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M2-like macrophages induce colon cancer cell invasion via matrix metalloproteinases

Vinnakota, Katyayni LU ; Zhang, Yuan LU ; Selvanesan, Benson Chellakkan LU ; Topi, Geriolda LU ; Salim, Tavga LU ; Sand-Dejmek, Janna LU ; Jönsson, Gunilla LU and Sjölander, Anita LU (2017) In Journal of Cellular Physiology 232(12). p.3468-3480
Abstract

The inflammatory milieu plays an important role in colon cancer development and progression. Previously, we have shown that tumor-associated macrophages (TAMs), an important component of the tumor microenvironment, are enriched in tumors compared with normal tissue and confer a poorer prognosis. In the present study, we found that matrix metallopeptidase-9 (MMP-9), which degrades extracellular matrix proteins, was increased in biopsies from colon cancer patients and in mouse xenografts with SW480 cell-derived tumors. SW480 colon cancer cells exposed to M2-like macrophage-conditioned medium (M2-medium) exhibited increased MMP-9 mRNA, protein expression and gelatinase activity. A similar effect was obtained by the addition of tumor... (More)

The inflammatory milieu plays an important role in colon cancer development and progression. Previously, we have shown that tumor-associated macrophages (TAMs), an important component of the tumor microenvironment, are enriched in tumors compared with normal tissue and confer a poorer prognosis. In the present study, we found that matrix metallopeptidase-9 (MMP-9), which degrades extracellular matrix proteins, was increased in biopsies from colon cancer patients and in mouse xenografts with SW480 cell-derived tumors. SW480 colon cancer cells exposed to M2-like macrophage-conditioned medium (M2-medium) exhibited increased MMP-9 mRNA, protein expression and gelatinase activity. A similar effect was obtained by the addition of tumor necrosis factor-α (TNFα) and leukotriene D4 (LTD4). MMP-9 expression and activity were reduced by a TNFα blocking antibody adalimumab and a cysteinyl leukotriene receptor 1 (CysLTR1, the receptor for LTD4) antagonist montelukast. M2-medium also induced changes in the epithelial-mesenchymal transition (EMT) markers E-cadherin, β-catenin, vimentin, and snail in SW480 cells. We also found that both M2-medium and TNFα and LTD4 induced stabilization/nuclear translocation of β-catenin. Furthermore, we also observed an elongated phenotype that may indicate increased invasiveness, as confirmed in a collagen I invasion assay. M2-medium increased the invasive ability, and a similar effect was also obtained by the addition of TNFα and LTD4. The specific MMP inhibitor I or adalimumab and montelukast reduced the number of invasive cells. In conclusion, our findings show that M2-medium enriched in TNFα and LTD4 promote colon cancer cell invasion via MMP-9 expression and activation and the induction of EMT.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Colon cancer, Epithelial-mesenchymal transition, LTD, M2 macrophages, MMPs, TNFα, Tumor cell invasion, Tumor-associated macrophages
in
Journal of Cellular Physiology
volume
232
issue
12
pages
3468 - 3480
publisher
John Wiley & Sons
external identifiers
  • scopus:85012252427
  • wos:000408155100025
ISSN
0021-9541
DOI
10.1002/jcp.25808
language
English
LU publication?
yes
id
e7bb7b92-4e53-454c-a755-d56083884453
date added to LUP
2017-03-02 10:30:57
date last changed
2018-05-20 04:32:08
@article{e7bb7b92-4e53-454c-a755-d56083884453,
  abstract     = {<p>The inflammatory milieu plays an important role in colon cancer development and progression. Previously, we have shown that tumor-associated macrophages (TAMs), an important component of the tumor microenvironment, are enriched in tumors compared with normal tissue and confer a poorer prognosis. In the present study, we found that matrix metallopeptidase-9 (MMP-9), which degrades extracellular matrix proteins, was increased in biopsies from colon cancer patients and in mouse xenografts with SW480 cell-derived tumors. SW480 colon cancer cells exposed to M2-like macrophage-conditioned medium (M2-medium) exhibited increased MMP-9 mRNA, protein expression and gelatinase activity. A similar effect was obtained by the addition of tumor necrosis factor-α (TNFα) and leukotriene D<sub>4</sub> (LTD<sub>4</sub>). MMP-9 expression and activity were reduced by a TNFα blocking antibody adalimumab and a cysteinyl leukotriene receptor 1 (CysLTR1, the receptor for LTD<sub>4</sub>) antagonist montelukast. M2-medium also induced changes in the epithelial-mesenchymal transition (EMT) markers E-cadherin, β-catenin, vimentin, and snail in SW480 cells. We also found that both M2-medium and TNFα and LTD<sub>4</sub> induced stabilization/nuclear translocation of β-catenin. Furthermore, we also observed an elongated phenotype that may indicate increased invasiveness, as confirmed in a collagen I invasion assay. M2-medium increased the invasive ability, and a similar effect was also obtained by the addition of TNFα and LTD<sub>4</sub>. The specific MMP inhibitor I or adalimumab and montelukast reduced the number of invasive cells. In conclusion, our findings show that M2-medium enriched in TNFα and LTD<sub>4</sub> promote colon cancer cell invasion via MMP-9 expression and activation and the induction of EMT.</p>},
  author       = {Vinnakota, Katyayni and Zhang, Yuan and Selvanesan, Benson Chellakkan and Topi, Geriolda and Salim, Tavga and Sand-Dejmek, Janna and Jönsson, Gunilla and Sjölander, Anita},
  issn         = {0021-9541},
  keyword      = {Colon cancer,Epithelial-mesenchymal transition,LTD,M2 macrophages,MMPs,TNFα,Tumor cell invasion,Tumor-associated macrophages},
  language     = {eng},
  number       = {12},
  pages        = {3468--3480},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Cellular Physiology},
  title        = {M2-like macrophages induce colon cancer cell invasion via matrix metalloproteinases},
  url          = {http://dx.doi.org/10.1002/jcp.25808},
  volume       = {232},
  year         = {2017},
}