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1.
Commun Biol ; 5(1): 137, 2022 02 17.
Article in English | MEDLINE | ID: mdl-35177769

ABSTRACT

How mechanical stress actively impacts the physiology and pathophysiology of cells and tissues is little investigated in vivo. The colon is constantly submitted to multi-frequency spontaneous pulsatile mechanical waves, which highest frequency functions, of 2 s period, remain poorly understood. Here we find in vivo that high frequency pulsatile mechanical stresses maintain the physiological level of mice colon stem cells (SC) through the mechanosensitive Ret kinase. When permanently stimulated by a magnetic mimicking-tumor growth analogue pressure, we find that SC levels pathologically increase and undergo mechanically induced hyperproliferation and tumorigenic transformation. To mimic the high frequency pulsatile mechanical waves, we used a generator of pulsed magnetic force stimulation in colonic tissues pre-magnetized with ultra-magnetic liposomes. We observed the pulsatile stresses using last generation ultra-wave dynamical high-resolution imaging. Finally, we find that the specific pharmacological inhibition of Ret mechanical activation induces the regression of spontaneous formation of SC, of CSC markers, and of spontaneous sporadic tumorigenesis in Apc mutated mice colons. Consistently, in human colon cancer tissues, Ret activation in epithelial cells increases with tumor grade, and partially decreases in leaking invasive carcinoma. High frequency pulsatile physiological mechanical stresses thus constitute a new niche that Ret-dependently fuels mice colon physiological SC level. This process is pathologically over-activated in the presence of permanent pressure due to the growth of tumors initiated by pre-existing genetic alteration, leading to mechanotransductive self-enhanced tumor progression in vivo, and repressed by pharmacological inhibition of Ret.


Subject(s)
Colonic Neoplasms/metabolism , Proto-Oncogene Proteins c-ret/metabolism , Animals , Biomarkers, Tumor , Cell Line, Tumor , Cell Transformation, Neoplastic , Female , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Mice, Inbred Strains , Neoplastic Stem Cells , Proto-Oncogene Proteins c-ret/genetics
2.
J Cell Biol ; 217(5): 1571-1587, 2018 05 07.
Article in English | MEDLINE | ID: mdl-29467174

ABSTRACT

Cancer has been characterized as a genetic disease, associated with mutations that cause pathological alterations of the cell cycle, adhesion, or invasive motility. Recently, the importance of the anomalous mechanical properties of tumor tissues, which activate tumorigenic biochemical pathways, has become apparent. This mechanical induction in tumors appears to consist of the destabilization of adult tissue homeostasis as a result of the reactivation of embryonic developmental mechanosensitive pathways in response to pathological mechanical strains. These strains occur in many forms, for example, hypervascularization in late tumors leads to high static hydrodynamic pressure that can promote malignant progression through hypoxia or anomalous interstitial liquid and blood flow. The high stiffness of tumors directly induces the mechanical activation of biochemical pathways enhancing the cell cycle, epithelial-mesenchymal transition, and cell motility. Furthermore, increases in solid-stress pressure associated with cell hyperproliferation activate tumorigenic pathways in the healthy epithelial cells compressed by the neighboring tumor. The underlying molecular mechanisms of the translation of a mechanical signal into a tumor inducing biochemical signal are based on mechanically induced protein conformational changes that activate classical tumorigenic signaling pathways. Understanding these mechanisms will be important for the development of innovative treatments to target such mechanical anomalies in cancer.


Subject(s)
Disease Progression , Mechanotransduction, Cellular , Neoplasms/pathology , Animals , Carcinogenesis/pathology , Extracellular Matrix/metabolism , Humans , Models, Biological
3.
J Hepatol ; 66(2): 424-441, 2017 02.
Article in English | MEDLINE | ID: mdl-27686679

ABSTRACT

Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a centre of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analysed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Epithelial-Mesenchymal Transition/physiology , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/pathology , Cholangiocarcinoma/diagnosis , Cholangiocarcinoma/pathology , Humans , Prognosis
4.
Free Radic Biol Med ; 89: 34-46, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26169728

ABSTRACT

The development and progression of liver cancer are characterized by increased levels of reactive oxygen species (ROS). ROS-induced oxidative stress impairs cell proliferation and ultimately leads to cell death. Although liver cancer cells are especially resistant to oxidative stress, mechanisms of such resistance remain understudied. We identified the MAPK-activated protein kinase 2 (MK2)/heat shock protein 27 (Hsp27) signaling pathway mediating defenses against oxidative stress. In addition to MK2 and Hsp27 overexpression in primary liver tumors compared to adjacent nontumorous tissues, the MK2/Hsp27 pathway is activated by hydrogen peroxide-induced oxidative stress in hepatobiliary cancer cells. MK2 inactivation or inhibition of MK2 or Hsp27 expression increases caspase-3 and PARP cleavage and DNA breaks and therefore cell death. Interestingly, MK2/Hsp27 inhibition decreases antioxidant defenses such as heme oxygenase 1 through downregulation of the transcription factor nuclear factor erythroid-derived 2-like 2. Moreover, MK2/Hsp27 inhibition decreases both phosphorylation of epidermal growth factor receptor (EGFR) and expression of its ligand, heparin-binding EGF-like growth factor. A new identified partner of MK2, the scaffold PDZ protein EBP50, could facilitate these effects through MK2/Hsp27 pathway regulation. These findings demonstrate that the MK2/Hsp27 pathway actively participates in resistance to oxidative stress and may contribute to liver cancer progression.


Subject(s)
Biliary Tract Neoplasms/pathology , Gene Expression Regulation, Neoplastic/drug effects , Hydrogen Peroxide/pharmacology , Intracellular Signaling Peptides and Proteins/metabolism , Liver Neoplasms/pathology , Oxidative Stress/drug effects , Protein Serine-Threonine Kinases/metabolism , Aged , Apoptosis/drug effects , Biliary Tract Neoplasms/drug therapy , Biliary Tract Neoplasms/genetics , Biliary Tract Neoplasms/metabolism , Blotting, Western , Cell Proliferation/drug effects , Female , HSP27 Heat-Shock Proteins/genetics , HSP27 Heat-Shock Proteins/metabolism , Humans , Immunoenzyme Techniques , Immunoprecipitation , Intracellular Signaling Peptides and Proteins/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Lymphatic Metastasis , Male , Middle Aged , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Staging , Oxidants/pharmacology , Phosphorylation/drug effects , Prognosis , Protein Serine-Threonine Kinases/genetics , RNA, Messenger/genetics , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Tumor Cells, Cultured , Two-Hybrid System Techniques
5.
J Hepatol ; 61(2): 325-32, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24704591

ABSTRACT

BACKGROUND & AIMS: Epithelial-mesenchymal transition (EMT) is a cellular process involved in cancer progression. The first step of EMT consists in the disruption of E-cadherin-mediated adherens junctions. Cholangiocarcinoma (CCA), a cancer with a poor prognosis due to local invasion and metastasis, displays EMT features. EGFR, a receptor tyrosine kinase, plays a major role in CCA progression. The aim of the study was to determine if EMT is induced by EGFR in CCA cells. METHODS: In vivo, the expression of E-cadherin was analysed in CCA tumours of 100 patients and correlated with pathological features and EGFR expression, and in a xenograft model in mice treated with gefitinib, an inhibitor of EGFR. In vitro, the regulation of EMT by EGFR was investigated in CCA cell lines. RESULTS: In human CCA, a cytoplasmic localization of E-cadherin occurred in 50% of the tumours was associated with the peripheral type of CCA, tumour size, the presence of satellite nodules and EGFR overexpression. In xenografted tumours, E-cadherin displayed a cytoplasmic pattern whereas the treatment of mice with gefitinib restored the membranous expression of E-cadherin. In vitro, EGF induced scattering of CCA cells that resulted from the disruption of adherens junctions. Internalization and decreased expression of E-cadherin, as well as nuclear translocation of ß-catenin, were observed in EGF-treated CCA cells. In these cells, EMT-transcription factors (i.e., Slug and Zeb-1) and mesenchymal markers (i.e., N-cadherin and α-SMA) were induced, favoring cell invasiveness through cytoskeleton remodeling. All these effects were inhibited by gefitinib. CONCLUSIONS: The EGF/EGFR axis triggers EMT in CCA cells highlighting the key role of this pathway in CCA progression.


Subject(s)
Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic , Cholangiocarcinoma/pathology , Epidermal Growth Factor/physiology , Epithelial-Mesenchymal Transition , ErbB Receptors/physiology , Animals , Cadherins/analysis , Cell Line, Tumor , Cell Movement , Disease Progression , Female , Humans , Mice , Neoplasm Invasiveness
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