95. The relationship between the tumour microenvironment and epithelial-mesenchymal transition in colorectal cancer

2014 ◽  
Vol 40 (11) ◽  
pp. S45
Author(s):  
C.Y. Kong ◽  
J.H. Park ◽  
J. Edwards ◽  
A. Powell ◽  
L. Bennett ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Tumour Microenvironment ◽  
Mesenchymal Transition ◽  
The Relationship

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 FOXO4 Inhibits the Migration and Metastasis of Colorectal Cancer by Regulating the APC2/β-Catenin Axis

2021 ◽  
Vol 9 ◽  
Author(s):  
Yan Sun ◽  
Lin Wang ◽  
Xuehu Xu ◽  
Puqing Han ◽  
Jinghao Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Hct116 Cell ◽  
Suppressor Gene ◽  
Mesenchymal Transition ◽  
Normal Tissues ◽  
Forkhead Box ◽  
The Relationship

Objective: Adenomatous polyposis coli 2 (APC2) is a colorectal cancer (CRC) tumor-suppressor gene. The progression of several kinds of cancer is closely associated with Forkhead box O4 (FOXO4). However, the function of FOXO4 in CRC is unclear. This study focused on the role of FOXO4 and the relationship between FOXO4 and APC2 in CRC migration and metastasis.Methods: The expressions of FOXO4, APC2, and p(S37)-β-catenin were detected in CRC tissues by immunohistochemistry, and their correlation was analyzed using the Spearman coefficient. Chromatin immunoprecipitation was used to test whether FOXO4 binds and regulates APC2 as a transcription factor. Either FOXO4 overexpression or APC2 knockdown was performed in CRC cell lines. The roles of FOXO4 and APC2 were investigated in CRC migration and metastasis.Results: FOXO4 was downregulated in CRC tissues compared with normal tissues and positively correlated with APC2 and p(S37)-β-catenin. FOXO4 could combine the promoter region of APC2 to upregulate its expression and increase the phosphorylated degradation of β-catenin. Stemness genes (CD133, ABCG1, and SOX2) were inhibited by FOXO4 overexpression in SW620 and HCT116 cell lines. Overexpressed FOXO4 suppressed epithelial–mesenchymal transition and the migration of CRC cell lines and metastasis of HCT116 in both the spleen and liver of nude mice, which was reversed by APC2 knockdown.Conclusion: This research demonstrates that overexpressed FOXO4 inhibits the migration and metastasis of CRC cells by enhancing the APC2/β-catenin axis, suggesting that FOXO4 is a potential therapeutic target of CRC.

scholarly journals Interleukin-6 Promotes Epithelial-Mesenchymal Transition and Cell Invasion through Integrin β6 Upregulation in Colorectal Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Qi Sun ◽  
Yukui Shang ◽  
Fengkai Sun ◽  
Xiwen Dong ◽  
Jun Niu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Cell Invasion ◽  
Interleukin 6 ◽  
Inflammatory Cytokine ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Potential ◽  
Mesenchymal Transition ◽  
New Directions ◽  
The Relationship

The metastatic potential of colorectal cancer (CRC) is intensively promoted by the tumor microenvironment (TME) in a paracrine manner. As a pleiotropic inflammatory cytokine, Interleukin-6 (IL-6) is produced and involved in CRC, the same scenario where integrin αvβ6 also becomes upregulated. However, the relationship between IL-6 and integrin αvβ6 as well as their involvement in the crosstalk between CRC and TME remains largely unclear. In the present study, we demonstrated a positive correlation between the expression of IL-6 and integrin β6 in CRC samples. The mutually promotive interaction between CRC and TME was further determined by an indirect coculture system. CRC cells could augment the secretion of IL-6 from fibroblasts, which in return induced invasion and integrin β6 expression of CRC cells. Through the classic IL-6 receptor/STAT-3 signaling pathway, IL-6 mediated the upregulation of integrin β6, which was involved in the invasion and epithelial-mesenchymal transition of CRC cells induced by IL-6. Taken together, our results reveal a paracrine crosstalk between IL-6 signals originating from the TME and increased the integrin β6 level of CRC. IL-6 induces CRC invasion via upregulation of integrin β6 through the IL-6 receptor/STAT-3 signaling pathway. Combined inhibition of IL-6 along with integrin β6-targeted strategy may indicate new directions for antitumor strategies for CRC.

scholarly journals Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 75
Author(s):  
Paula I. Escalante ◽  
Luis A. Quiñones ◽  
Héctor R. Contreras
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Methylenetetrahydrofolate Reductase ◽  
Epithelial Mesenchymal Transition ◽  
Late Onset ◽  
Dihydropyrimidine Dehydrogenase ◽  
Acquired Resistance ◽  
Potential Effect ◽  
Mesenchymal Transition ◽  
Folfox Chemotherapy

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

B7-H4 induces epithelial–mesenchymal transition and promotes colorectal cancer stemness

2021 ◽  
pp. 153323
Author(s):  
Ying Feng ◽  
Zhaoting Yang ◽  
Chengye Zhang ◽  
Nan Che ◽  
Xingzhe Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Stemness ◽  
Mesenchymal Transition

scholarly journals The microRNA-210-Stathmin1 Axis Decreases Cell Stiffness to Facilitate the Invasiveness of Colorectal Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1833
Author(s):  
Tsai-Tsen Liao ◽  
Wei-Chung Cheng ◽  
Chih-Yung Yang ◽  
Yin-Quan Chen ◽  
Shu-Han Su ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Motility ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Cell Stiffness ◽  
Mesenchymal Transition ◽  
Cytoskeletal Dynamics ◽  
Colorectal Cancer Stem Cells

Cell migration is critical for regional dissemination and distal metastasis of cancer cells, which remain the major causes of poor prognosis and death in patients with colorectal cancer (CRC). Although cytoskeletal dynamics and cellular deformability contribute to the migration of cancer cells and metastasis, the mechanisms governing the migratory ability of cancer stem cells (CSCs), a nongenetic source of tumor heterogeneity, are unclear. Here, we expanded colorectal CSCs (CRCSCs) as colonospheres and showed that CRCSCs exhibited higher cell motility in transwell migration assays and 3D invasion assays and greater deformability in particle tracking microrheology than did their parental CRC cells. Mechanistically, in CRCSCs, microRNA-210-3p (miR-210) targeted stathmin1 (STMN1), which is known for inducing microtubule destabilization, to decrease cell elasticity in order to facilitate cell motility without affecting the epithelial–mesenchymal transition (EMT) status. Clinically, the miR-210-STMN1 axis was activated in CRC patients with liver metastasis and correlated with a worse clinical outcome. This study elucidates a miRNA-oriented mechanism regulating the deformability of CRCSCs beyond the EMT process.

scholarly journals AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 801
Author(s):  
Joyce Y. Buikhuisen ◽  
Patricia M. Gomez Barila ◽  
Arezo Torang ◽  
Daniëlle Dekker ◽  
Joan H. de Jong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Surrogate Marker ◽  
High Expression ◽  
Mesenchymal Transition ◽  
High Propensity ◽  
Colorectal Cancer Cells ◽  
Epithelial Compartment ◽  
Selection Of

Colorectal cancer (CRC) is a heterogeneous disease that can currently be subdivided into four distinct consensus molecular subtypes (CMS) based on gene expression profiling. The CMS4 subtype is marked by high expression of mesenchymal genes and is associated with a worse overall prognosis compared to other CMSs. Importantly, this subtype responds poorly to the standard therapies currently used to treat CRC. We set out to explore what regulatory signalling networks underlie the CMS4 phenotype of cancer cells, specifically, by analysing which kinases were more highly expressed in this subtype compared to others. We found AKT3 to be expressed in the cancer cell epithelium of CRC specimens, patient derived xenograft (PDX) models and in (primary) cell cultures representing CMS4. Importantly, chemical inhibition or knockout of this gene hampers outgrowth of this subtype, as AKT3 controls expression of the cell cycle regulator p27KIP1. Furthermore, high AKT3 expression was associated with high expression of epithelial-mesenchymal transition (EMT) genes, and this observation could be expanded to cell lines representing other carcinoma types. More importantly, this association allowed for the identification of CRC patients with a high propensity to metastasise and an associated poor prognosis. High AKT3 expression in the tumour epithelial compartment may thus be used as a surrogate marker for EMT and may allow for a selection of CRC patients that could benefit from AKT3-targeted therapy.

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