scholarly journals Extracellular Vesicles: Messengers of p53 in Tumor–Stroma Communication and Cancer Metastasis

2020 ◽  
Vol 21 (24) ◽  
pp. 9648
Author(s):  
Evangelos Pavlakis ◽  
Michelle Neumann ◽  
Thorsten Stiewe
Keyword(s):  
Extracellular Vesicles ◽  
Cancer Metastasis ◽  
Tumor Stroma ◽  
Metastatic Tumor ◽  
Genetic Alterations ◽  
Host Cells ◽  
Mutant P53 ◽  
Wild Type ◽  
Tumor Protein P53 ◽  
Cell Dissemination

Tumor progression to a metastatic and ultimately lethal stage relies on a tumor-supporting microenvironment that is generated by reciprocal communication between tumor and stromal host cells. The tumor–stroma crosstalk is instructed by the genetic alterations of the tumor cells—the most frequent being mutations in the gene Tumor protein p53 (TP53) that are clinically correlated with metastasis, drug resistance and poor patient survival. The crucial mediators of tumor–stroma communication are tumor-derived extracellular vesicles (EVs), in particular exosomes, which operate both locally within the primary tumor and in distant organs, at pre-metastatic niches as the future sites of metastasis. Here, we review how wild-type and mutant p53 proteins control the secretion, size, and especially the RNA and protein cargo of tumor-derived EVs. We highlight how EVs extend the cell-autonomous tumor suppressive activity of wild-type p53 into the tumor microenvironment (TME), and how mutant p53 proteins switch EVs into oncogenic messengers that reprogram tumor–host communication within the entire organism so as to promote metastatic tumor cell dissemination.

scholarly journals Bioinformatics Analysis Identifies Precision Treatment with Paclitaxel for Hepatocellular Carcinoma Patients Harboring Mutant TP53 or Wild-Type CTNNB1 Gene

2021 ◽  
Vol 11 (11) ◽  
pp. 1199
Author(s):  
Jiunn-Chang Lin ◽  
Tsang-Pai Liu ◽  
Vivin Andriani ◽  
Muhammad Athoillah ◽  
Chih-Yang Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mitotic Cell ◽  
Gene Signature ◽  
Genetic Alterations ◽  
Cancer Type ◽  
Wild Type ◽  
Tumor Protein P53 ◽  
Novel Therapeutic Strategies ◽  
Cycle Regulation ◽  
Lower Expression

Hepatocellular carcinoma (HCC) is an aggressive and chemoresistant cancer type. The development of novel therapeutic strategies is still urgently needed. Personalized or precision medicine is a new trend in cancer therapy, which treats cancer patients with specific genetic alterations. In this study, a gene signature was identified from the transcriptome of HCC patients, which was correlated with the patients’ poorer prognoses. This gene signature is functionally related to mitotic cell cycle regulation, and its higher or lower expression is linked to the mutation in tumor protein p53 (TP53) or catenin beta 1 (CTNNB1), respectively. Gene–drug association analysis indicated that the taxanes, such as the clinically approved anticancer drug paclitaxel, are potential drugs targeting this mitotic gene signature. Accordingly, HCC cell lines harboring mutant TP53 or wild-type CTNNB1 genes are more sensitive to paclitaxel treatment. Therefore, our results imply that HCC patients with mutant TP53 or wild-type CTNNB1 genes may benefit from the paclitaxel therapy.

scholarly journals Tumor Extracellular Vesicles Regulate Macrophage-Driven Metastasis through CCL5

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3459
Author(s):  
Daniel C. Rabe ◽  
Nykia D. Walker ◽  
Felicia D. Rustandy ◽  
Jessica Wallace ◽  
Jiyoung Lee ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Tumor Metastasis ◽  
Tumor Stroma ◽  
Metastatic Tumor ◽  
Mouse Bone Marrow ◽  
Metastatic Phenotype ◽  
Immune Infiltrate ◽  
Phenotype Analysis

Purpose: To understand how tumor cells alter macrophage biology once they are recruited to triple-negative breast cancer (TNBC) tumors by CCL5. Method: Mouse bone marrow derived macrophage (BMDMs) were isolated and treated with recombinant CCL5 protein alone, with tumor cell conditioned media, or with tumor extracellular vesicles (EVs). Media from these tumor EV-educated macrophages (TEMs) was then used to determine how these macrophages affect TNBC invasion. To understand the mechanism, we assayed the cytokine secretion from these macrophages to determine how they impact tumor cell invasion. Tumor CCL5 expression was varied in tumors to determine its role in regulating macrophage biology through EVs. Results: Tumor EVs are a necessary component for programming naïve macrophages toward a pro-metastatic phenotype. CCL5 expression in the tumor cells regulates both EV biogenesis/secretion/cargo and macrophage EV-education toward a pro-metastatic phenotype. Analysis of the tumor EV-educated macrophages (TEMs) showed secretion of a variety of factors including CXCL1, CTLA-4, IFNG, OPN, HGF, TGFB, and CCL19 capable of remodeling the surrounding tumor stroma and immune infiltrate. Injection of tumor cells with macrophages educated by metastatic tumor cell EVs into mice increased tumor metastasis to the lung. Conclusion: These results demonstrate that tumor-derived EVs are key mediators of macrophage education and likely play a more complex role in modulating tumor therapeutic response by regulating the tumor immune infiltrate.

scholarly journals CD44 and Tumor-Derived Extracellular Vesicles (TEVs). Possible Gateway to Cancer Metastasis

2021 ◽  
Vol 22 (3) ◽  
pp. 1463
Author(s):  
Rafał Szatanek ◽  
Monika Baj-Krzyworzeka
Keyword(s):  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Cancer Metastasis ◽  
Complex Process ◽  
Present Information ◽  
Membrane Bound ◽  
Favorable Conditions ◽  
Cell Dissemination ◽  
Cluster Of Differentiation ◽  
The Impact

Cancer metastasis, the final stage of tumor progression, is a complex process governed by the interplay of multiple types of cells and the tumor microenvironment. One of the aspects of this interplay involves the release of various factors by the tumor cells alone or by forcing other cells to do so. As a consequence of these actions, tumor cells are prepared in favorable conditions for their dissemination and spread to other sites/organs, which guarantees their escape from immunosurveillance and further progression. Tumor-derived extracellular vesicles (TEVs) represent a heterogeneous population of membrane-bound vesicles that are being actively released by different tumors. The array of proteins (i.e., receptors, cytokines, chemokines, etc.) and nucleic acids (i.e., mRNA, miR, etc.) that TEVs can transfer to other cells is often considered beneficial for the tumor’s survival and proliferation. One of the proteins that is associated with many different tumors as well as their TEVs is a cluster of differentiation 44 in its standard (CD44s) and variant (CD44v) form. This review covers the present information regarding the TEVs-mediated CD44s/CD44v transfer/interaction in the context of cancer metastasis. The content and the impact of the transferred cargo by this type of TEVs also are discussed with regards to tumor cell dissemination.

Analysis of HPV16 E6 and mutant p53-transfected keratinocytes in reconstituted epidermis suggests that wild-type p53 inhibits cytokeratin 19 expression

1994 ◽  
Vol 107 (2) ◽  
pp. 435-441
Author(s):  
J.P. Moles ◽  
J.T. Schiller ◽  
A. Tesniere ◽  
I.M. Leigh ◽  
J.J. Guilhou ◽  
...  
Keyword(s):  
Human Keratinocytes ◽  
Genetic Alterations ◽  
Cytokeratin 19 ◽  
Mutant P53 ◽  
Wild Type ◽  
Early Passage ◽  
Hpv16 E6 ◽  
Ck19 Expression ◽  
Wild Type P53

Using a reconstituted skin culture model we have analysed the effects of oncogenic human papillomavirus (HPV) and mutant TP53 genes on the proliferation and differentiation of human keratinocytes. Immortal cell lines generated by transfection of early passage normal human keratinocytes with HPV16 E7 plus mutant human TP53 (KN #1), HPV16 E7/E6 (KN #2), or HPV16 E7 plus murine p53 (KN #3) were examined. KN #1 and KN #2 behaved identically, reconstructing a tumor-like epidermis characterized by the lack of differentiation and the presence of an aberrant epidermal architecture. In contrast, KN #3 reconstructed an epidermis that was more similar to that obtained with normal keratinocytes. KN #1 and KN #2 were further characterized by the inversion of the proliferative compartment and the abnormal expression of cytokeratin 19 (CK19). Because p53 function is reduced in these cells, either by heterocomplex formation between endogenous wild-type p53 and transfected mutant p53 or by E6-induced degradation of wild-type p53, we hypothesized that CK19 expression may be normally repressed by wild-type p53. This hypothesis was supported by the strict correlation observed between TP53 mutation and CK19 expression in a set of human skin tumors. CK19 was detected in all eight carcinomas containing a mutated TP53 gene but in none of the 16 carcinomas containing only wild-type TP53. These results illustrate the utility of the in vitro reconstituted skin model for investigating the consequences of genetic alterations in human keratinocytes.

scholarly journals Potential Roles of Muscle-Derived Extracellular Vesicles in Remodeling Cellular Microenvironment: Proposed Implications of the Exercise-Induced Myokine, Irisin

2021 ◽  
Vol 9 ◽  
Author(s):  
Samuel Darkwah ◽  
Eun Jeong Park ◽  
Phyoe Kyawe Myint ◽  
Atsushi Ito ◽  
Michael G. Appiah ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Tumor Metastasis ◽  
Cellular Differentiation ◽  
Metabolic Disorders ◽  
Cancer Metastasis ◽  
Metastatic Tumor ◽  
Exercise Induced ◽  
Organotropic Metastasis

Extracellular vesicles (EVs) have emerged as key players of intercellular communication and mediate crosstalk between tissues. Metastatic tumors release tumorigenic EVs, capable of pre-conditioning distal sites for organotropic metastasis. Growing evidence identifies muscle cell-derived EVs and myokines as potent mediators of cellular differentiation, proliferation, and metabolism. Muscle-derived EVs cargo myokines and other biological modulators like microRNAs, cytokines, chemokines, and prostaglandins hence, are likely to modulate the remodeling of niches in vital sites, such as liver and adipose tissues. Despite the scarcity of evidence to support a direct relationship between muscle-EVs and cancer metastasis, their indirect attribution to the regulation of niche remodeling and the establishment of pre-metastatic homing niches can be put forward. This hypothesis is supported by the role of muscle-derived EVs in findings gathered from other pathologies like inflammation and metabolic disorders. In this review, we present and discuss studies that evidently support the potential roles of muscle-derived EVs in the events of niche pre-conditioning and remodeling of metastatic tumor microenvironment. We highlight the potential contributions of the integrin-mediated interactions with an emerging myokine, irisin, to the regulation of EV-driven microenvironment remodeling in tumor metastasis. Further research into muscle-derived EVs and myokines in cancer progression is imperative and may hold promising contributions to advance our knowledge in the pathophysiology, progression and therapeutic management of metastatic cancers.

scholarly journals Antitumor Effects of PRIMA-1 and PRIMA-1Met (APR246) in Hematological Malignancies: Still a Mutant P53-Dependent Affair?

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 98
Author(s):  
Paola Menichini ◽  
Paola Monti ◽  
Andrea Speciale ◽  
Giovanna Cutrona ◽  
Serena Matis ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Cell Metabolism ◽  
Therapy Response ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Lower Percentage ◽  
Mutant P53 ◽  
Wild Type ◽  
Antitumor Effects ◽  
Tp53 Tumor Suppressor Gene

Because of its role in the regulation of the cell cycle, DNA damage response, apoptosis, DNA repair, cell migration, autophagy, and cell metabolism, the TP53 tumor suppressor gene is a key player for cellular homeostasis. TP53 gene is mutated in more than 50% of human cancers, although its overall dysfunction may be even more frequent. TP53 mutations are detected in a lower percentage of hematological malignancies compared to solid tumors, but their frequency generally increases with disease progression, generating adverse effects such as resistance to chemotherapy. Due to the crucial role of P53 in therapy response, several molecules have been developed to re-establish the wild-type P53 function to mutant P53. PRIMA-1 and its methylated form PRIMA-1Met (also named APR246) are capable of restoring the wild-type conformation to mutant P53 and inducing apoptosis in cancer cells; however, they also possess mutant P53-independent properties. This review presents the activities of PRIMA-1 and PRIMA-1Met/APR246 and describes their potential use in hematological malignancies.

scholarly journals New insights in the expression of stromal caveolin 1 in breast cancer spread to axillary lymph nodes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cristian Scatena ◽  
Giovanni Fanelli ◽  
Giuseppe Nicolò Fanelli ◽  
Michele Menicagli ◽  
Paolo Aretini ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Cancer Metastasis ◽  
Tumor Stroma ◽  
Disease Recurrence ◽  
Metastatic Spread ◽  
Axillary Lymph Nodes ◽  
Axillary Lymph ◽  
Axillary Lymph Node Metastases ◽  
Stromal Compartment ◽  
Metastatic Sites

AbstractRecent evidence suggests that a loss of expression of caveolin in the stromal compartment (sCav-1) of human invasive breast carcinoma (IBC) may be a predictor of disease recurrence, metastasis and poor outcome. At present, there is little knowledge regarding the expression of sCav-1 at the metastatic sites. We therefore studied sCav-1 expression in IBCs and in their axillary lymph nodes to seek a correlation with cancer metastasis. 189 consecutive invasive IBCs (53 with axillary lymph node metastases and 136 without) were studied by immunohistochemistry, using a rabbit polyclonal anti-Cav-1 antibody. In IBCs sCav-1 was evaluated in fibroblasts scattered in the tumor stroma whereas in lymph nodes sCav-1 was assessed in fibroblast-like stromal cells. For the first time, we observed a statistically significant progressive loss of sCav-1 from normal/reactive axillary lymph nodes of tumors limited to the breast to metastatic axillary lymph nodes, through normal/reactive axillary lymph nodes of tumors with axillary metastatic spread. These data indicate that Cav-1 expressed by the stromal compartment of lymph nodes, somehow, may possibly contribute to metastatic spread in IBC.

scholarly journals Helicobacter pylori Outer Membrane Vesicles and Extracellular Vesicles from Helicobacter pylori-Infected Cells in Gastric Disease Development

2021 ◽  
Vol 22 (9) ◽  
pp. 4823
Author(s):  
María Fernanda González ◽  
Paula Díaz ◽  
Alejandra Sandoval-Bórquez ◽  
Daniela Herrera ◽  
Andrew F. G. Quest
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Outer Membrane ◽  
Extracellular Vesicles ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Host Cells ◽  
Gastric Epithelium ◽  
Infected Cells ◽  
H Pylori

Extracellular vesicles (EVs) are cell-derived vesicles important in intercellular communication that play an essential role in host-pathogen interactions, spreading pathogen-derived as well as host-derived molecules during infection. Pathogens can induce changes in the composition of EVs derived from the infected cells and use them to manipulate their microenvironment and, for instance, modulate innate and adaptive inflammatory immune responses, both in a stimulatory or suppressive manner. Gastric cancer is one of the leading causes of cancer-related deaths worldwide and infection with Helicobacter pylori (H. pylori) is considered the main risk factor for developing this disease, which is characterized by a strong inflammatory component. EVs released by host cells infected with H. pylori contribute significantly to inflammation, and in doing so promote the development of disease. Additionally, H. pylori liberates vesicles, called outer membrane vesicles (H. pylori-OMVs), which contribute to atrophia and cell transformation in the gastric epithelium. In this review, the participation of both EVs from cells infected with H. pylori and H. pylori-OMVs associated with the development of gastric cancer will be discussed. By deciphering which functions of these external vesicles during H. pylori infection benefit the host or the pathogen, novel treatment strategies may become available to prevent disease.

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