The Clinical Significance and Mechanisms of REG4 in Human Cancers

Zhang, Junyan; Zhu, Zhi; Zhang, Miao; Huang, Xiaoxian; Sun, Zhe; Xu, Hui; Wang, Zhenning

doi:10.3389/fonc.2020.559230

Cited by 13 publications

(8 citation statements)

References 87 publications

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“…Similarly, at day 4 MC-treated tumors had significant upregulation of inhibitors of angiogenesis [CNNM1 ( 35 ), FILIP1L ( 36 )], tumor suppressors [VWA5A ( 37 ), SYNPO2 ( 38 ), ALDH1A2 ( 39 )], and those found overexpressed in certain tumors with unknown function [MPV17 ( 40 )] ( Figures 6D–F ). Tumors treated with tumor-specific IgE-sensitized MCs compared to controls also had several downregulated signaling intermediates including those shown to promote tumor growth and progression in tumor microenvironments [PRSS2 ( 41 ), PRSS1 ( 42 ), REG4 ( 43 ), PRKAR2B ( 44 ), NDUFA4L2 ( 45 ), LRFN5 ( 46 ), and ANGPTL4 ( 47 )]. These signaling intermediates and pathways provide a unique overview of the mechanisms of MC-induced killing of tumor cells and work is underway to further validate and delineate the anti-tumor mechanisms involved.…”

Section: Resultsmentioning

confidence: 99%

Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy

et al. 2022

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The diversity of autologous cells being used and investigated for cancer therapy continues to increase. Mast cells (MCs) are tissue cells that contain a unique set of anti-cancer mediators and are found in and around tumors. We sought to exploit the anti-tumor mediators in MC granules to selectively target them to tumor cells using tumor specific immunoglobin E (IgE) and controllably trigger release of anti-tumor mediators upon tumor cell engagement. We used a human HER2/neu-specific IgE to arm human MCs through the high affinity IgE receptor (FcεRI). The ability of MCs to bind to and induce apoptosis of HER2/neu-positive cancer cells in vitro and in vivo was assessed. The interactions between MCs and cancer cells were investigated in real time using confocal microscopy. The mechanism of action using cytotoxic MCs was examined using gene array profiling. Genetically manipulating autologous MC to assess the effects of MC-specific mediators have on apoptosis of tumor cells was developed using siRNA. We found that HER2/neu tumor-specific IgE-sensitized MCs bound, penetrated, and killed HER2/neu-positive tumor masses in vitro. Tunneling nanotubes formed between MCs and tumor cells are described that parallel tumor cell apoptosis. In solid tumor, human breast cancer (BC) xenograft mouse models, infusion of HER2/neu IgE-sensitized human MCs co-localized to BC cells, decreased tumor burden, and prolonged overall survival without indications of toxicity. Gene microarray of tumor cells suggests a dependence on TNF and TGFβ signaling pathways leading to apoptosis. Knocking down MC-released tryptase did not affect apoptosis of cancer cells. These studies suggest MCs can be polarized from Type I hypersensitivity-mediating cells to cytotoxic cells that selectively target tumor cells and specifically triggered to release anti-tumor mediators. A strategy to investigate which MC mediators are responsible for the observed tumor killing is described so that rational decisions can be made in the future when selecting which mediators to target for deletion or those that could further polarize them to cytotoxic MC by adding other known anti-tumor agents. Using autologous human MC may provide further options for cancer therapeutics that offers a unique anti-cancer mechanism of action using tumor targeted IgE’s.

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Section: Resultsmentioning

confidence: 99%

Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy

et al. 2022

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“…Other genes involved in metabolism such as REG4 and CTSE, were also overexpressed in the metabolic subtype and they have been previously related to CRC prognosis. Regenerating islet-derived type 4 (REG4) is a member of the calcium-dependent lectin gene superfamily and it was associated with a relatively unfavourable prognosis in various cancers including CRC [67, 68]. Cathepsin E (CTSE) is an adverse prognostic factor for survival among rectal cancer patients receiving chemo-radiotherapy [69].…”

Section: Discussionmentioning

confidence: 99%

A novel molecular analysis approach in colorectal cancer suggests new treatment opportunities

López-Camacho

Prado-Vázquez

Martínez-Pérez

et al. 2023

Preprint

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Colorectal cancer (CRC) is a molecular and clinically heterogeneous disease. In 2015, the Colorectal Cancer Subtyping Consortium classified CRC into four consensus molecular subtypes (CMS), but these CMS have had little impact on the clinical practice. The purpose of this study is to deepen into the molecular characterization of CRC. A novel approach, based on probabilistic graphical models (PGM) and sparse k-means-Consensus Cluster layer analyses was applied in order to functionally characterize CRC tumors. First, PGM was used to functionally characterize CRC, and then, sparse k-means-Consensus cluster was used to explore layers of biological information and establish classifications. To this aim, gene expression and clinical data of 805 CRC samples from three databases were analyzed. Tree different layers based on biological features were identified: adhesion, immune and molecular. The adhesion layer divided patients into high and low adhesion groups, with prognostic value. The immune layer divided patients into immune-high and immune-low groups, according to the expression of immune-related genes. The molecular layer established four molecular groups related to stem cells, metabolism, Wnt signalling pathway and extracellular functions. Immune-high patients, with a higher expression of immune-related genes and genes involved in viral mimicry response may be benefit for immunotherapy and viral mimicry-related therapies. Additionally, several possible therapeutic targets have been identified in each molecular group. Therefore, this improved CRC classification could be useful for searching new therapeutic targets and specific therapeutic strategies in CRC disease.

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“…Regulated genes that shared up or downregulation in CNS vs spleen lymphoma cells originating from both PCNSL and SCNSL are potential candidates for a role in CNS lymphoma pathogenesis and tropism. Regenerating islet‐derived type 4 ( REG4 ) showed a 2.3‐fold (PCNSL) and 3.5‐fold (SCNSL) upregulation in CNS vs spleen lymphoma cells and has been described to promote invasion and migration of cancer cells in various human cancers [66]. Recently, REG4 was found to interact with the CD44 receptor, which then can activate the transcription of pro‐proliferative, pro‐metastatic and anti‐apoptotic genes [67].…”

Section: Discussionmentioning

confidence: 99%

Patient‐derived xenograft mouse models to investigate tropism to the central nervous system and retina of primary and secondary central nervous system lymphoma

Isbell

Tschuch

Doostkam

et al. 2023

Neuropathology Appl Neurobio

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Aims How and why lymphoma cells home to the central nervous system and vitreoretinal compartment in primary diffuse large B‐cell lymphoma of the central nervous system remain unknown. Our aim was to create an in vivo model to study lymphoma cell tropism to the central nervous system. Methods We established a patient‐derived central nervous system lymphoma xenograft mouse model and characterised xenografts derived from four primary and four secondary central nervous system lymphoma patients using immunohistochemistry, flow cytometry and nucleic acid sequencing technology. In reimplantation experiments, we analysed dissemination patterns of orthotopic and heterotopic xenografts and performed RNA sequencing of different involved organs to detect differences at the transcriptome level. Results We found that xenografted primary central nervous system lymphoma cells home to the central nervous system and eye after intrasplenic transplantation, mimicking central nervous system and primary vitreoretinal lymphoma pathology, respectively. Transcriptomic analysis revealed distinct signatures for lymphoma cells in the brain in comparison to the spleen as well as a small overlap of commonly regulated genes in both primary and secondary central nervous system lymphoma. Conclusion This in vivo tumour model preserves key features of primary and secondary central nervous system lymphoma and can be used to explore critical pathways for the central nervous system and retinal tropism with the goal to find new targets for novel therapeutic approaches.

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The Clinical Significance and Mechanisms of REG4 in Human Cancers

Cited by 13 publications

References 87 publications

Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy

Human Tumor Targeted Cytotoxic Mast Cells for Cancer Immunotherapy

A novel molecular analysis approach in colorectal cancer suggests new treatment opportunities

Patient‐derived xenograft mouse models to investigate tropism to the central nervous system and retina of primary and secondary central nervous system lymphoma

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