion and ECM remodeling, which further contribute to therapy resistance. Other aspects are the presence of exosomes contributed by both malignant and benign cells, circulating deregulated microRNAs and TME-specific metabolic patterns which further potentiate the progression and/or resistance to therapy. In addition to biochemical signaling, specific TME characteristics such as the hypoxic environment, metabolic derangements, and abnormal mechanical forces have been implicated in the development of treatment resistance. In this review, we will provide an overview of tumor microenvironmental composition, structure, and features that influence immune suppression and contribute to treatment resistance.

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New tools to prevent cancer growth and spread: a ‘Clever’ approach

Cited by 46 publications

References 68 publications

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

The blood transcriptome prior to ovarian cancer diagnosis: A case-control study in the NOWAC postgenome cohort

Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance

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