Extracellular vesicles in Inter-Kingdom communication in gastrointestinal cancer

xlomafota13 shared this article with you from Inoreader Extracellular vesicles in Inter-Kingdom communication in gastrointestinal cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1087-1103. eCollection 2021. ABSTRACT The production and secretion of extracellular vesicles (EVs) are common features of cells (including various normal cells, neoplastic cell lines as well as bacteria) that span all domains of life. Tumor-derived exosomes are enriched with kinds of tumorigenesis mediators which are derived from the cytoplasm of cancer cells and fully reflect the tumor conditions. Indeed, the major topics and challenges on current oncological research are the identification of tumorigenic and metastatic molecules in tumor-cell-derived exosomes as well as elucidating the pathways that guarantee these components to be included in exosomes. The bacterial EVs have also been implicated in the pathogenesis of gastrointestinal (GI) tumors and chronic inflammatory diseases; however, the possible function of outer membrane vesicles (OMVs) in tumorigenesis remains largely underestimated. We su ggest that EVs from both eukaryotic cells and different microbes in GI tract act as regulators of intracellular and cross-species communication, thus particularly facilitate tumor cell survival and multi-drug resistance. Therefore, our review introduces comprehensive knowledge on the promising role of EVs (mainly exosomes and OMVs) production of GI cancer development and gut microbiome, as well as its roles in developing novel therapeutic strategies. PMID:33948347 | PMC:PMC8085842 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Quantitative evaluation and comparison of two prodrug-activating suicide gene therapies on oral squamous cell carcinoma

xlomafota13 shared this article with you from Inoreader Quantitative evaluation and comparison of two prodrug-activating suicide gene therapies on oral squamous cell carcinoma Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1672-1682. eCollection 2021. ABSTRACT Prodrug-activating suicide gene therapy (PA suicide gene therapy for short) for cancer is to introduce cancer cells with suicide genes. The enzyme encoded by suicide gene is not toxic but is able to kill cancer cells by converting a non-toxic prodrug into a toxic compound. This approach is a promising cancer gene therapy that could reduce non-specific toxicity to normal tissue. However, there is no quantitative method to evaluate efficacy of suicide gene therapy in preclinical study. The aim of this study is to develop a new method to quantitatively evaluate and compare prodrug-activating suicide gene therapies. This study was carried out on an oral squamous cell carcinoma (OSCC) cell line CAL-27. Suicide genes were integrated into ROSA26 locus of CAL-27 by CRISPR-Cas9. CAL-27 cell lines stably expressing herpes simplex virus-thymidine kinase (TK) or yeast cytosine deaminase (CD) were used to evaluate and compare PA suicide gene therapies. The efficacies of PA suicide gene therapies were quantitatively evaluated from three aspects: effective prodrug concentration, prodrug treatment time, and bystander effect. This method also could be used for different types of suicide gene therapies and different types of cancer. When the prodrug concentration, treatment time, and rate of suicide gene-positive cells (related to bystander effect) are fixed, anti-cancer effects could be quantitatively measured. This information is important for suicide gene therapy preclinical development. PMID:33948381 | PMC:PMC8085848 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cilostazol eliminates radiation-resistant glioblastoma by re-evoking big conductance calcium-activated potassium channel activity

xlomafota13 shared this article with you from Inoreader Cilostazol eliminates radiation-resistant glioblastoma by re-evoking big conductance calcium-activated potassium channel activity Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1148-1169. eCollection 2021. ABSTRACT In spite of radio- and chemotherapy, glioblastoma (GBM) develops therapeutic resistance leading to recurrence and poor prognosis. Therefore, understanding the underlying mechanisms of resistance is important to improve the treatment of GBM. To this end, we developed a radiation-resistant cell model by exposure to consecutive periods of irradiation. Simultaneously, single high-dose irradiation was introduced to determine "when" GBM developed consecutive irradiation-induced resistance (CIIR). We found that CIIR promoted TGF-β secretion, activated pro-survival Akt, and downregulated p21 in a p53-independent manner. Furthermore, CIIR upregulated multidrug-resistant proteins, resulting in temozolomide resistance. CIIR GBM also enhanced cell mobility and accelerated cell proliferation. The big-conductance calcium-activated potassium channel (BK channel) is highly expre ssed and activated in GBM. However, CIIR diminishes BK channel activity in an expression-independent manner. Cilostazol is a phosphodiesterase-3 inhibitor for the treatment of intermittent claudication and was able to reverse CIIR-induced BK channel inactivation. Paxilline, a BK channel blocker, promoted cell migration and proliferation in parental GBM cells. In contrast, Cilostazol inhibited CIIR-induced cell motility, proliferation, and the ability to form tumor spheres. Moreover, we established a radiation-resistant GBM in vivo model by intracranially injecting CIIR GBM cells into the brains of NOD/SCID mice. We found that Cilostazol delayed tumor in vivo growth and prolonged survival. As such, inactivation of the BK channel assists GBM in developing radiation resistance. Accordingly, restoring BK channel activity may be an effective strategy to improve therapeutic efficacy, and cilostazol could be repurposed to treat GBM. PMID:33948351 | PMC:PMC8085866 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Allogeneic hematopoietic stem cell transplantation overcomes the poor prognosis in MLL-rearranged solid tumor therapy related-acute myeloid leukemia

xlomafota13 shared this article with you from Inoreader Allogeneic hematopoietic stem cell transplantation overcomes the poor prognosis in MLL-rearranged solid tumor therapy related-acute myeloid leukemia Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1683-1696. eCollection 2021. ABSTRACT MLL rearrangement is very common in solid tumor therapy-related acute myeloid leukemia (t-AML). To investigated the prognosis of solid tumor MLL t-AML, 157 patients were divided into 3 groups: non-MLL t-AML (n=41), MLL t-AML (n=18) and MLL de novo AML (n=98). Of the 150 patients underwent anti-leukemia therapy, the complete remission (CR) was similar in MLL t-AML, non-MLL t-AML and MLL de novo AML (P=0.251). 3-years overall survival (OS) was 37.5%, 21.5% and 20.4% (P=0.046), and leukemia-free survival (LFS) was 28.0%, 32.2% and 22.7% (P=0.031), and the incidence of relapse was 30.0%, 50.4% and 53.5% (P=0.382), respectively, in the three groups. Multivariate analysis revealed that MLL t-AML was a risk factor while allo-HSCT was a protective factor for OS, LFS, and relapse (P<0.001, P<0.001 and P=0.005) (P=0.002, P<0.001 and P<0.001, respectively). The 3 -years OS was 0%, 17.9% and 2.3% (P=0.038), and LFS was 0%, 23.1% and 3.3% (P=0.017), and relapse was 100%, 53.1% and 74.4% (P=0.001), respectively, among three groups in patients undergoing chemotherapy alone, while OS was 64.3%, 52.7% and 40.7% (P=0.713), LFS was 60.0%, 48.8% and 37.0% (P=0.934), and relapse was 25.0%, 47.4% and 47.5% (P=0.872), respectively, among these groups in patients undergoing allo-HSCT. Intriguingly, MLL t-AML was no longer risk factor for relapse and LFS (P=0.882 and P=0.484, respectively), and it became a favorable factor for OS (P=0.011) in patients undergoing allo-HSCT. In conclusion, MLL t-AML had poor prognosis compared with non-MLL t-AML and MLL de novo AML, but allo-HSCT might overcome the poor prognosis of MLL t-AML. PMID:33948382 | PMC:PMC8085874 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Comprehensive analysis of multi-omics data of recurrent gliomas identifies a recurrence-related signature as a novel prognostic marker

xlomafota13 shared this article with you from Inoreader Comprehensive analysis of multi-omics data of recurrent gliomas identifies a recurrence-related signature as a novel prognostic marker Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1226-1246. eCollection 2021. ABSTRACT Tumor recurrence is a common clinical dilemma in diffuse gliomas. We aimed to identify a recurrence-related signature to predict the prognosis for glioma patients. In the public Chinese Glioma Genome Atlas dataset, we enrolled multi-omics data including genome, epigenome and transcriptome across primary and recurrent gliomas. We included RNA sequencing data from the batch 1 patients (325 patients) as the training set, while RNA sequencing data from the batch 2 patients (693 patients) were selected as the validation set. The R language was used for subsequent analysis. Compared with primary gliomas, more somatic mutations and copy number alterations were revealed in recurrent gliomas. In recurrent gliomas, we identified 113 genes whose methylation levels were significantly different from those of the primary glioma. Through differential expression analysis between primary and recurrent gliomas, we screened 121 recurrence-related genes. Based on these 121 gene expression profiles, consensus clustering of 325 patients yielded two robust groups with different molecular and prognostic features. We developed a recurrence-related risk signature with the lasso regression algorithm. High-risk group had shorter survival and earlier tumor recurrence than the low-risk group. Compared with traditional indicators, the signature showed better prognostic value. In addition, we constructed a nomogram model to predict glioma survival. Functional characteristics analysis found that the signature was associated with cell division and cell cycle. Immune analysis suggested that immunosuppressive status and macrophages might promote glioma recurrence. We demonstrated a novel 18-gene signature that could effectively predict recurrence and prognosis for glioma patients. PMID:33948355 | PMC:PMC8085869 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

CAN017, a novel anti-HER3 antibody, exerted great potency in mouse avatars of esophageal squamous cell carcinoma with NRG1 as a biomarker

xlomafota13 shared this article with you from Inoreader CAN017, a novel anti-HER3 antibody, exerted great potency in mouse avatars of esophageal squamous cell carcinoma with NRG1 as a biomarker Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1697-1708. eCollection 2021. ABSTRACT CAN017 (AV-203), a novel anti-HER3 antibody, exerts very promising anti-tumor activities in several human tumor models. The aim of this study was to further investigated the efficacy and possible responsive biomarkers of CAN017 in esophageal squamous cell carcinoma (ESCC) with Chinese characteristics. Two separate cohorts of ESCC patient-derived xenograft (PDX) models including 24 (cohort 1 as training models, from Crown Bioscience Inc.) and 22 (cohort 2 as validating models, from Peking University Cancer Hospital) models, respectively, were used to study the efficacy and safety of CAN017, as well as the correlation of NRG1 expression to the response of CAN017. In cohort 1, all PDX models showed good tolerance to CAN017 and 8 out of 24 (33.3%) PDX models responded to CAN017 with tumor growth inhibition (TGI) ≥70% compared to controls. Furthermore, the efficacy o f CAN017 was positively correlated with NRG1 expression and the response rates in cohort 1 were 73% (8/11) versus 0% (0/13) in NRG1 high and low expression models, respectively. These results were also validated in PDX models of cohort 2 indicated as the powerful anti-tumor activity of CAN017 in PDX models with NRG1 high expression. In our study, HER3-targeting therapy was first demonstrated to have potency in inhibiting ESCC tumor growth, and NRG1 served as a predictive biomarker to screen patients in future clinical trials. PMID:33948383 | PMC:PMC8085865 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Decursin inhibits cell growth and autophagic flux in gastric cancer via suppression of cathepsin C

xlomafota13 shared this article with you from Inoreader Decursin inhibits cell growth and autophagic flux in gastric cancer via suppression of cathepsin C Via American Journal of Cancer Research Am J Cancer Res. 2021 Apr 15;11(4):1304-1320. eCollection 2021. ABSTRACT Autophagy plays an important role in the survival of cancer cells under stressful conditions, such as nutrient or oxygen deficiency. Therefore, autophagy inhibition is being considered as a novel therapeutic strategy for cancer. Decursin is a natural compound derived from Angelica gigas; it has been used in the treatment of various diseases, including cancer. However, the mechanism by which decursin regulates autophagy in gastric cancer and other carcinomas remains unclear. Here, we demonstrated that decursin reduced the growth and induced cell cycle arrest in gastric cancer cells in vitro. Decursin blocked autophagic flux by reducing the expression of lysosomal protein cathepsin C (CTSC) and attenuating its activity, thereby causing autophagic dysregulation (i.e., accumulation of LC3 and SQSTM1). Decursin also inhibited cell proliferation and cell c ycle progression by inhibiting CTSC and E2F3, both of which were linked to gastric cancer aggressiveness. The antitumor effects of decursin were confirmed in vivo. We established spheroid and patient-derived organoid models and found that decursin decreased the growth of spheroids and patient-derived gastric organoids, as well as modulated the expression of CTSC and autophagy-related proteins. Hence, our findings uncovered a previously unknown mechanism by which decursin regulates cell growth and autophagy and suggests that decursin may act as a potential therapeutic agent that simultaneously inhibits cell growth and autophagy. PMID:33948359 | PMC:PMC8085838 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.