An antisense oligonucleotide targeting TGF-β2 inhibits lung metastasis and induces CD86 expression in tumor-associated macrophages

Huber-Ruano, Isabel; Raventós, C.; Cuartas, Isabel; Sánchez-Jaro, C.; Arias, Adelis; Parra, Josep-Lluís; Wosikowski, Katja; Janicot, Michel; Seoane, Joan

doi:10.1093/annonc/mdx314

Cited by 20 publications

(22 citation statements)

References 21 publications

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“…Understanding how tumor cells communicate with and control the microenvironment will assist in discovering why patients with osteosarcoma have shown little or no response to immunotherapy and may help in designing combination approaches to block this pathway during immunotherapy. The data from this study together with our previously published data showing that M1 macrophages are critical in the antitumor response to anti-PD-1 30 as well as previously published data indicating that the inhibition of TGFB2 can reeducate M1 macrophages to an M2 phenotype 39 suggest that targeting TGFB2 may improve macrophage M1 function and response to treatment by redirecting tumor-associated macrophages from the M2 to the M1 phenotype.…”

Section: Discussionsupporting

confidence: 78%

“…29,38 When TGFB2 was inhibited through the use of an antisense oligonucleotide, lung metastases of breast and kidney tumors were reduced in part through the reeducation of M2 macrophages to the M1 antitumor phenotype. 39 Furthermore, TGFB1 and TGFB2 were found to be differentially regulated in central nervous system and peripheral nerve injury, and TGFB2 was the principal cytokine that controlled microglia and macrophage phagocytic function, rather than TGFB1. 40 Finally, exosomes produced by mesenchymal stem cells have been shown to contain TGFB and drive differentiation of myeloid cells to an immunosuppressive M2 phenotype in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

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Exosomal communication by metastatic osteosarcoma cells modulates alveolar macrophages to an M2 tumor-promoting phenotype and inhibits tumoricidal functions

2020

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Exosomal communication by metastatic osteosarcoma cells modulates alveolar macrophages to an M2 tumor-promoting phenotype and inhibits tumoricidal functions

2020

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“…These were engineered as 17-mer full phosphorothioate LNA-modified antisense oligodeoxynucleotides ‘4+4’ gapmers (primary sequence in online supplementary figure 4). As published by Huber-Ruano et al ,30 after subcutaneous (s.c.) injection, the AONs rapidly translocate from the blood circulation predominantly to livers (37.52% of total signal) and kidneys (38.06% of total signal) of wild-type mice where they are stably present for 2 weeks.…”

Section: Resultsmentioning

confidence: 83%

“…Based on drug delivery and safety testing data, we s.c. applied the AON or Co at a dose of 15 mg/kg body weight,29 30 to 14 weeks old MDR2-KO mice according to the protocol depicted in figure 3A. In untreated MDR2-KO mice, TgfB2 expression was markedly elevated as compared with wild-type animals (~8.7 fold).…”

Section: Resultsmentioning

confidence: 99%

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TGF-β2 silencing to target biliary-derived liver diseases

Dropmann

Dooley

Dewidar

et al. 2020

Gut

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ObjectiveTGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.DesignAs we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.ResultsTgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.ConclusionsTaken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.

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CT23 knockdown attenuating malignant behaviors of hepatocellular carcinoma cell is associated with upregulation of metallothionein 1

Ning

Huang

et al. 2021

Cell Biology International

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The cancer‐testis antigen 23 (CT23) gene has been reported in association with the pathogenesis and progress of hepatocellular carcinoma (HCC). However, the alterations of gene expression profiling induced by CT23 knockdown in HCC cells remains largely unknown. In this study, the RNA interfering (RNAi) method was used to silence CT23 expression in BEL‐7404 cells. Microarray analysis was performed on mRNA extracted from the CT23 knockdown cells and the control cells to determine the alterations of gene expression profiles. The result showed a total of 1051 genes expressed differentially (two‐fold change), including 470 genes upregulated and 581 gene downregulated in the CT23 knockdown cells. A bioinformatic analysis showed that the functional differentially expressed genes (DEGs) were linked to cell proliferation, migration, and apoptosis, and metallothionein 1 (MT1) attained the maximum enrichment scores in functional annotation, classification, and pathway analysis of DEGs. Furthermore, Western blot analysis and cell behaviors assays verified that CT23 modulates cell proliferation, migration, and apoptosis by regulating MT1 expression in HCC cells and non‐neoplastic hepatocytes. In summary, downregulated CT23 gene in BEL‐7404 cells might change the expressions of carcinogenesis and progression related genes in HCC by upregulating MT1 expression, which would provide insight into searching for a novel therapeutic target for HCC.

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An antisense oligonucleotide targeting TGF-β2 inhibits lung metastasis and induces CD86 expression in tumor-associated macrophages

Abstract: Overall, our data point to TGF-β2 as a therapeutic target and ISTH0047 as a novel anticancer drug to prevent lung metastasis by impacting on the tumor niche, in part, through the induction of CD86 in tumor-associated macrophages.

Cited by 20 publications

References 21 publications

Exosomal communication by metastatic osteosarcoma cells modulates alveolar macrophages to an M2 tumor-promoting phenotype and inhibits tumoricidal functions

Exosomal communication by metastatic osteosarcoma cells modulates alveolar macrophages to an M2 tumor-promoting phenotype and inhibits tumoricidal functions

TGF-β2 silencing to target biliary-derived liver diseases

CT23 knockdown attenuating malignant behaviors of hepatocellular carcinoma cell is associated with upregulation of metallothionein 1

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