Tumour microenvironment: a non-negligible driver for epithelial−mesenchymal transition in colorectal cancer

2021 ◽  
Vol 23 ◽  
Author(s):  
Lei Han ◽  
Shuyi Wang ◽  
Chen Wei ◽  
Yan Fang ◽  
Sihao Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Critical Role ◽  
Inflammatory Cells ◽  
Tumour Microenvironment ◽  
Tumour Cells ◽  
Mesenchymal Transition ◽  
Tumour Metastasis ◽  
Favourable Environment

Abstract Cancer remains the leading cause of death worldwide, and metastasis is still the major cause of treatment failure for cancer patients. Epithelial–mesenchymal transition (EMT) has been shown to play a critical role in the metastasis cascade of epithelium-derived carcinoma. Tumour microenvironment (TME) refers to the local tissue environment in which tumour cells produce and live, including not only tumour cells themselves, but also fibroblasts, immune and inflammatory cells, glial cells and other cells around them, as well as intercellular stroma, micro vessels and infiltrated biomolecules from the nearby areas, which has been proved to widely participate in the occurrence and progress of cancer. Emerging and accumulating studies indicate that, on one hand, mesenchymal cells in TME can establish ‘crosstalk’ with tumour cells to regulate their EMT programme; on the other, EMT-tumour cells can create a favourable environment for their own growth via educating stromal cells. Recently, our group has conducted a series of studies on the interaction between tumour-associated macrophages (TAMs) and colorectal cancer (CRC) cells in TME, confirming that the interaction between TAMs and CRC cells mediated by cytokines or exosomes can jointly promote the metastasis of CRC by regulating the EMT process of tumour cells and the M2-type polarisation process of TAMs. Herein, we present an overview to describe the current knowledge about EMT in cancer, summarise the important role of TME in EMT, and provide an update on the mechanisms of TME-induced EMT in CRC, aiming to provide new ideas for understanding and resisting tumour metastasis.

scholarly journals Recent Advances: The Imbalance of Immune Cells and Cytokines in the Pathogenesis of Hepatocellular Carcinoma

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 338
Author(s):  
Kumar Jayant ◽  
Nagy Habib ◽  
Kai W. Huang ◽  
Jane Warwick ◽  
Ramesh Arasaradnam
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Cells ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Liver Parenchyma ◽  
Tumour Microenvironment ◽  
Tumour Immunity ◽  
Mesenchymal Transition ◽  
Increased Risk ◽  
Inflammatory State

Recent advancement in the immunological understanding of genesis of hepatocellular carcinoma (HCC) has implicated a decline in anti-tumour immunity on the background of chronic inflammatory state of liver parenchyma. The development of HCC involves a network of immunological activity in the tumour microenvironment involving continuous interaction between tumour and stromal cells. The reduction in anti-tumour immunity is secondary to changes in various immune cells and cytokines, and the tumour microenvironment plays a critical role in modulating the process of liver fibrosis, hepatocarcinogenesis, epithelial-mesenchymal transition (EMT), tumor invasion and metastasis. Thus, it is considered as one of primary factor behind the despicable tumour behavior and observed poor survival; along with increased risk of recurrence following treatment in HCC. The primary intent of the present review is to facilitate the understanding of the complex network of immunological interactions of various immune cells, cytokines and tumour cells associated with the development and progression of HCC.

scholarly journals Role of circadian rhythm disorders in EMT and tumor–immune interactions in endocrine-related cancers

2021 ◽  
Author(s):  
Eva Hadadi ◽  
Hervé Acloque
Keyword(s):  
Circadian Rhythm ◽  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Tumour Microenvironment ◽  
Tissue Level ◽  
Mesenchymal Transition ◽  
Animal Physiology ◽  
Molecular Machinery ◽  
Epithelial Tumours ◽  
Cell Dissemination

The circadian rhythm is a major environmental regulator of plants and animal physiology. The alternation of days and nights is translated at the cell and tissue level thanks to a molecular machinery, called the circadian clock. This clock controls in particular numerous endocrine functions and its imbalances can have serious consequences on homeostasis. This is particularly true for the development of endocrine-related cancers, like breast, ovarian and prostate cancer. Circadian rhythm disorder (CRD) not only affects key hormone levels (including estrogen, melatonin, insulin, glucagon, cortisol) but also favors a pro-inflammatory and immunosuppressive phenotype in the tumour microenvironment. This particular aspect is conducive to epithelial-mesenchymal transition (EMT) of solid epithelial tumours and cancer cell dissemination. It also favors resistance to chemo- and immunotherapy. Here, we discuss the current knowledge on this crosstalk between CRD, EMT and the immune microenvironment in endocrine-related cancers and its consequences for the development of efficient therapies.

scholarly journals DNAJB6 governs a novel regulatory loop determining Wnt/β-catenin signalling activity

2012 ◽  
Vol 444 (3) ◽  
pp. 573-580 ◽  
Author(s):  
Mitchell E. Menezes ◽  
Aparna Mitra ◽  
Lalita A. Shevde ◽  
Rajeev S. Samant
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Tumour Microenvironment ◽  
Negative Control ◽  
Signalling Pathway ◽  
Transition Analysis ◽  
Mesenchymal Transition ◽  
Tumour Metastasis ◽  
Dkk1 Expression ◽  
Exogenous Expression ◽  
Regulatory Loop

DKK1 (dickkopf 1 homologue) is a secreted inhibitor of the Wnt signalling pathway and a critical modulator of tumour promotion and the tumour microenvironment. However, mechanisms regulating DKK1 expression are understudied. DNAJB6 {DnaJ [HSP40 (heat-shock protein 40 kDa)] homologue, subfamily B, member 6} is an HSP40 family member whose expression is compromized during progression of breast cancer and melanoma. Inhibition of the Wnt/β-catenin signalling pathway by up-regulation of DKK1 is one of the key mechanisms by which DNAJB6 suppresses tumour metastasis and EMT (epithelial–mesenchymal transition). Analysis of the DKK1 promoter to define the cis-site responsible for its up-regulation by DNAJB6 revealed the presence of two binding sites for a transcriptional repressor, MSX1 (muscle segment homeobox 1). Our investigations showed that MSX1 binds the DKK1 promoter and inhibits DKK1 transcription. Interestingly, silencing DNAJB6 resulted in up-regulation of MSX1 concomitant with increased stabilization of β-catenin. ChIP (chromatin immunoprecipitation) studies revealed that β-catenin binds the MSX1 promoter and stabilization of β-catenin elevates MSX1 transcription, indicating that β-catenin works as a transcription co-activator for MSX1. Functionally, exogenous expression of MSX1 in DNAJB6-expressing cells promotes the mesenchymal phenotype by suppression of DKK1. Thus we have identified a novel regulatory mechanism of DNAJB6-mediated DKK1 transcriptional up-regulation that can influence EMT. DKK1 is a feedback regulator of β-catenin levels and thus our studies also define an additional negative control of this β-catenin/DKK1 feedback loop by MSX1, which may potentially contribute to excessive stabilization of β-catenin.

scholarly journals The Biological and Biomechanical Role of Transglutaminase-2 in the Tumour Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2788
Author(s):  
Robert Tempest ◽  
Sonia Guarnerio ◽  
Rawan Maani ◽  
Jamie Cooper ◽  
Nicholas Peake
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Transglutaminase 2 ◽  
Biomechanical Properties ◽  
Tumour Microenvironment ◽  
Cell Phenotype ◽  
Tissue Remodelling ◽  
Direct Role ◽  
Mesenchymal Transition ◽  
Cellular Processes

Transglutaminase-2 (TG2) is the most highly and ubiquitously expressed member of the transglutaminase enzyme family and is primarily involved in protein cross-linking. TG2 has been implicated in the development and progression of numerous cancers, with a direct role in multiple cellular processes and pathways linked to apoptosis, chemoresistance, epithelial-mesenchymal transition, and stem cell phenotype. The tumour microenvironment (TME) is critical in the formation, progression, and eventual metastasis of cancer, and increasing evidence points to a role for TG2 in matrix remodelling, modulation of biomechanical properties, cell adhesion, motility, and invasion. There is growing interest in targeting the TME therapeutically in response to advances in the understanding of its critical role in disease progression, and a number of approaches targeting biophysical properties and biomechanical signalling are beginning to show clinical promise. In this review we aim to highlight the wide array of processes in which TG2 influences the TME, focussing on its potential role in the dynamic tissue remodelling and biomechanical events increasingly linked to invasive and aggressive behaviour. Drug development efforts have yielded a range of TG2 inhibitors, and ongoing clinical trials may inform strategies for targeting the biomolecular and biomechanical function of TG2 in the TME.

Circulating tumour cells and the epithelial mesenchymal transition in colorectal cancer

2014 ◽  
Vol 67 (10) ◽  
pp. 848-853 ◽  
Author(s):  
S H-S Lim ◽  
T M Becker ◽  
W Chua ◽  
W L Ng ◽  
P de Souza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Tumour Cells ◽  
Circulating Tumour Cells ◽  
Mesenchymal Transition

scholarly journals LincHOXA10 Facilitates Colorectal Cancer Development By Regulating HOXA10-Mediated Epithelial-Mesenchymal Transtion

2020 ◽  
Author(s):  
Huifang Zhu ◽  
Yongzhen Li ◽  
Yinghui Zhang ◽  
Zheying Zhang ◽  
Yongxia Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Mesenchymal Transition

Abstract Background: Long non-coding RNAs (lncRNAs) have been reported to play an important role in tumorigenesis and metastasis of human colorectal cancer (CRC). However, the specific role of LincHOXA10 in CRC remains unknown.Methods: The expression of LincHOXA10 and HOXA10 in CRC cells and tissue samples was measured by quantitative reverse transcription PCR (qRT-PCR). The protein expression of HOXA10, E-cadherin, N-cadherin, Vinmentin, p-smad2 and p-smad3 was assessed by Western blotting or immunofluorescence staining. Cell proliferation, migration, and invasion were assessed by the MTT and transwell assays. Tumor growth in vivo was carried out by subcutaneous tumor formation in nude mice.Results: In the present study, we found that LincHOXA10 expression was significantly higher in human CRC tissues than the paired normal tissues. In fact, LincHOXA10 level correlated with the CRC tumor sizes and lymphatic metastasis. In cultured CRC cells, knockdown of LincHOXA10 inhibited cell proliferation, migration and invasion. LincHOXA10 deficiency also attenuated CRC tumor growth in vivo. Mechanistically, LincHOXA10 interacted with HOXA10 and regulated its expression. HOXA10 levels were interrelated to the LincHOXA10 level in CRC cells. Functionally, HOXA10 was essential for TGF-β1/SMADs-induced epithelial -mesenchymal transition of CRC cells, and HOXA10 played a critical role in mediating the function of LincHOXA10. Importantly, HOXA10 expression was significantly up-regulated in human CRC tissues.Conclusions: LincHOXA10 facilitates CRC development and metastasis via regulating HOXA10-mediated epithelial-mesenchymal transition of CRC cells.

scholarly journals IL-13/STAT6 signaling plays a critical role in the epithelial-mesenchymal transition of colorectal cancer cells

Oncotarget ◽  
2016 ◽  
Vol 7 (38) ◽  
pp. 61183-61198 ◽  
Author(s):  
Hui Cao ◽  
Jing Zhang ◽  
Hong Liu ◽  
Ledong Wan ◽  
Honghe Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mesenchymal Transition ◽  
Colorectal Cancer Cells

scholarly journals 25-hydroxycholesterol Regulates Migration, Invasion and EMT of Colorectal Cancer through miR-92a-3p/ACAA1/NF-κB Pathway

2021 ◽  
Author(s):  
Saisai Wang ◽  
Rushan Fei ◽  
Xijuan Xu ◽  
Jie Xu ◽  
Yuanyuan Yao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Plasma Cholesterol ◽  
Critical Role ◽  
Xenograft Model ◽  
Immunofluorescent Staining ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Abstract Background: Colorectal cancer (CRC) is one of the most common malignances worldwide. Several studies suggest a positive association between high plasma cholesterol level and CRC. 25-hydroxycholesterol (25-HC) is enzymatically produced by cholesterol 25-hydorxylase in various organs and is involved in many processes. However, the critical role of 25-HC in the tumor growth and progression of CRC is largely unknown. Methods: CCK-8 assay, flow cytometry and Transwell migration and invasion assays were used to determine the effects of 25-HC on CRC cells proliferation, apoptosis and metastasis. Subcutaneous xenograft model and intra-splenic injection mouse model were established to investigate the effects of 25-HC on CRC in vivo. Immunohistochemistry staining was performed to determine the matrix metalloproteinases (MMPs) expressions in mice tumors and acetyl-CoA acyltransferase 1 (ACAA1) expression in human CRC tissues. The expressions of E-cadherin, N-cadherin and Vimentin were examined by immunofluorescent staining. MiR-92a-3p mimic, inhibitor and ACAA1 vector were constructed and transfected into LoVo cells. Results: 25-HC promotes CRC cells migration, invasion, and metastasis both in vitro and in vivo without affecting cells proliferation and apoptosis, accompanied by the upregulation of the expressions of MMPs and epithelial-mesenchymal transition (EMT) related markers. Mechanistically, miR-92a-3p expression is significantly elevated after 25-HC stimulation, while ACAA1 expression is down-regulated and negatively associated with tumor progression. Luciferase reporter assay confirms that miR-92a-3p could directly target ACAA1. Subsequent investigation indicates that nuclear factor (NF)-κB signaling is the downstream pathways of miR-92a-3p-ACAA1 axis in CRC cells. Conclusions: 25-HC promotes CRC cells metastasis by regulating cells migration, invasion and EMT through miR-92a-3p/ACAA1/NF-κB pathway.Trial registration: The current study was approved by the Ethics Committee of the First Affiliated Hospital, Zhejiang University on March22, 2018. The permission number was 2018-706 and 2020-1000.

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