The use of potent therapies inhibiting critical oncogenic pathways active in epithelial cancers has led to multiple resistance mechanisms including the development of highly aggressive, small cell neuroendocrine carcinoma (SCNC). SCNC patients have a dismal prognosis due in part to a limited understanding of the molecular mechanisms driving this malignancy and the lack of effective treatments. Here we demonstrate that a common set of defined oncogenic drivers reproducibly reprograms normal human prostate and lung epithelial cells to small cell prostate cancer (SCPC) and small cell lung cancer (SCLC), respectively. We identify shared active transcription factor binding regions in the reprogrammed prostate and lung SCNCs by integrative analyses of epigenetic and transcriptional landscapes. These results suggest that neuroendocrine cancers arising from distinct epithelial tissues may share common vulnerabilities that could be exploited for the development of drugs targeting SCNCs.
Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent cells characterized by their selfrenewal and differentiation potential. Accumulating clinical and preclinical evidence indicate MSCs are a promising cell source for regenerative medical therapies. However, undesirable immortalization, spontaneous transformation, and tumorigenic potential from long-term cultured MSCs have been reported in human and mouse. We report rat MSCs isolated from young donors could undergo transformation in early passage culture. We aimed to characterize the transformed population and determine their therapeutic effects after intracardiac transplantation in the infarcted myocardium. MSCs were isolated from bone marrow of Lewis rats according to standard protocols and cultured under standard conditions. Phenotype of growing cells was assessed by flow cytometry. Following acute myocardial infarction in rats, cells were delivered by intracardiac injection. Cardiac functions were assessed by pressure-volume loops. Infarction size and pathologic effects were evaluated after 6 weeks. The abnormal colonies were detected in culture as early at passage 3. They were noted to appear as distinctly different morphology from typical MSCs, which changed from a normal elongated spindle shape to a compact abnormal morphology. They exhibited rapid cell proliferation. Some subclones lost contact inhibition of cell division and formed multilayer aggregates. Chromosomal instability was detected. They were devoid of surface markers CD29, CD44, CD90, and CD117. Furthermore, there was no significant improvement on infarction size and cardiac function 6 weeks after cell transplantation. Our study highlights the need for establishment of biosafety criteria in regulating cultureexpanded MSCs to achieve the full clinical therapeutic benefits.
Anxa2 is the most studied member of the calcium-mediated phospholipid-binding protein family annexins and is a biomarker in cancers. In this review, we listed clinical findings and confirmed the value of Anxa2 in early diagnosis and prognostic prediction due to its overexpression and adverse effect on the outcome in most tumors. Anxa2 plays a pivotal role in cancer cell proliferation, migration, invasion, metastasis, and treatment resistance. Improved understanding of its cancer-promoting function might make it an ideal target for cancer therapy. Here, we systematically summarized the mechanism of Anxa2 in regulating epithelial-mesenchymal transition (EMT), cytoskeleton dynamicity, cell cycle, apoptosis, angiogenesis, and immunology by using various tumor models. These data emphasize the potential of Anxa2 for targeted intervention in tumors. Altering Anxa2 expression, neutralizing the cell surface Anxa2, or inhibiting its activation, such as through Tyr23 phosphorylation, could be considered based on the regulatory mechanism of Anxa2 in tumor progression.
We studied the expression of axin and beta-catenin and their relation to clinicopathologic factors in 100 non-small cell lung cancers (NSCLCs) by immunohistochemical analysis. The mutation in exon 3 of the beta-catenin gene was examined by polymerase chain reaction and direct sequencing. Preserved axin expression was significantly higher in well- and moderately differentiated NSCLC samples than in poorly differentiated ones. Reduced membranous expression of beta-catenin was shown in 80 cases, whereas 26 cases had aberrant nuclear expression. Poor differentiation and lymph node metastasis were associated significantly with reduced beta-catenin expression. Lower axin expression was related significantly to higher nuclear beta-catenin expression. However, this study failed to detect any exon 3 mutation in the beta-catenin gene in the 100 NSCLC samples. We conclude that reduced beta-catenin and axin expression might predict poor differentiation in NSCLC. Reduced axin expression, but not mutation in exon 3, might be an important explanation for the abnormal beta-catenin expression in NSCLC.
CD147, also known as extracellular matrix metalloproteinase inducer, is a widely distributed cell surface glycoprotein that belongs to the immunoglobulin superfamily. CD147 has been proved to be enriched on the surface of many tumor cells, promoting tumor growth, invasion and metastasis by its stimulation effect on adjacent fibroblasts to produce matrix metalloproteinases. In this study, we aimed to explore the expression pattern of CD147 in glioblastoma (GBM) and investigate whether it could be used to assess subsequent prognosis of patients. For that, we recruited a total of 206 patients with pathologically confirmed GBM and 36 normal control brain tissue specimens. The expression of CD147 in GBM and normal tissues was investigated by immunohistochemistry assay. Genetic factors including MGMT and IDH1 mutation were also investigated to justify the prognostic significance of CD147. Results showed that CD147 expression was increased in GBM compared with that in normal tissues. Kaplan-Meier analysis showed that increased CD147 expression was associated with poor overall survival of patients with GBM. Moreover, Cox's proportional hazards model revealed that CD147 expression was an independent and significant prognostic marker of overall survival in GBM patients. These results proved that CD147 expression was relatively abundant in GBM and can be potentially used to predict prognosis and treatment response in GBM patients.
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