Molecular signatures of mesenchymal stem cell-derived extracellular vesicle-mediated tissue repair

AbstractExtracellular vesicles (EVs) play important roles in intercellular communications via their content molecules, and mimic, at least in part, the roles that are played by their originating cells. Consistent with this notion, an increasing number of reports have suggested that EVs derived from mesenchymal stem cells (MSCs), which are therapeutically beneficial to a wide range of diseases, can serve as drugs to treat multiple diseases. EVs contain a variety of molecules, including proteins, microRNAs, and mRNAs, and are associated with biological processes in a content molecule-dependent manner. In this article, we review the latest reports regarding the therapeutic potential of MSC-EVs by focusing on the underlying molecular mechanisms of their effects. Specifically, we feature the effects of MSC-EVs in terms of their content molecules and of the tissue recovery processes endowed by these molecules.</jats:p

The Biological Role and Clinical Implication of MicroRNAs in Osteosarcoma

The main causes of death in osteosarcoma (OS) patients are the development of distant metastasis and resistance to chemotherapy. Clarification of the pathophysiological molecular mechanisms that contribute to the malignant phenotype in OS and identification of a molecular target, such as a diagnostic marker, prognostic predictor, or chemosensitivity sensor, are strongly desired to develop therapeutics for OS patients. Accumulating evidence has demonstrated that microRNAs (miRNAs), small endogenous single‐stranded noncoding RNAs, play critical roles not only in biological but also pathological processes such as cancer. miRNAs can function as oncogenes or tumor‐suppressive genes depending on the mRNA they target. They are strongly associated with OS invasion, metastasis, and chemoresistance as well as OS cancer stemness. Furthermore, miRNAs are associated with commonly altered genes, such as TP53 and RB1. Additionally, recent global microRNA expression analyses have identified specific miRNAs correlated with the clinical stage and the response to chemotherapy. In this chapter, we summarize the current understanding of the pathological roles of miRNAs as well as their potential utility as OS biomarkers

Epigenetic therapy in urologic cancers: an update on clinical trials

Epigenetic dysregulation is one of many factors that contribute to cancer development and progression. Numerous epigenetic alterations have been identified in urologic cancers including histone modifications, DNA methylation changes, and microRNA expression. Since these changes are reversible, efforts are being made to develop epigenetic drugs that restore the normal epigenetic patterns of cells, and many clinical trials are already underway to test their clinical potential. In this review we analyze multiple clinical trials (n=51) that test the efficacy of these drugs in patients with urologic cancers. The most frequently used epigenetic drugs were histone deacetylase inhibitors followed by antisense oligonucleotides, DNA methyltransferase inhibitors and histone demethylase inhibitors, the last of which are only being tested in prostate cancer. In more than 50% of the clinical trials considered, epigenetic drugs were used as part of combination therapy, which achieved the best results. The epigenetic regulation of some cancers is still matter of research but will undoubtedly open a window to new therapeutic approaches in the era of personalized medicine. The future of therapy for urological malignancies is likely to include multidrug regimens in which epigenetic modifying drugs will play an important role

Silencing of S100A4, a metastasis-associated protein, in endothelial cells inhibits tumor angiogenesis and growth

Endothelial cells express S100A4, a metastasis-associated protein, but its role in angiogenesis remains to be elucidated. Here we show that knockdown of S100A4 in mouse endothelial MSS31 cells by murine specific small interference RNA (mS100A4 siRNA) markedly suppressed capillary-like tube formation in vitro, in early stage after the treatment, along with down- and up-regulation of some of the pro-angiogenic and anti-angiogenic gene expression, respectively. Of particular note is that intra-tumor administration of the mS100A4 siRNA in a human prostate cancer xenograft significantly reduced tumor vascularity and resulted in the inhibition of tumor growth. These findings show that S100A4 in endothelial cells is involved in tube formation, and suggest its potential as a molecular target for inhibiting tumor angiogenesis, which warrants further development of endothelial S100A4-based strategies for cancer treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10456-013-9372-7) contains supplementary material, which is available to authorized users

Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention

The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstream HER2 has been associated with breast cancer initiating cells (CICs) and in some cases resistance to treatment. The anti-diabetes drug metformin can suppress the growth of breast CICs and herceptin-resistant HER2+ cells. This review will discuss the importance of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but will also include relevant examples from other cancer types. The targeting of this pathway will be discussed as well as clinical trials with novel small molecule inhibitors. The targeting of the hormone receptor, HER2 and EGFR1 in breast cancer will be reviewed in association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway.USAMRMC {[}BC022276]; Intramural RECDA Award; Italian Association for Cancer Research (AIRC); MIUR-PRIN; Italian MIUR-FIRB Accordi di Programma; Italian ``Ministero dell'Istruzione, dell'Universita e della Ricerca (Ministry for Education, Universities and Research) - FIRB-MERIT {[}RBNE08YYBM]; Italian Ministry of Economy and Finance; Italian Ministry of Health, Ricerca Finalizzata Stemness; MIUR FIRB {[}RBAP11ZJFA\_001]; CRO; Italian Association for Cancer Research, (AIRC) (RM PI); Italian Association for Cancer Research, (AIRC) {[}MCO10016]; Italian Ministry of Health; Regione Friuli Venezia-Giuli