Molecular Pathways: Linking Tumor Microenvironment to Epithelial–Mesenchymal Transition in Metastasis

Jung, Hae-Yun; Fattet, Laurent; Yang, Jing

doi:10.1158/1078-0432.ccr-13-3173

Cited by 269 publications

(240 citation statements)

References 57 publications

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“…This inflammatory milieu is thought to be due to a combination of factors, including mechanical factors, such disturbed shear stress (2) and lipid-induced changes in the vascular wall. With regard to the former, a number of studies have linked disturbed shear stress and endothelial production of fibronectin (17,22), a well-established marker of epithelial-to-mesenchymal transition (23,24). Fibronectin has a major role in promoting inflammatory signaling in ECs (2, 21), and multiple studies in mice demonstrate a causal role for fibronectin ground.…”

Section: Discussionmentioning

confidence: 99%

Endothelial-to-mesenchymal transition drives atherosclerosis progression

Chen

Qin

Baeyens

et al. 2015

Journal of Clinical Investigation

410

504

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IntroductionAtherosclerosis is a progressive disorder initiated by biomechanical forces in areas of the vascular tree subjected to disturbed blood flow and a number of systemic factors, including hyperlipidemia, smoking, and diabetes (1, 2). Lipid uptake by the vascular wall leads over time to a gradual buildup of atherosclerotic plaques. Once formed, the plaque continues to expand, leading to a gradual restriction in lumen diameter and compromise of blood flow. Under certain conditions, plaque rupture can precipitate intravascular thrombosis, resulting in complete and sudden interruption of the arterial blood supply. The buildup, growth, and rupture of the plaque have all been associated with the presence of systemic and vascular wall inflammation (3-5). Despite strong data linking vessel wall inflammation to atherosclerosis progression, the mechanism(s) of inflammation-induced atherosclerotic disease progression remains obscure (4), while efforts to halt disease progression by antiinflammatory therapies have failed in clinical trial (3).Recent studies have documented a high incidence of endothelial-to-mesenchymal transition (EndMT) in a number of pathological conditions associated with inflammation, such as myocardial infarction (6), cerebral cavernous malformations (7), portal hypertension (8), pulmonary hypertension (9), and vascular graft failure (10, 11) among others. EndMT is characterized by a change in phenotype of normal endothelial cells (ECs) that assume the shape and properties of mesenchymal cells (fibroblasts, smooth muscle cells [SMCs]), including enhanced proliferation and migration; secretion of extracellular matrix proteins, such as fibronectin and collagen; and expression of various leukocyte adhesion molecules.TGF-β has been identified as the central player in driving EndMT progression (12, 13), but the processes leading to activation of its signaling remain poorly defined. We have previously reported that a reduction in endothelial FGF-mediated signaling induced by knockout of either the key intracellular signal mediator FGF receptor substrate 2 α (FRS2α) (10) or the primary FGF receptor in the endothelium (FGF receptor 1 [FGFR1]) (14) activates TGF-β signaling, leading to EndMT.The unusual feature of FGFR1 biology is that FGFR1's expression in ECs is affected by certain inflammatory stimuli, including IFN-γ, TNF-α, and IL-1β, that induce a profound reduction in its expression (10). Since these are precisely the inflammatory mediators found in atherosclerotic plaques, we set out to investigate the occurrence and role of EndMT in atherosclerosis.Studies in cell culture and mouse models demonstrated that both oscillatory fluid shear stress and soluble inflammatory mediators reduced FGFR1 expression and signaling and promoted TGF-β signaling and EndMT. In addition, analysis of human coronary arteries demonstrated a strong correlation among endothelial FGFR1 expression, increased TGF-β signaling, and the appearance of EndMT with the severity of atherosclerosis. Together, these findings point to...

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Section: Discussionmentioning

confidence: 99%

Endothelial-to-mesenchymal transition drives atherosclerosis progression

Chen

Qin

Baeyens

et al. 2015

Journal of Clinical Investigation

410

504

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“…HIF‐1α is known to induce transcription of more than 60 genes and to play an important role in CAFs activation and release of a great number of proangiogenic factors including SDF‐1, IL‐8, and VEGF35, 65 also examined in our present study. CAFs produce a variety of ECM proteins such as fibronectin, TNC, and collagens, the structural components that make up connective tissue and contribute to the dense fibrous nature of solid tumors 66, 67, 68, 69, 70, 71. The metabolism of collagen is deregulated in cancer by the increased expression, turnover, elevated deposition, and altered organization with enhanced matrix metalloproteinases (MMPs) activity, all implicated in tumor progression 67, 68.…”

Section: Discussionmentioning

confidence: 99%

“…The tumor invasion and metastasis are initiated by EMT program involving cells acquiring mesenchymal phenotype characterized with decreased cell‐to‐cell adhesion, increased motility and invasive properties. Such cells once detached from primary tumor invade surrounding tissues through collective or individual cell migration 3, 20, 21, 22, 23, 24, 25, 26, 67, 68, 69, 70, 71, 73. Therefore, we propose that fibroblasts infected with H. pylori (cagA+vacA+) likely acquired characteristics of CAFs with changes in morphology and elevated HGF, TGFβ, and additionally IL‐6 and SDF‐1 release, which may enhance EMT program in epithelial gastric cells.…”

Section: Discussionmentioning

confidence: 99%

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

et al. 2018

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BackgroundMajor human gastrointestinal pathogen Helicobacter pylori (H. pylori) colonizes the gastric mucosa causing inflammation and severe complications including cancer, but the involvement of fibroblasts in the pathogenesis of these disorders in H. pylori‐infected stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts. Their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue; however, the interaction between H. pylori and fibroblasts remains unknown. We determined the effect of coincubation of normal rat gastric fibroblasts with alive H. pylori (cagA+vacA+) and H. pylori (cagA−vacA−) strains on the differentiation of these fibroblasts into cells possessing characteristics of cancer‐associated fibroblasts (CAFs) able to induce epithelial‐mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM‐1).Materials and MethodsThe panel of CAFs markers mRNA was analyzed in H. pylori (cagA+vacA+)‐infected fibroblasts by RT‐PCR. After insert coculture of differentiated fibroblasts with RGM‐1 cells from 24 up to 48, 72, and 96 hours, the mRNA expression for EMT‐associated genes was analyzed by RT‐PCR.ResultsThe mRNA expression for CAFs markers was significantly increased after 72 hours of infection with H. pylori (cagA+vacA+) but not H. pylori (cagA−vacA−) strain. Following coculture with CAFs, RGM‐1 cells showed significant decrease in E‐cadherin mRNA, and the parallel increase in the expression of Twist and Snail transcription factors mRNA was observed along with the overexpression of mRNAs for TGFβR, HGFR, FGFR, N‐cadherin, vimentin, α‐SMA, VEGF, and integrin‐β1.Conclusion Helicobacter pylori (cagA+vacA+) strain induces differentiation of normal fibroblasts into CAFs, likely to initiate the EMT process in RGM‐1 epithelial cell line.

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“…During EMT, CTCs are generated from the primary tumor and, subsequently, invade and colonize distant organs (41). Hypoxia is involved directly and indirectly in the induction of EMT and, consequently, in higher rates of metastases (49). Although the relationship between CTCs and tumor hypoxia has not been fully investigated, some preliminary reports demonstrated an impact of hypoxic tumor microenvironment on modulation and determination of the metastatic ability of CTCs.…”

Section: Effect Of Hypoxic Stress On Tumor Target Plasticitymentioning

confidence: 99%

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Noman

Hasmim

Messai

et al. 2015

American Journal of Physiology-Cell Physiology

320

310

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-The tumor microenvironment is a complex system, playing an important role in tumor development and progression. Besides cellular stromal components, extracellular matrix fibers, cytokines, and other metabolic mediators are also involved. In this review we outline the potential role of hypoxia, a major feature of most solid tumors, within the tumor microenvironment and how it contributes to immune resistance and immune suppression/tolerance and can be detrimental to antitumor effector cell functions. We also outline how hypoxic stress influences immunosuppressive pathways involving macrophages, myeloid-derived suppressor cells, T regulatory cells, and immune checkpoints and how it may confer tumor resistance. Finally, we discuss how microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions.hypoxia; hypoxia-inducible factor; tumor microenvironment; myeloid cells; lymphoid cells; immune suppression; cancer stem cells; programmed death-ligand 1; epithelial-mesenchymal transition; circulating tumor cells; autophagy and antitumor immune response IT HAS BECOME INCREASINGLY apparent that malignant cells exist in a complex cellular and extracellular microenvironment that plays key roles in the initiation and maintenance of the malignant phenotype. Among the microenvironmental factors that play a dominant role in neoplasia, hypoxia is believed to be one of the most relevant in the neoplastic response of tumor cells. It is widely appreciated that the majority of malignancies create a hostile hypoxic microenvironment that can hamper cellmediated immunity and dampen the efficacy of the immune response. Poorly vascularized and hypoxic zones inside solid tumors contribute to immune tolerance of tumor cells by impeding the homing of immunocompetent cells into tumors and inhibiting their antitumor efficacy. Several regulatory mechanisms can occur concurrently within the hypoxic tumor microenvironment, resulting in multiple redundant levels of immune cell plasticity and suppression, tumor plasticity, and functional heterogeneity. Hypoxic stress clearly plays a crucial role in tumor promotion and immune escape by controlling angiogenesis and favoring immune suppression and tumor resistance. Like other therapeutic attempts, immunotherapy is heavily hampered by the morphologically aberrant tumor microvasculature, preventing migration of immune effector cells into established tumors. Many strategies are emerging for changing the immunosuppressive nature of the tumor to a microenvironment able to support antitumor immunity. The identification of ways to induce a permissive and less hostile tumor microenvironment to avoid tumor resistance and immune suppression is of major interest and pertinence. Hypoxia as an Integral Component of the Tumor MicroenvironmentAll life on Earth depends on O 2 , and all physiological and pathological processes of a living cell rely principally on O 2 (103). Hypoxia is characterized by lack of O 2 , and hypoxic tissues are inadequately oxygenated (107). A p...

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Molecular Pathways: Linking Tumor Microenvironment to Epithelial–Mesenchymal Transition in Metastasis

Cited by 269 publications

References 57 publications

Endothelial-to-mesenchymal transition drives atherosclerosis progression

Endothelial-to-mesenchymal transition drives atherosclerosis progression

Role of Helicobacter pylori infection in cancer‐associated fibroblast‐induced epithelial‐mesenchymal transition in vitro

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

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