scholarly journals Biomimetic Nanoparticles Blocking Autophagy for Enhanced Chemotherapy and Metastasis Inhibition via Reversing Focal Adhesion Disassembly

2021 ◽  
Author(s):  
Yesi Shi ◽  
Gan Lin ◽  
Huili Zheng ◽  
Dan Mu ◽  
Hu Chen ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Mouse Models ◽  
Focal Adhesions ◽  
Migration And Invasion ◽  
Autophagic Flux ◽  
Tumor Cell Migration ◽  
Tumor Cell Motility ◽  
Metastasis Inhibition

Abstract BackgroundAutophagy is a conserved catabolic process, which plays an important role in regulating tumor cell motility and degrading protein aggregates. Chemotherapy-induced autophagy may lead to tumor distant metastasis and even chemo-insensitivity in the therapy of hepatocellular carcinoma (HCC). However, a vast majority of HCC cases do not produce a significant response to monotherapy with autophagy inhibitors. ResultsIn this work, we develop a biomimetic co-delivery nanoformulation (TH-NP) co-encapsulating Oxaliplatin (OXA)/HCQ (hydroxychloroquine, an autophagy inhibitor) to execute targeted autophagy inhibition, reduce tumor cell migration and invasion in vitro and attenuate metastasis in vivo. Especially, TH-NPs can significantly improve OXA and HCQ concentration with approximately 21 and 13-fold increment in tumor tissues compared to the free mixture of HCQ/OXA. Moreover, the tumor-targeting TH-NPs release HCQ can alkalize the acidic lysosomes and thus inhibit the fusion of autophagosomes and lysosomes, leading to most effective blockade of autophagic flux compared to various controls. This largely improves chemotherapeutic performance of OXA in subcutaneous and orthotopic HCC mouse models. Importantly, TH-NPs also exhibit the most effective inhibition of tumor metastasis in orthotopic HCCLM3 models, and in the HepG2, Huh-7 or HCCLM3 metastatic mouse models. Then, we illustrate the enhanced metastasis inhibition is attributed to the blockade or reverse of the autophagy-mediated degradation of focal adhesions (FAs) including E-cadherin and paxillin. ConclusionsTH-NPs can perform an enhanced chemotherapy and antimetastatic effect, and may represent a promising strategy for HCC therapy in clinics.

scholarly journals Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yesi Shi ◽  
Gan Lin ◽  
Huili Zheng ◽  
Dan Mu ◽  
Hu Chen ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Focal Adhesions ◽  
Membrane Vesicles ◽  
Migration And Invasion ◽  
Autophagic Flux ◽  
Tumor Cell Migration ◽  
Tumor Cell Motility ◽  
Metastasis Inhibition

Abstract Background Autophagy is a conserved catabolic process, which plays an important role in regulating tumor cell motility and degrading protein aggregates. Chemotherapy-induced autophagy may lead to tumor distant metastasis and even chemo-insensitivity in the therapy of hepatocellular carcinoma (HCC). Therefore, a vast majority of HCC cases do not produce a significant response to monotherapy with autophagy inhibitors. Results In this work, we developed a biomimetic nanoformulation (TH-NP) co-encapsulating Oxaliplatin (OXA)/hydroxychloroquine (HCQ, an autophagy inhibitor) to execute targeted autophagy inhibition, reduce tumor cell migration and invasion in vitro and attenuate metastasis in vivo. The tumor cell-specific ligand TRAIL was bioengineered to be stably expressed on HUVECs and the resultant membrane vesicles were wrapped on OXA/HCQ-loaded PLGA nanocores. Especially, TH-NPs could significantly improve OXA and HCQ effective concentration by approximately 21 and 13 times in tumor tissues compared to the free mixture of HCQ/OXA. Moreover, the tumor-targeting TH-NPs released HCQ alkalized the acidic lysosomes and inhibited the fusion of autophagosomes and lysosomes, leading to effective blockade of autophagic flux. In short, the system largely improved chemotherapeutic performance of OXA on subcutaneous and orthotopic HCC mice models. Importantly, TH-NPs also exhibited the most effective inhibition of tumor metastasis in orthotopic HCCLM3 models, and in the HepG2, Huh-7 or HCCLM3 metastatic mice models. Finally, we illustrated the enhanced metastasis inhibition was attributed to the blockade or reverse of the autophagy-mediated degradation of focal adhesions (FAs) including E-cadherin and paxillin. Conclusions TH-NPs can perform an enhanced chemotherapy and antimetastatic effect, and may represent a promising strategy for HCC therapy in clinics. Graphical Abstract

scholarly journals Compensation mechanism in tumor cell migration

2003 ◽  
Vol 160 (2) ◽  
pp. 267-277 ◽  
Author(s):  
Katarina Wolf ◽  
Irina Mazo ◽  
Harry Leung ◽  
Katharina Engelke ◽  
Ulrich H. von Andrian ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Shape Change ◽  
Proteolytic Degradation ◽  
Amoeboid Movement ◽  
Tumor Cell Migration ◽  
Tumor Dissemination ◽  
Β1 Integrins

Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor–based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of β1 integrins and MT1–matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered β1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.

scholarly journals Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility

2006 ◽  
Vol 176 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Erik Sahai ◽  
Raquel Garcia-Medina ◽  
Jacques Pouysségur ◽  
Emmanuel Vial
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Rho Gtpases ◽  
Rho Kinase ◽  
Cell Movement ◽  
Leading Edge ◽  
Cell Periphery ◽  
Tumor Cell Migration ◽  
Tumor Cell Motility

Rho GTPases participate in various cellular processes, including normal and tumor cell migration. It has been reported that RhoA is targeted for degradation at the leading edge of migrating cells by the E3 ubiquitin ligase Smurf1, and that this is required for the formation of protrusions. We report that Smurf1-dependent RhoA degradation in tumor cells results in the down-regulation of Rho kinase (ROCK) activity and myosin light chain 2 (MLC2) phosphorylation at the cell periphery. The localized inhibition of contractile forces is necessary for the formation of lamellipodia and for tumor cell motility in 2D tissue culture assays. In 3D invasion assays, and in in vivo tumor cell migration, the inhibition of Smurf1 induces a mesenchymal–amoeboid–like transition that is associated with a more invasive phenotype. Our results suggest that Smurf1 is a pivotal regulator of tumor cell movement through its regulation of RhoA signaling.

scholarly journals The human vault RNA enhances tumorigenesis and chemoresistance through the lysosome

2020 ◽  
Author(s):  
Iolanda Ferro ◽  
Jacopo Gavini ◽  
Lisamaria Bracher ◽  
Marc Landolfo ◽  
Daniel Candinas ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Chemotherapy Resistance ◽  
Autophagic Flux ◽  
Tumor Cell Proliferation ◽  
Apoptosis Resistance ◽  
Knock Out ◽  
Vault Rna

AbstractThe small non-coding vault RNA (vtRNA) 1-1 has been shown to confer apoptosis resistance in several malignant cell lines and also to modulate the autophagic flux in hepatocytes, thus highlighting its pro-survival role. Here we describe a new function of vtRNA1-1 in regulating in vitro and in vivo tumor cell proliferation, tumorigenesis and chemoresistance. By activating extracellular signal-regulated kinases (ERK 1/2), vtRNA1-1 knock-out (KO) inhibits transcription factor EB (TFEB), leading to a downregulation of the coordinated lysosomal expression and regulation (CLEAR) network genes and lysosomal compartment dysfunction. Pro-tumorigenic pathways dysregulation and decreased lysosome functionality potentiate the anticancer effect of conventional targeted cancer drugs in the absence of vtRNA1-1. Finally, vtRNA1-1 KO-reduced lysosomotropism, together with a higher intracellular compound availability, significantly reduced tumor cell proliferation in vitro and in vivo. These findings reveal the role of vtRNA1-1 in ensuring intracellular catabolic compartment stability and functionality, suggesting its importance in lysosome-mediated chemotherapy resistance.

scholarly journals Primary Cilia Blockage Promotes the Malignant Behaviors of Hepatocellular Carcinoma via Induction of Autophagy

2019 ◽  
Vol 2019 ◽  
pp. 1-14
Author(s):  
Lian Liu ◽  
Jia-Qi Sheng ◽  
Mu-Ru Wang ◽  
Yun Gan ◽  
Xiao-Li Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Primary Cilia ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Serum Starvation ◽  
Autophagic Flux ◽  
And Function ◽  
Hcc Cells

Primary cilia are organelles protruding from cell surface into environment that function in regulating cell cycle and modulating cilia-related signal. Primary ciliogenesis and autophagy play important roles in tumorigenesis. However, the functions and interactions between primary cilia and autophagy in hepatocellular carcinoma (HCC) have not been reported yet. Here, we aimed to investigate the relationship and function of primary cilia and autophagy in HCC. In vitro, we showed that serum starvation stimuli could trigger primary ciliogenesis in HCC cells. Blockage of primary ciliogenesis by IFT88 silencing enhanced the proliferation, migration, and invasion ability of HCC cells. In addition, inhibition of primary cilia could positively regulate autophagy. However, the proliferation, migration, and invasion ability which were promoted by IFT88 silencing could be partly reversed by inhibition of autophagy. In vivo, interference of primary cilia led to acceleration of tumor growth and increase of autophagic flux in xenograft HCC mouse models. Moreover, IFT88 high expression or ATG7 low expression in HCC tissues was correlated with longer survival time indicated by the Cancer Genome Atlas (TCGA) analysis. In conclusion, our study demonstrated that blockage of primary ciliogenesis by IFT88 silencing had protumor effects through induction of autophagy in HCC. These findings define a newly recognized role of primary cilia and autophagy in HCC.

scholarly journals RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo

2017 ◽  
Vol 114 (8) ◽  
pp. E1413-E1421 ◽  
Author(s):  
Twana Alkasalias ◽  
Andrey Alexeyenko ◽  
Katharina Hennig ◽  
Frida Danielsson ◽  
Robert Jan Lebbink ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Rho Gtpase ◽  
Focal Adhesions ◽  
Cancer Associated Fibroblasts ◽  
Inhibitory Capacity ◽  
Promote Tumor Growth ◽  
Pc3 Cells

Fibroblasts are a main player in the tumor-inhibitory microenvironment. Upon tumor initiation and progression, fibroblasts can lose their tumor-inhibitory capacity and promote tumor growth. The molecular mechanisms that underlie this switch have not been defined completely. Previously, we identified four proteins overexpressed in cancer-associated fibroblasts and linked to Rho GTPase signaling. Here, we show that knocking out the Ras homolog family member A (RhoA) gene in normal fibroblasts decreased their tumor-inhibitory capacity, as judged by neighbor suppression in vitro and accompanied by promotion of tumor growth in vivo. This also induced PC3 cancer cell motility and increased colony size in 2D cultures. RhoA knockout in fibroblasts induced vimentin intermediate filament reorganization, accompanied by reduced contractile force and increased stiffness of cells. There was also loss of wide F-actin stress fibers and large focal adhesions. In addition, we observed a significant loss of α-smooth muscle actin, which indicates a difference between RhoA knockout fibroblasts and classic cancer-associated fibroblasts. In 3D collagen matrix, RhoA knockout reduced fibroblast branching and meshwork formation and resulted in more compactly clustered tumor-cell colonies in coculture with PC3 cells, which might boost tumor stem-like properties. Coculturing RhoA knockout fibroblasts and PC3 cells induced expression of proinflammatory genes in both. Inflammatory mediators may induce tumor cell stemness. Network enrichment analysis of transcriptomic changes, however, revealed that the Rho signaling pathway per se was significantly triggered only after coculturing with tumor cells. Taken together, our findings in vivo and in vitro indicate that Rho signaling governs the inhibitory effects by fibroblasts on tumor-cell growth.

scholarly journals Diosmin Inhibits Glioblastoma Growth through Inhibition of Autophagic Flux

2021 ◽  
Vol 22 (19) ◽  
pp. 10453
Author(s):  
Yung-Lung Chang ◽  
Yao-Feng Li ◽  
Chung-Hsing Chou ◽  
Li-Chun Huang ◽  
Yi-Ping Wu ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Primary Brain Tumor ◽  
Migration And Invasion ◽  
Autophagic Flux ◽  
Mesenchymal Transition ◽  
Cycle Arrest ◽  
Average Survival ◽  
High Concentrations

Diosmin, a natural flavone glycoside acquired through dehydrogenation of the analogous flavanone glycoside hesperidin, is plentiful in many citrus fruits. Glioblastoma multiforme (GBM) is the most malignant primary brain tumor; the average survival time of GBM patients is less than 18 months after standard treatment. The present study demonstrated that diosmin, which is able to cross the blood–brain barrier, inhibited GBM cell growth in vitro and in vivo. Diosmin also impeded migration and invasion by GBM8401and LN229 GBM cells by suppressing epithelial-mesenchymal transition, as indicated by increased expression of E-cadherin and decreased expression of Snail and Twist. Diosmin also suppressed autophagic flux, as indicated by increased expression of LC3-II and p62, and induced cell cycle arrest at G1 phase. Importantly, diosmin did not exert serious cytotoxic effects toward control SVG-p12 astrocytes, though it did reduce astrocyte viability at high concentrations. These findings provide potentially helpful support to the development of new therapies for the treatment of GBM.

scholarly journals The role of brevican in glioma: promoting tumor cell motility in vitro and in vivo

BMC Cancer ◽  
2012 ◽  
Vol 12 (1) ◽  
Author(s):  
Renquan Lu ◽  
Chengsheng Wu ◽  
Lin Guo ◽  
Yingchao Liu ◽  
Wei Mo ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Motility ◽  
Tumor Cell Motility

Platelets, Tumor Cell Invasiveness, and Metastasis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-31-SCI-31
Author(s):  
Richard O. Hynes ◽  
Shahinoor Begum ◽  
Myriam Labelle
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Conflicts Of Interest ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Migration And Invasion ◽  
Cell Contact ◽  
Cell Arrest

Abstract Platelets have long been known to promote metastasis, and multiple mechanisms have been proposed to explain this phenomenon, including adhesion, coagulation, and protection against natural killer (NK) cells or turbulence. One mechanism that has been little explored is the possibility that platelets might secrete growth factors or provide other stimuli that could enhance the malignant properties of tumor cells. We have shown that pretreatment of carcinoma cells with platelets induces an EMT-like transformation in their properties in vitro and renders them much more metastatic after introduction into mice. TGF-β, produced by platelets and released on their activation is essential for both the in vitro and the in vivo effects. However, TGF-β alone is insufficient; platelet-tumor cell contact is also required and this contact activates NFkB signaling, which synergizes with the TGF-β signaling. Both signals are required for the enhancement of metastasis. In addition to enhancing migration and invasion in vitro, platelets enhance extravasation in vivo. Earlier work has shown that both P-selectin (expressed on platelets) and L-selectin (expressed on leukocytes) are essential for efficient metastasis, and aggregates of tumor cells, platelets, and leukocytes can be observed at sites of tumor cell arrest and extravasation. It has also been demonstrated by others that leukocytes can enhance extravasation and metastatic seeding. Therefore, we have been interested in the question of the relative roles of platelets and leukocytes in these processes. Which cell types are recruited at the sites of metastatic seeding? Does one cell type depend on another? Which cell types enhance metastasis? What roles do the platelets play in recruiting the other cell types? The involvement of platelets in enhancing metastasis also raises questions about the effects of platelets on circulating tumor cells (CTCs). Could platelets enhance the metastatic capacity of CTCs? Could it be the case that only those CTCs that are associated with platelets and/or leukocytes are functionally involved in seeding metastases? Such aggregates are not scored in most current assays for CTCs and will require new investigative approaches. Platelet participation in metastasis also raises the possibility of therapeutic interventions targeting platelet-specific targets and the paracrine interactions between them and other cells. Disclosures: No relevant conflicts of interest to declare.

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