Inflammation-Associated Cytotoxic Agents in Tumorigenesis

Oncocytic cell tumours (OCTs), formerly known as Hürthle cell tumours in thyroid, are a subset of thyroid and other endocrine neoplasms that present diagnostic and therapeutic challenges due to their variable clinical behaviour. Considering the limited exploration of transcriptomic and proteomic profiles of OCTs compared to MRNs in the literature, we conducted RNA and protein sequencing on 12 OCTs (5 oncocytic adenomas and 7 oncocytic carcinomas) and 6 MRNs, based on the fact that oncocytic morphology alone does not determine biological behavior. RNA sequencing data analysis revealed the presence of 47 downregulated and 38 upregulated differentially expressed genes (DEGs) in OCTs when compared to MRNs. Significant signalling pathways affecting OCTs were associated with the heme metabolism. Protein sequencing data analysis showed the presence of 20 underexpressed and 64 overexpressed differentially expressed proteins (DEPs) in OCTs than in MRNs, and all of the OCAs were found to cluster together, constituting a distinct cluster than the one comprising the MRNs. The majority of DEPs affected three major cellular pathways in OCTs, including epigenetic modifications, tumor microenvironment, and protein biogenesis, that may shape the behavior and morphology of these tumors. Hence, further research into these mechanisms and their impact on tumour phenotype and behaviour may lead to better diagnostic and therapeutic strategies for patients with OCTs.

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Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer model

Napp,

Siebel,

Rausch

et al. 2024

Front. Oncol.

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by its poor prognosis. Traditional Japanese herbal medicine (Kampo), such as Juzentaihoto (a standardized combination of 10 herbal extracts), has shown immune modulatory effects, modulation of microcirculation, and amelioration of fatigue. It is administered to patients to prevent deterioration of cachexia and counteract side effects of chemotherapy. The effect of Juzentaihoto with or without standard chemotherapy (Gemcitabine) on survival and tumor microenvironment was studied in an immunocompetent pancreatic cancer mouse model. Following tumor development ±12 days after orthotopic implantation of murine pancreatic cancer cells (KPC) into the pancreas of C57BL/6 mice, the mice were treated with Gemcitabine, Juzentaihoto, their combination (Gem/Juz) or NaCl (Ctr.). Combination treatment significantly prolonged survival (+38%) of tumor bearing mice, compared to controls as well as Gemcitabine or Juzentaihoto monotherapy. Macrophage (CD68+) infiltration in pancreatic tumors was significantly enhanced in Gem/Juz – treated animals, compared with controls (p < 0,001), with significant increases of both, macrophages (CD68+) and for lymphocytes (CD45+), especially at the tumor front. In vitro, Juz- or Gem/Juz-treated KPC tumor cells secreted significantly more macrophage-chemoattractant cytokines, e.g., CCL2, CCL20, and CXCL2, whilst Juz- and Gem/Juz-treated macrophages (MH-S) secreted cytokines of the M1 phenotype, e.g., IL6, TNF-α, and IL12. It has been shown that tumor cells recruit and polarize macrophages towards tumor-associated macrophages (TAM). Our results indicate a change in macrophage polarization which not only induced anti-tumor immune-cell activity and cytokine release, but also suggests amelioration of Gemcitabine efficacy as DNA-analogue and as partial antitumor antigen. We propose that the increased survival of tumor bearing mice after Gem/Juz combination treatment is due to the restored cytotoxicity of Gemcitabine and changes in the tumor-microenvironment - induced by Juzentaihoto - such as an increased number of M1 macrophages.

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Inflammation-Associated Cytotoxic Agents in Tumorigenesis

Cited by 3 publications

References 424 publications

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Inflammatory factor TNFα-induced circDMD mediates R-loop formation to promote tumorigenesis

Unravelling the Tumourigenesis Mechanisms of Oncocytic Cell Tumours: Discoveries from a Comparative Omics Study

Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer model

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