Invasive Colon Cancer Cells Induce Transdifferentiation of Endothelium to Cancer-Associated Fibroblasts through Microtubules Enriched in Tubulin-β3

Colon cancer, the second leading cause of cancer-related deaths in the world, is usually diagnosed in invasive stages. The interactions between cancer cells and cells located in their niche remain the crucial mechanism inducing tumor metastasis. The most important among those cells are cancer-associated fibroblasts (CAFs), the heterogeneous group of myofibroblasts transdifferentiated from numerous cells of different origin, including endothelium. The endothelial-to-mesenchymal transition (EndMT) is associated with modulation of cellular morphology, polarization and migration ability as a result of microtubule cytoskeleton reorganization. Here we reveal, for the first time, that invasive colon cancer cells regulate EndMT of endothelium via tubulin-β3 upregulation and its phosphorylation. Thus, we concluded that therapies based on inhibition of tubulin-β3 expression or phosphorylation, or blocking tubulin-β3’s recruitment to the microtubules, together with anti-inflammatory chemotherapeutics, are promising means to treat advanced stages of colon cancer.

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Epithelial–mesenchymal transition and metastasis of colon cancer cells induced by the FAK pathway in cancer-associated fibroblasts

Journal of International Medical Research ◽

10.1177/0300060520931242 ◽

2020 ◽

Vol 48 (6) ◽

pp. 030006052093124

Author(s):

Xuefeng Xuefeng ◽

Ming-Xing Hou ◽

Zhi-Wen Yang ◽

Agudamu Agudamu ◽

Feng Wang ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Epithelial Mesenchymal Transition ◽

3D Culture ◽

Cancer Associated Fibroblasts ◽

Colon Cancer Cells ◽

Mesenchymal Transition ◽

Lovo Cells ◽

Related Proteins

Objective The role and mechanism of tetrathiomolybdate (TM) in cancer-associated fibroblasts (CAFs) in colon cancer using three-dimensional (3D) culture were investigated, and the associations between the focal adhesion kinase (FAK) pathway and epithelial–mesenchymal transition (EMT) in CAFs were explored. Methods A 3D co-culture model of colon cancer LOVO cells with CAFs and normal fibroblasts (NFs) was established using Matrigel as a scaffold material. The differential expression of LOXL2 (lysyl oxidase-like 2) in the supernatant of CAFs and NFs was determined using ELISA, and expression levels of EMT-related proteins and FAK signaling pathway-related proteins were determined using western blot. Results LOXL2 levels secreted by CAFs were higher compared with that secreted by NFs. In the CAF + LOVO group, compared with the LOVO group, E-cadherin expression decreased significantly, while N-cadherin and F-PAK expression increased significantly. TM results were opposite compared with the above results. Conclusions CAFs stimulate EMT in human colon cancer LOVO cells by secreting LOXL2 to activate the FAK signaling pathway, thereby promoting tumor metastasis. TM inhibited the occurrence of EMT in the CAF-induced colon cancer LOVO cell line, thereby reducing the invasion and metastasis of colon cancer cells.

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Phospholipase D activation mediates growth and migration of colon cancer cells interacting with cancer-associated fibroblasts

Cellular and Molecular Biology ◽

10.14715/cmb/2018.64.14.14 ◽

2018 ◽

Vol 64 (14) ◽

pp. 84 ◽

Cited By ~ 2

Author(s):

Salem Majdop ◽

Yehuda Skornick ◽

Shmuel Avital ◽

Liron Berkovich

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Phospholipase D ◽

Cancer Associated Fibroblasts ◽

Colon Cancer Cells ◽

And Migration

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CXCL2-CXCR2 axis mediates αV integrin-dependent peritoneal metastasis of colon cancer cells

Clinical & Experimental Metastasis ◽

10.1007/s10585-021-10103-0 ◽

2021 ◽

Author(s):

Mattias Lepsenyi ◽

Nader Algethami ◽

Amr A. Al-Haidari ◽

Anwar Algaber ◽

Ingvar Syk ◽

...

Keyword(s):

Colon Cancer ◽

Cell Adhesion ◽

Cancer Cells ◽

Cancer Cell ◽

Colon Cancer Cell ◽

Colon Cancer Cells ◽

Cancer Cell Adhesion ◽

And Migration ◽

Cxcr2 Antagonist

AbstractPeritoneal metastasis is an insidious aspect of colorectal cancer. The aim of the present study was to define mechanisms regulating colon cancer cell adhesion and spread to peritoneal wounds after abdominal surgery. Mice was laparotomized and injected intraperitoneally with CT-26 colon carcinoma cells and metastatic noduli in the peritoneal cavity was quantified after treatment with a CXCR2 antagonist or integrin-αV-antibody. CT-26 cells expressed cell surface chemokine receptors CXCR2, CXCR3, CXCR4 and CXCR5. Stimulation with the CXCR2 ligand, CXCL2, dose-dependently increased proliferation and migration of CT-26 cells in vitro. The CXCR2 antagonist, SB225002, dose-dependently decreased CXCL2-induced proliferation and migration of colon cancer cells in vitro. Intraperitoneal administration of CT-26 colon cancer cells resulted in wide-spread growth of metastatic nodules at the peritoneal surface of laparotomized animals. Laparotomy increased gene expression of CXCL2 at the incisional line. Pretreatment with CXCR2 antagonist reduced metastatic nodules by 70%. Moreover, stimulation with CXCL2 increased CT-26 cell adhesion to extracellular matrix (ECM) proteins in a CXCR2-dependent manner. CT-26 cells expressed the αV, β1 and β3 integrin subunits and immunoneutralization of αV abolished CXCL2-triggered adhesion of CT-26 to vitronectin, fibronectin and fibrinogen. Finally, inhibition of the αV integrin significantly attenuated the number of carcinomatosis nodules by 69% in laparotomized mice. These results were validated by use of the human colon cancer cell line HT-29 in vitro. Our data show that colon cancer cell adhesion and growth on peritoneal wound sites is mediated by a CXCL2-CXCR2 signaling axis and αV integrin-dependent adhesion to ECM proteins.

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Role of SPARC in the epithelial mesenchymal transition induced by PTHrP in human colon cancer cells

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2021.111253 ◽

2021 ◽

pp. 111253

Author(s):

Pedro Carriere ◽

Natalia Calvo ◽

María Belén Novoa ◽

Fernanda Lopez-Moncada ◽

Alexander Riquelme ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Human Colon ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Mesenchymal Transition ◽

Human Colon Cancer Cells

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EMT Participates in the Regulation of Exosomes Secretion and Function in Esophageal Cancer Cells

Technology in Cancer Research & Treatment ◽

10.1177/15330338211033077 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110330

Author(s):

Chuangui Chen ◽

Zhao Ma ◽

Hongjing Jiang

Keyword(s):

Esophageal Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Promoting Effect ◽

Migration Ability ◽

Mesenchymal Transition ◽

Invasion And Migration ◽

And Migration ◽

And Function ◽

Esophageal Cancer Cells

Epithelial-mesenchymal transition (EMT) is a key step in tumor invasion and distant metastasis. Abundant evidence has documented that exosomes can mediate EMT of tumor cells and endow them with the ability of invasion and migration. However, there are few studies focusing on whether EMT can reverse the secretion of exosomes. In this study, 2 esophageal cancer cells (FLO-1 and SK-GT-4) were selected to compare the migration ability and EMT activation, and to further analyze the secretion ability of exosomes of the 2 cell lines. According to the results, inhibited activation of EMT in FLO-1 cells with relatively high migration ability could effectively reduce the secretion of exosomes. Besides, in SK-GT-4 cells, EMT activation induced by TGF-β could promote the secretion of exosomes. FLO-1 cell derived exosomes exhibited a paracrine effect of promoting the migration of SK-GT-4 cells, and the use of EMT inhibitors could weaken this ability. Furthermore, inhibition of EMT could change the relative content of some miRNAs in exosomes, with a particularly significant downregulation in the expression of miR-196-5p, miR-21-5p and miR-194-5p. Significantly, artificial transfection of the 3 miRNAs into exosomes by electroporation resulted in the recovery of migration-promoting effect of exosomes. Subsequent experiments further revealed that the effect of EMT on these miRNAs could be explained by the intracellular transcription level or the specific sorting mechanism of exosomes. To sum up, our study undoubtedly reveals that EMT has a regulatory effect on exosomes in the quantity and contents in esophageal cancer cells. Significantly, findings in our study provide experimental evidence for the interaction of EMT with the secretion and sorting pathway of exosomes, and also give a new direction for the further study of tumor metastasis.

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SRPK2 promotes the growth and migration of the colon cancer cells

Gene ◽

10.1016/j.gene.2016.03.051 ◽

2016 ◽

Vol 586 (1) ◽

pp. 41-47 ◽

Cited By ~ 13

Author(s):

Jian Wang ◽

Hai-Feng Wu ◽

Wei Shen ◽

Dong-Yan Xu ◽

Ting-Yan Ruan ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Colon Cancer Cells ◽

And Migration

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Kopsanone inhibits proliferation and migration of invasive colon cancer cells

Phytotherapy Research ◽

10.1002/ptr.7078 ◽

2021 ◽

Author(s):

Daniella Paiva Bonfim ◽

Celso Vataru Nakamura ◽

João Xavier Araújo Júnior ◽

Greisiele Lorena Pessini ◽

Paulo Emílio Correa Leite ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Colon Cancer Cells ◽

And Migration ◽

Proliferation And Migration

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Prevention of High Glucose-Mediated EMT by Inhibition of Hsp70 Chaperone

International Journal of Molecular Sciences ◽

10.3390/ijms22136902 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6902

Author(s):

Alina D. Nikotina ◽

Snezhana A. Vladimirova ◽

Elena Y. Komarova ◽

Dmitry Alexeev ◽

Sergey Efremov ◽

...

Keyword(s):

Colon Cancer ◽

Transcription Factors ◽

Cell Motility ◽

Cancer Cells ◽

High Glucose ◽

Binding Capacity ◽

Colon Cancer Cells ◽

Mesenchymal Transition ◽

Hsp70 Chaperone ◽

Migration Capacity

Hyperglycemia may contribute to the progression of carcinomas by triggering epithelial-to-mesenchymal transition (EMT). Some proteostasis systems are involved in metastasis; in this paper, we sought to explore the mechanism of Hsp70 chaperone in EMT. We showed that knockdown of Hsp70 reduced cell migration capacity concomitantly with levels of mRNA of the Slug, Snail, and Twist markers of EMT, in colon cancer cells incubated in high glucose medium. Conversely, treatment of cells with Hsp70 inducer U-133 were found to elevate cell motility, along with the other EMT markers. To prove that inhibiting Hsp70 may reduce EMT efficiency, we treated cells with a CL-43 inhibitor of the HSF1 transcription factor, which lowered Hsp70 and HSF1 content in the control and induced EMT in carcinoma cells. Importantly, CL-43 reduced migration capacity, EMT-linked transcription factors, and increased content of epithelial marker E-cadherin in colon cancer cells of three lines, including one derived from a clinical sample. To prove that Hsp70 chaperone should be targeted when inhibiting the EMT pathway, we treated cancer cells with 2-phenylethynesulfonamide (PES) and demonstrated that the compound inhibited substrate-binding capacity of Hsp70. Furthermore, PES suppressed EMT features, cell motility, and expression of specific transcription factors. In conclusion, the Hsp70 chaperone machine efficiently protects mechanisms of the EMT, and the safe inhibitors of the chaperone are needed to hamper metastasis at its initial stage.

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