M2-like macrophages induce colon cancer cell invasion via matrix metalloproteinases
(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
- 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
- organization
- publishing date
- 2017
- 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 Inc.
- external identifiers
-
- scopus:85012252427
- pmid:28098359
- 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
- 2024-03-31 05:07:45
@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}},
keywords = {{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 Inc.}},
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}},
doi = {{10.1002/jcp.25808}},
volume = {{232}},
year = {{2017}},
}