Faculty Opinions recommendation of OVOL2, an Inhibitor of WNT Signaling, Reduces Invasive Activities of Human and Mouse Cancer Cells and Is Down-regulated in Human Colorectal Tumors.

ABSTRACT Despite important advances in understanding the molecular basis of cancer, few treatments have been devised which rationally target known causal oncogenic defects. Selectively replicating viruses have a major advantage over nonreplicating viruses to target these defects because the therapeutic effect of the injected virus is augmented by virus produced within the tumor. To permit rational targeting of colon tumors, we have developed replicating adenoviruses that express the viral E1B and E2 genes from promoters controlled by the Tcf4 transcription factor. Tcf4 is constitutively activated by mutations in the adenomatous polyposis coli and β-catenin genes in virtually all colon tumors and is constitutively repressed by Groucho and CtBP in normal tissue. The Tcf-E2 and Tcf-E1B promoters are active in many, but not all, cell lines with activation of the wnt pathway. Viruses with Tcf regulation of E2 expression replicate normally in SW480 colon cancer cells but show a 50- to 100-fold decrease in replication in H1299 lung cancer cells and WI38 normal fibroblasts. Activation of wnt signaling by transduction of a stable β-catenin mutant into normal fibroblasts renders the cells permissive for virus replication. Insertion of Tcf4 sites in the E1B promoter has only small effects on replication in vitro but significantly reduces the inflammatory response in a rodent lung model in vivo. Replicating adenoviruses with Tcf regulation of both E1B and E2 transcription are potentially useful for the treatment of liver metastases from colorectal tumors, but additional changes will be required to produce a virus that can be used to treat all colon tumors.

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Faculty Opinions recommendation of Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1016828.204353 ◽

2004 ◽

Author(s):

Gerald Spangrude

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Wnt Signaling ◽

Embryonic Stem ◽

Specific Inhibitor ◽

Mouse Embryonic Stem Cells ◽

Human And Mouse

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89Zr anti-CD44 immuno-PET monitors CD44 expression on splenic myeloid cells and HT29 colon cancer cells

Scientific Reports ◽

10.1038/s41598-021-83496-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jin Won Park ◽

Kyung-Ho Jung ◽

Jin Hee Lee ◽

Seung Hwan Moon ◽

Young Seok Cho ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Nude Mice ◽

Myeloid Cells ◽

Human Antibody ◽

Tumor Uptake ◽

Colon Cancer Cells ◽

Cell Surface Glycoprotein ◽

Cd44 Expression ◽

Human And Mouse

AbstractCD44 is a cell-surface glycoprotein involved in cell–cell interaction, adhesion, and migration. CD44 is found on colon cancer cells and on immune cells. Previous studies of 89Zr PET imaging of CD44 have relied on an anti-human antibody (Ab), which can influence biodistribution in murine models. In this study, we used an Ab that cross-reacts with both human and mouse origin CD44 of all isoforms to unveil the type of leukocyte responsible for high splenic anti-CD44 uptake and investigate how its regulation can influence tumor immuno-PET. The Ab was site-specifically labeled with 89Zr-deferoxamine on cysteine residues. 89Zr-anti-CD44 demonstrated high-specific binding to HT29 human colon cancer cells and monocytic cells that showed CD44 expression. When 89Zr-anti-CD44 was administered to Balb/C nude mice, there was remarkably high splenic uptake but low SNU-C5 tumor uptake (1.2 ± 0.7%ID/g). Among cells isolated from Balb/C mouse spleen, there was greater CD44 expression on CD11b positive myeloid cells than lymphocytes. In cultured monocytic and macrophage cells, LPS stimulation upregulated CD44 expression and increased 89Zr-anti-CD44 binding. Similarly, normal Balb/C mice that underwent lipopolysaccharide (LPS) stimulation showed a significant upregulation of CD44 expression on splenic myeloid cells. Furthermore, LPS treatment stimulated a 2.44-fold increase of 89Zr-anti-CD44 accumulation in the spleen, which was attributable to splenic myeloid cells. Finally, in Balb/C nude mice bearing HT29 tumors, we injected 89Zr-anti-CD44 with greater Ab doses to reduce binding to splenic cells. The results showed lower spleen uptake and improved tumor uptake (2.9 ± 1.3%ID/g) with a total of 300 μg of Ab dose, and further reduction of spleen uptake and greater tumor uptake (5.7 ± 0.0%ID/g) with 700 μg Ab dose. Thus, using an 89Zr labeled Ab that cross-reacts with both human and mouse CD44, we demonstrate that CD44 immuno-PET has the capacity to monitor CD44 regulation on splenic myeloid cells and may also be useful for imaging colon tumors.

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Resolvin D1 reduces cancer growth stimulating a protective neutrophil-dependent recruitment of anti-tumor monocytes

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01937-3 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Domenico Mattoscio ◽

Elisa Isopi ◽

Alessia Lamolinara ◽

Sara Patruno ◽

Alessandro Medda ◽

...

Keyword(s):

Cancer Cells ◽

Growth Curve ◽

Immune Cells ◽

Cancer Growth ◽

Resolvin D1 ◽

Anti Cancer ◽

Classical Monocytes ◽

Human And Mouse

Abstract Background Innovative therapies to target tumor-associated neutrophils (PMN) are of clinical interest, since these cells are centrally involved in cancer inflammation and tumor progression. Resolvin D1 (RvD1) is a lipid autacoid that promotes resolution of inflammation by regulating the activity of distinct immune and non-immune cells. Here, using human papilloma virus (HPV) tumorigenesis as a model, we investigated whether RvD1 modulates PMN to reduce tumor progression. Methods Growth-curve assays with multiple cell lines and in vivo grafting of two distinct HPV-positive cells in syngeneic mice were used to determine if RvD1 reduced cancer growth. To investigate if and how RvD1 modulates PMN activities, RNA sequencing and multiplex cytokine ELISA of human PMN in co-culture with HPV-positive cells, coupled with pharmacological depletion of PMN in vivo, were performed. The mouse intratumoral immune cell composition was evaluated through FACS analysis. Growth-curve assays and in vivo pharmacological depletion were used to evaluate anti-tumor activities of human and mouse monocytes, respectively. Bioinformatic analysis of The Cancer Genome Atlas (TCGA) database was exploited to validate experimental findings in patients. Results RvD1 decreased in vitro and in vivo proliferation of human and mouse HPV-positive cancer cells through stimulation of PMN anti-tumor activities. In addition, RvD1 stimulated a PMN-dependent recruitment of classical monocytes as key determinant to reduce tumor growth in vivo. In human in vitro systems, exposure of PMN to RvD1 increased the production of the monocyte chemoattractant protein-1 (MCP-1), and enhanced transmigration of classical monocytes, with potent anti-tumor actions, toward HPV-positive cancer cells. Consistently, mining of immune cells infiltration levels in cervical cancer patients from the TCGA database evidenced an enhanced immune reaction and better clinical outcomes in patients with higher intratumoral monocytes as compared to patients with higher PMN infiltration. Conclusions RvD1 reduces cancer growth by activating PMN anti-cancer activities and encouraging a protective PMN-dependent recruitment of anti-tumor monocytes. These findings demonstrate efficacy of RvD1 as an innovative therapeutic able to stimulate PMN reprogramming to an anti-cancer phenotype that restrains tumor growth.

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MicroRNA-154 Inhibits the Growth and Invasion of Gastric Cancer Cells by Targeting DIXDC1/WNT Signaling

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504017x15016337254632 ◽

2018 ◽

Vol 26 (6) ◽

pp. 847-856 ◽

Cited By ~ 9

Author(s):

Jifu Song ◽

Zhibin Guan ◽

Maojiang Li ◽

Sha Sha ◽

Chao Song ◽

...

Keyword(s):

Gastric Cancer ◽

Wnt Signaling ◽

Cancer Cells ◽

Quantitative Polymerase Chain Reaction ◽

Inverse Correlation ◽

Inhibitory Effect ◽

Luciferase Reporter ◽

Gastric Cancer Cells ◽

Cancer Cell Growth ◽

Cancer Tissues

MicroRNAs (miRNAs) have emerged as pivotal regulators of the development and progression of gastric cancer. Studies have shown that miR-154 is a novel cancer-associated miRNA involved in various cancers. However, the role of miR-154 in gastric cancer remains unknown. Here we aimed to investigate the biological function and the potential molecular mechanism of miR-154 in gastric cancer. We found that miR-154 was significantly downregulated in gastric cancer tissues and cell lines. The overexpression of miR-154 significantly repressed the growth and invasion of gastric cancer cells. Bioinformatics analysis and Dual-Luciferase Reporter Assay data showed that miR-154 directly targeted the 3′-untranslated region of Dishevelled‐Axin domain containing 1 (DIXDC1). Real-time quantitative polymerase chain reaction and Western blot analyses showed that miR-154 overexpression inhibited DIXDC1 expression. An inverse correlation of miR-154 and DIXDC1 was also demonstrated in gastric cancer specimens. Overexpression of miR-154 also significantly suppressed the activation of WNT signaling. Moreover, restoration of DIXDC1 expression significantly reversed the inhibitory effect of miR-154 overexpression on the cell proliferation, invasion, and WNT signaling in gastric cancer cells. Overall, these results suggest that miR-154 inhibits gastric cancer cell growth and invasion by targeting DIXDC1 and could serve as a potential therapeutic target for the treatment of gastric cancer.

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