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Crosstalk between colorectal cancer cells and tumour-associated macrophages

Zhang, Yuan LU (2013) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2013:92.
Abstract (Swedish)
Popular Abstract in English

Colorectal cancer (CRC) is a cancer caused by uncontrolled cell growth in colon or rectum. CRC is the third most common cancer and the fourth leading cause of cancer related death in the world. It is a multifactorial disease, both genetic predisposition and environmental play a role in the development of CRC. CRC is closely linked to chronic inflammation. Patients with inflammatory bowel disease (IBD) have an increased risk of developing CRC. Tumours are surrounded by the cellular milieu called tumour microenvironment, which is an important hallmark of cancer. In this study, we investigated how colon cancer crosstalk with its microenvironment.

Extracellular matrix (ECM) maintains the... (More)
Popular Abstract in English

Colorectal cancer (CRC) is a cancer caused by uncontrolled cell growth in colon or rectum. CRC is the third most common cancer and the fourth leading cause of cancer related death in the world. It is a multifactorial disease, both genetic predisposition and environmental play a role in the development of CRC. CRC is closely linked to chronic inflammation. Patients with inflammatory bowel disease (IBD) have an increased risk of developing CRC. Tumours are surrounded by the cellular milieu called tumour microenvironment, which is an important hallmark of cancer. In this study, we investigated how colon cancer crosstalk with its microenvironment.

Extracellular matrix (ECM) maintains the morphology of cells, as well as mediates various signalling pathways. Under inflammatory or tumoral conditions, remodelling of ECM often occurs. Matrix metalloproteinases (MMPs) are the predominant ECM-degrading enzymes. MMPs and other factors abound in tumour microenvironment alter ECM synthesis and/or selectively cleave ECM domains. These processes can influence cell proliferation and invasion, failure of cell death, and loss of cell differentiation. When cells are exposed to aberrantly expressed ECM proteins, various downstream signalling pathways will be activated. Signals from ECM can be transduced intracellularly by integrins and CD47. In the first article, CD47, associated with integrin, was shown to play a role in ECM mediated cell migration of intestinal epithelial cells. This increased migration was regulated by inflammatory mediator cyclooxygenase-2 (COX-2).

Macrophages are important phagocytes involved in host defence. They are also major components of inflammatory tumour microenvironment. Tumour cells can recruit macrophages and change their behaviour. These tumour-associated macrophages (TAMs) perform crosstalk between colon cancer cells via CD47 associated with signal-regulatory protein ! (SIRP!). This association and TAM- derived factors was shown to contribute to colon cancer cell migration. TAM-derived factors can also induce mRNA expression and activity of MMPs in colon cancer cells. This might be one explanation how TAMs can induce colon cancer cell invasion.

In summary, these new findings provide an important clue for better understanding of the crosstalk between tumour microenvironment and colon cancers cells, and help to identify new therapeutic targets for colon cancer treatment. (Less)
Abstract
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of death from cancer worldwide. People suffering from inflammatory bowel disease, such as Crohns’ disease and ulcerative colitis, are at an increased risk of developing CRC. The development of CRC is highly influenced by the tumour microenvironment. Tumour cells are able to recruit macrophages and change their behaviour. These tumour-associated macrophages (TAMs) were of the M2 phenotype (CD206+). In CRC patient tissues and xenografts from mouse model, presence of increased amount of M2 macrophages was observed. M2 macrophages derived from human monocyte cell line THP-1 secreted high levels of IL-8 and leukotriene D4 (LTD4), which induced colon cancer cell... (More)
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of death from cancer worldwide. People suffering from inflammatory bowel disease, such as Crohns’ disease and ulcerative colitis, are at an increased risk of developing CRC. The development of CRC is highly influenced by the tumour microenvironment. Tumour cells are able to recruit macrophages and change their behaviour. These tumour-associated macrophages (TAMs) were of the M2 phenotype (CD206+). In CRC patient tissues and xenografts from mouse model, presence of increased amount of M2 macrophages was observed. M2 macrophages derived from human monocyte cell line THP-1 secreted high levels of IL-8 and leukotriene D4 (LTD4), which induced colon cancer cell migration, and Th2 cytokines (IL-4, IL-10) to maintain a tumoral immunosuppressive environment. Remodelling of extracellular matrix (ECM) occurs in CRC. CD47 binding to α2β1 integrin could regulate cyclooxygenase-2 expression and cell migration on collagen I surface in intestinal epithelial cells. CD47 is involved in crosstalk between colon cancer cells and macrophages by interacting with its ligand signal-regulatory protein α on macrophages. This interaction enhanced cell migration of CRC cells and TAMs. IL-8 and LTD4 could induce CD47 expression in CRC cells. Matrix metalloproteinases (MMPs) are enzymes degrading ECM. The enhanced levels of MMP-7 and -9 mRNA expressions and increased cell invasion into matrigel were observed in colon cancer cells upon stimulation with TAM-conditioned medium. These findings provide more evidence that TAMs play an important role in CRC progression. CD47, as a key regulator of crosstalk between colon cancer cells and TAMs, could thus be a therapeutic target for CRC. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Doc Fuxe, Jonas, Karolinska Institutet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
CD47, tumour-associated macrophage, matrix metalloproteinase, cell migration, colon cancer
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2013:92
pages
104 pages
publisher
Cell Pathology
defense location
Lilla Aulan, Jan Waldenströms gata 5, Malmö
defense date
2013-09-05 13:00
ISSN
1652-8220
ISBN
978-91-87449-64-2
language
English
LU publication?
yes
id
7f4f9cf7-ac9f-4eaf-b82b-bc4ca966267e (old id 3971997)
date added to LUP
2013-08-15 13:01:19
date last changed
2019-05-22 04:40:37
@phdthesis{7f4f9cf7-ac9f-4eaf-b82b-bc4ca966267e,
  abstract     = {Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of death from cancer worldwide. People suffering from inflammatory bowel disease, such as Crohns’ disease and ulcerative colitis, are at an increased risk of developing CRC. The development of CRC is highly influenced by the tumour microenvironment. Tumour cells are able to recruit macrophages and change their behaviour. These tumour-associated macrophages (TAMs) were of the M2 phenotype (CD206+). In CRC patient tissues and xenografts from mouse model, presence of increased amount of M2 macrophages was observed. M2 macrophages derived from human monocyte cell line THP-1 secreted high levels of IL-8 and leukotriene D4 (LTD4), which induced colon cancer cell migration, and Th2 cytokines (IL-4, IL-10) to maintain a tumoral immunosuppressive environment. Remodelling of extracellular matrix (ECM) occurs in CRC. CD47 binding to α2β1 integrin could regulate cyclooxygenase-2 expression and cell migration on collagen I surface in intestinal epithelial cells. CD47 is involved in crosstalk between colon cancer cells and macrophages by interacting with its ligand signal-regulatory protein α on macrophages. This interaction enhanced cell migration of CRC cells and TAMs. IL-8 and LTD4 could induce CD47 expression in CRC cells. Matrix metalloproteinases (MMPs) are enzymes degrading ECM. The enhanced levels of MMP-7 and -9 mRNA expressions and increased cell invasion into matrigel were observed in colon cancer cells upon stimulation with TAM-conditioned medium. These findings provide more evidence that TAMs play an important role in CRC progression. CD47, as a key regulator of crosstalk between colon cancer cells and TAMs, could thus be a therapeutic target for CRC.},
  author       = {Zhang, Yuan},
  isbn         = {978-91-87449-64-2},
  issn         = {1652-8220},
  keyword      = {CD47,tumour-associated macrophage,matrix metalloproteinase,cell migration,colon cancer},
  language     = {eng},
  pages        = {104},
  publisher    = {Cell Pathology},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Crosstalk between colorectal cancer cells and tumour-associated macrophages},
  volume       = {2013:92},
  year         = {2013},
}