TP53-dependent release of Extracellular Vesicles (EVs) from urological malignancies affects functional status of tumor associated macrophages and therapy response

2021 ◽  
Vol 79 ◽  
pp. S983
Author(s):  
B. Köditz ◽  
E. Izquierdo ◽  
T. Nestler ◽  
M. Hallek ◽  
A. Heidenreich ◽  
...  
Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 52 ◽  
Author(s):  
Flora Guerra ◽  
Aurora Paiano ◽  
Danilo Migoni ◽  
Giulia Girolimetti ◽  
Anna Myriam Perrone ◽  
...  

Background: Cisplatin (CDDP) is widely used in treatment of cancer, yet patients often develop resistance with consequent therapeutical failure. In CDDP-resistant cells alterations of endocytosis and lysosomal functionality have been revealed, although their causes and contribution to therapy response are unclear. Methods: We investigated the role of RAB7A, a key regulator of late endocytic trafficking, in CDDP-resistance by comparing resistant and sensitive cells using western blotting, confocal microscopy and real time PCR. Modulation of RAB7A expression was performed by transfection and RNA interference, while CDDP sensitivity and intracellular accumulation were evaluated by viability assays and chemical approaches, respectively. Also extracellular vesicles were purified and analyzed. Finally, correlations between RAB7A and chemotherapy response was investigated in human patient samples. Results: We demonstrated that down-regulation of RAB7A characterizes the chemoresistant phenotype, and that RAB7A depletion increases CDDP-resistance while RAB7A overexpression decreases it. In addition, increased production of extracellular vesicles is modulated by RAB7A expression levels and correlates with reduction of CDDP intracellular accumulation. Conclusions: We demonstrated, for the first time, that RAB7A regulates CDDP resistance determining alterations in late endocytic trafficking and drug efflux through extracellular vesicles.


2019 ◽  
Vol 122 (3) ◽  
pp. 295-305 ◽  
Author(s):  
Juliana Müller Bark ◽  
Arutha Kulasinghe ◽  
Benjamin Chua ◽  
Bryan W. Day ◽  
Chamindie Punyadeera

Abstract Gliomas are the most common tumours of the central nervous system and the most aggressive form is glioblastoma (GBM). Despite advances in treatment, patient survival remains low. GBM diagnosis typically relies on imaging techniques and postoperative pathological diagnosis; however, both procedures have their inherent limitations. Imaging modalities cannot differentiate tumour progression from treatment-related changes that mimic progression, known as pseudoprogression, which might lead to misinterpretation of therapy response and delay clinical interventions. In addition to imaging limitations, tissue biopsies are invasive and most of the time cannot be performed over the course of treatment to evaluate ‘real-time’ tumour dynamics. In an attempt to address these limitations, liquid biopsies have been proposed in the field. Blood sampling is a minimally invasive procedure for a patient to endure and could provide tumoural information to guide therapy. Tumours shed tumoural content, such as circulating tumour cells, cell-free nucleic acids, proteins and extracellular vesicles, into the circulation, and these biomarkers are reported to cross the blood–brain barrier. The use of liquid biopsies is emerging in the field of GBM. In this review, we aim to summarise the current literature on circulating biomarkers, namely circulating tumour cells, circulating tumour DNA and extracellular vesicles as potential non-invasively sampled biomarkers to manage the treatment of patients with GBM.


BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Atene Ito ◽  
Shunsuke Kagawa ◽  
Shuichi Sakamoto ◽  
Kazuya Kuwada ◽  
Hiroki Kajioka ◽  
...  

Abstract Background Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated. Methods The association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored. Results Immunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein. Conclusion EVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment.


2019 ◽  
Vol 17 (1) ◽  
pp. 11-27 ◽  
Author(s):  
Johannes Linxweiler ◽  
Kerstin Junker

2018 ◽  
Author(s):  
Daniel C Rabe ◽  
Felicia D Rustandy ◽  
Jiyoung Lee ◽  
Marsha Rich Rosner

SummaryTriple-negative breast cancers (TNBC) are highly infiltrated by tumor-associated macrophages (TAMs) that promote tumor growth, survival, metastasis and therapeutic resistance. Although cytokines such as CCL5 have been implicated in TAM recruitment to TNBC tumors, the mechanism by which tumor cells educate TAMs is not understood. Here we show that tumor EVs are both necessary and sufficient for programming TAMs toward a pro-metastatic phenotype. The mechanism involves CCL5 regulation of tumor extracellular vesicles (EVs), which activate TLR2 and TLR3, leading to secretion of a common set of cytokines that further stimulate tumor cell invasion and metastasis as well as alter the tumor microenvironment. Cytokine expression is significantly correlated to CCL5 expression and up-regulated in TNBC patient tumors. These results demonstrate for the first time that tumor EVs are key mediators of TAM education, phenocopy the pro-metastatic and drug resistant state of the tumors to TAMs, and illustrate the potential clinical relevance of these findings to TNBC patients.HighlightsTumor extracellular vesicles (EVs) are required for pro-metastatic programming of tumor-associated macrophages (TAMs)Tumor CCL5 and macrophage TLR signaling mediate tumor EV programming of TAMs in TNBCsTumor EVs mediate drug resistance in TAMs and alter recruitment of regulatory T-cells.Cytokines expressed by EV-educated TAMs are enriched and correlate with CCL5 in human TNBC patients.eTOCChemokines such as CCL5 recruit tumor-associated macrophages (TAMs) that are required for metastasis, but TAM programming is not understood. Rabe et al. show that tumor extracellular vesicles (EVs) are required for programming TAMs via Toll-like Receptors (TLRs) to phenocopy the tumor, rewire the microenvironment, drive metastasis and promote immune cell evasion.


2017 ◽  
Vol 199 (4) ◽  
pp. 1505-1515 ◽  
Author(s):  
Haruka Shinohara ◽  
Yuki Kuranaga ◽  
Minami Kumazaki ◽  
Nobuhiko Sugito ◽  
Yuki Yoshikawa ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document