buparlisib and Cell-Transformation--Neoplastic

Chronic inflammation is an important process leading to tumorigenesis. Therefore, targeting and controlling inflammation can be a promising cancer therapy. Inflammation is often caused by a variety of inflammatory cytokine such as the interleukin (IL)-6, a pleiotrophic cytokine known to be involved in the tumorigenesis. In this study, an in vivo hepatic tumorigenesis model of zebrafish was generated to demonstrate a direct consequence of the human IL6 expression causing hepatocarcinogenesis. To do this, an elevated expression of the hIL6 gene was established to specifically target the zebrafish hepatocytes by transgenesis. Interestingly, the elevated hIL6 expression caused the chronic inflammation which results in a massive infiltration of inflammatory cells. This eventually resulted in the generation of various dysplastic lesions such as clear cell, small cell, and large cell changes, and also eosinophilic and basophilic foci of hepatocellular alteration. Hepatocellular carcinoma was then developed in the transgenic zebrafish. Molecular characterization revealed upregulation of the downstream components involved in the IL6-mediated signaling pathways, especially PI3K/Akt and JAK/STAT3 pathways. Further investigation indicated that PI3K was the most reactive to the infiltrated inflammatory cells and dysplasia with large cell change, whereas STAT3 was heavily activated in the region with dysplastic foci, suggesting that the JAK/STAT3 pathway was mainly implicated in the hepatic tumorigenesis in the current model. Our present study provides an in vivo evidence of the relationship between chronic inflammation and tumorigenesis and reinforces the pivotal role of IL6 in the inflammation-associated hepatocarcinogenesis.

Topics: Aminopyridines; Animals; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cyclic S-Oxides; Disease Models, Animal; Enzyme Activation; Humans; Inflammation; Interleukin-6; Janus Kinases; Liver; Liver Neoplasms; Morpholines; Niclosamide; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction; STAT3 Transcription Factor; Zebrafish; Zebrafish Proteins

Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit overexpression or amplification of the MYC oncogene (c-MYC) usually have an extremely poor prognosis, but there are no animal models of this subtype of the disease. Here, we show that cerebellar stem cells expressing Myc and mutant Trp53 (p53) generate aggressive tumors following orthotopic transplantation. These tumors consist of large, pleiomorphic cells and resemble human MYC-driven MB at a molecular level. Notably, antagonists of PI3K/mTOR signaling, but not Hedgehog signaling, inhibit growth of tumor cells. These findings suggest that cerebellar stem cells can give rise to MYC-driven MB and identify a novel model that can be used to test therapies for this devastating disease.

Topics: Aminopyridines; Animals; Cell Proliferation; Cell Transformation, Neoplastic; Cerebellar Neoplasms; Cerebellum; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Genes, p53; Imidazoles; Medulloblastoma; Mice; Morpholines; Neural Stem Cells; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Quinolines; TOR Serine-Threonine Kinases