Exosomes participate in cancer progression and metastasis by transferring bioactive molecules between cancer and various cells in the local and distant microenvironments. Such intercellular ...cross‐talk results in changes in multiple cellular and biological functions in recipient cells. Several hallmarks of cancer have reportedly been impacted by this exosome‐mediated cell‐to‐cell communication, including modulating immune responses, reprogramming stromal cells, remodeling the architecture of the extracellular matrix, or even endowing cancer cells with characteristics of drug resistance. Selectively, loading specific oncogenic molecules into exosomes highlights exosomes as potential diagnostic biomarkers as well as therapeutic targets. In addition, exosome‐based drug delivery strategies in preclinical and clinical trials have been shown to dramatically decrease cancer development. In the present review, we summarize the significant aspects of exosomes in cancer development that can provide novel strategies for potential clinical applications.
Exosomes in cancer development.
Focal adhesion kinase (FAK) is a cytoplasmic nonreceptor tyrosine kinase that enables activation by growth factor receptors or integrins in various types of human cancers. The kinase-dependent and ...kinase-independent scaffolding functions of FAK modulate the authentic signaling and fundamental functions not only in cancer cells but also in tumor microenvironment to facilitate cancer progression and metastasis. The overexpression and activation of FAK are usually investigated in primary or metastatic cancers and correlated with the poor clinical outcome, highlighting FAK as a potential prognostic marker and anticancer target. Small molecule inhibitors targeting FAK kinase activity or FAK-scaffolding functions impair cancer development in preclinical or clinical trials. In this review, we give an overview for FAK signaling in cancer cells as well as tumor microenvironment that provides new strategies for the invention of cancer development and malignancy.
Extracellular vesicle (EV)-mediated intercellular communication acts as a critical culprit in cancer development. The selective packaging of oncogenic molecules renders tumor-derived EVs capable of ...altering the tumor microenvironment and thereby modulating cancer developments that may contribute to drug resistance and cancer recurrence. Moreover, the molecular and functional characteristics of cancer through its development and posttreatment evolve over time. Tumor-derived EVs are profoundly involved in this process and can, therefore, provide valuable real-time information to reflect dynamic changes occurring within the body. Because they bear unique molecular profiles or signatures, tumor-derived EVs have been highlighted as valuable diagnostic and predictive biomarkers as well as novel therapeutic targets. In addition, the use of an advanced EV-based drug delivery system for cancer therapeutics has recently been emphasized in both basic and clinical studies. In this review, we highlight comprehensive aspects of tumor-derived EVs in oncogenic processes and their potential clinical applications.
Tea is one of the most popular beverages across the world and is made exclusively from cultivars of Camellia sinensis. Many wild relatives of the genus Camellia that are closely related to C. ...sinensis are native to Southwest China. In this study, we first identified the distinct genetic divergence between C. sinensis and its wild relatives and provided a glimpse into the artificial selection of tea plants at a genome-wide level by analyzing 15,444 genomic SNPs that were identified from 18 cultivated and wild tea accessions using a high-throughput genome-wide restriction site-associated DNA sequencing (RAD-Seq) approach. Six distinct clusters were detected by phylogeny inferrence and principal component and genetic structural analyses, and these clusters corresponded to six Camellia species/varieties. Genetic divergence apparently indicated that C. taliensis var. bangwei is a semi-wild or transient landrace occupying a phylogenetic position between those wild and cultivated tea plants. Cultivated accessions exhibited greater heterozygosity than wild accessions, with the exception of C. taliensis var. bangwei. Thirteen genes with non-synonymous SNPs exhibited strong selective signals that were suggestive of putative artificial selective footprints for tea plants during domestication. The genome-wide SNPs provide a fundamental data resource for assessing genetic relationships, characterizing complex traits, comparing heterozygosity and analyzing putatitve artificial selection in tea plants.
A subpopulation of cancer stem cells (CSCs) plays a critical role of cancer progression, recurrence, and therapeutic resistance. Many studies have indicated that castration-resistant prostate cancer ...(CRPC) is associated with stem cell phenotypes, which could further promote neuroendocrine transdifferentiation. Although only a small subset of genetically pre-programmed cells in each organ has stem cell capability, CSCs appear to be inducible among a heterogeneous cancer cell population. However, the inductive mechanism(s) leading to the emergence of these CSCs are not fully understood in CRPC. Tumor cells actively produce, release, and utilize exosomes to promote cancer development and metastasis, cancer immune evasion as well as chemotherapeutic resistance; the impact of tumor-derived exosomes (TDE) and its cargo on prostate cancer (PCa) development is still unclear. In this study, we demonstrate that the presence of Cav-1 in TDE acts as a potent driver to induce CSC phenotypes and epithelial-mesenchymal transition in PCa undergoing neuroendocrine differentiation through NFκB signaling pathway. Furthermore, Cav-1 in mCRPC-derived exosomes is capable of inducing radio- and chemo-resistance in recipient cells. Collectively, these data support Cav-1 as a critical driver for mCRPC progression.
Neuroblastoma is the most common malignant disease of infancy, and amplification of the
oncogene is closely associated with poor prognosis. Recently, expression of MYCN was shown to be inversely ...correlated with aryl hydrocarbon receptor (AHR) expression in neuroblastoma, and overexpression of AHR downregulated MYCN expression, promoting cell differentiation. Therefore, we further investigated the potential of AHR to serve as a prognostic indicator or a therapeutic target in neuroblastoma. First, the clinical significance of AHR in neuroblastoma was examined. Positive AHR immunostaining strongly correlated with differentiated histology of neuroblastoma and predicted better survival for patients. The mouse xenograft model showed that overexpression of AHR significantly suppressed neuroblastoma tumor growth. In addition, activation of AHR by the endogenous ligand kynurenine inhibited cell proliferation and promoted cell differentiation
and
. kynurenine treatment also upregulated the expression of
, a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Finally, analysis of
levels in neuroblastoma patient tumors using the R2: Genomics Analysis and Visualization Platform revealed that
expression positively correlated with
, and high
expression predicted better survival for patients. In conclusion, our results indicate that AHR is a novel prognostic biomarker for neuroblastoma, and that overexpression or activation of AHR offers a new therapeutic possibility for patients with neuroblastoma. SIGNIFICANCE: These findings show that AHR may function as a tumor suppressor in childhood neuroblastoma, potentially influencing the aetiologic and therapeutic targeting of the disease.
High expression of either β4 integrin or focal adhesion kinase (FAK) has been reported in human colon cancer. However, it remains unclear how β4 integrin together with FAK contributes to the ...tumorigenicity of colon cancer. Here, we demonstrate that the co‐overexpression of β4 integrin and FAK positively correlates with advanced stages of human colon cancer. Activated β4 integrin interacts with FAK and subsequently induces FAK phosphorylation at Tyr397. Furthermore, ablation of the β4 integrin/FAK complex and/or FAK activation impair colon cancer cell proliferation, anchorage‐independent growth, and tumorigenicity. Our data indicate that the β4 integrin/FAK complex and subsequent FAK activation are essential regulators during the tumorigenicity of colon cancer, and we suggest an alternative strategy for colon cancer therapy.
Multiple types of stem cells have been proposed for the treatment of spinal cord injury, but their comparative information remains elusive. In this study, a rat model of T10 contusion spinal cord ...injury was established by the impactor method. Human umbilical cord-derived mesenchymal stem cells (UCMSCs) or human adipose tissue-derived mesenchymal stem cells (ADMSCs) (2.5 μL/injection site, 1 × 105 cells/μL) was injected on rostral and caudal of the injury segment on the ninth day after injury. Rats injected with mesenchymal stem cell culture medium were used as controls. Our results show that although transplanted UCMSCs and ADMSCs failed to differentiate into neurons or glial cells in vivo, both significantly improved motor and sensory function. After spinal cord injury, UCMSCs and ADMSCs similarly promoted spinal neuron survival and axonal regeneration, decreased glial scar and lesion cavity formation, and reduced numbers of active macrophages. Bio-Plex analysis of spinal samples showed a specific increase of interleukin-10 and decrease of tumor necrosis factor α in the ADMSC group, as well as a downregulation of macrophage inflammatory protein 3α in both UCMSC and ADMSC groups at 3 days after cell transplantation. Upregulation of interleukin-10 and interleukin-13 was observed in both UCMSC and ADMSC groups at 7 days after cell transplantation. Isobaric tagging for relative and absolute quantitation proteomics analyses showed that UCMSCs and ADMSCs induced changes of multiple genes related to axonal regeneration, neurotrophy, and cell apoptosis in common and specific manners. In conclusion, UCMSC and ADMSC transplants yielded quite similar contributions to motor and sensory recovery after spinal cord injury via anti-inflammation and improved axonal growth. However, there were some differences in cytokine and gene expression induced by these two types of transplanted cells. Animal experiments were approved by the Laboratory Animal Ethics Committee at Jinan University (approval No. 20180228026) on February 28, 2018, and the application of human stem cells was approved by the Medical Ethics Committee of Medical College of Jinan University of China (approval No. 2016041303) on April 13, 2016.
Objective:
It has been reported that antroquinonol extracted from Golden-
Antrodia camphorate
exerts protective effects on liver function both
in vitro and in vivo
. However, the protective effects ...of Golden-
Antrodia camphorata
on liver function have not been fully investigated in human clinical studies. Therefore, the present study aimed to evaluate the beneficial effects of Golden-
Antrodia camphorata
on hepatic function after alcohol consumption in human subjects.
Methods:
A total of 80 participants with increased γ-glutamyl transferase levels (60–180 U/L) were enrolled in the current study and were randomly divided into two groups. Participants in the first group were orally administrated with 300 mg/day Golden-
Antrodia camphorata
(tablets), while those in the second group received placebo tablets for 12 weeks. Biochemical routine blood tests were performed at 6 and 12 weeks following the first administration.
Results:
At 12 weeks post the first Golden-
Antrodia camphorata
administration, the serum levels of aspartate aminotransferase (AST;
p
< 0.0001), alanine aminotransferase (ALT;
p
= 0.0002) and triglyceride (
p
= 0.0158) were notably declined in the Golden-
Antrodia camphorata
treatment group compared with the placebo group. No clinically significant differences were observed between the Golden-
Antrodia camphorata
treatment and placebo groups in terms of general safety parameters.
Conclusion:
A statistically significant difference was obtained in the serum levels of AST, ALT and triglycerides between the Golden-
Antrodia camphorata
and placebo groups. However, no clinical significance was observed in any of the safety parameters examined. Overall, these findings indicated that treatment with Golden-
Antrodia camphorata
exerted protective effects on liver function.
Growth factor receptor bound protein-7 (Grb7) is a multi-domain adaptor protein that is co-opted by numerous tyrosine kinases involved in various cellular signaling and functions. The molecular ...mechanisms underlying the regulation of Grb7 remain unclear. Here, we revealed a novel negative post-translational regulation of Grb7 by the peptidyl-prolyl cis/trans isomerase, Pin1. Our data show that phosphorylation of Grb7 protein on the Ser194-Pro motif by c-Jun N-terminal kinase facilitates its binding with the WW domain of Pin1. Subsequently, Grb7 is degraded by the ubiquitin- and proteasome-dependent proteolytic pathway. Indeed, we found that Pin1 exerts its peptidyl-prolyl cis/trans isomerase activity in the modulation of Grb7 protein stability in regulation of cell cycle progression at the G2-M phase. This study illustrates a novel regulatory mechanism in modulating Grb7-mediated signaling, which may take part in pathophysiological consequences.
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