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Inflammatory Molecule, PSGL-1 , Deficiency Activates Macrophages to Promote Colorectal Cancer Growth through NFκB Signaling.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2017 Apr; Vol. 15 (4), pp. 467-477. Date of Electronic Publication: 2017 Jan 20. - Publication Year :
- 2017
-
Abstract
- P-selectin glycoprotein ligand 1 (SELPLG/ PSGL-1 ) is an inflammatory molecule that is functionally related to immune cell differentiation and leukocyte mobilization. However, the role of PSGL-1 in tumor development remains unknown. Therefore, this study investigates the mechanistic role of PSGL-1 in the development of intestinal tumors in colorectal cancer. Apc <superscript>Min/+</superscript> mice are highly susceptible to spontaneous intestinal adenoma formation, and were crossbred with PSGL1-null mice to generate compound transgenic mice with a Apc <superscript>Min/+</superscript> ; PSGL-1 <superscript>-/-</superscript> genotype. The incidence and pathologic features of the intestinal tumors were compared between the Apc <superscript>Min/+</superscript> mice and Apc <superscript>Min/+</superscript> ; PSGL-1 <superscript>-/-</superscript> mice. Importantly, PSGL-1 -deficient mice showed increased susceptibility to develop intestinal tumors and accelerated tumor growth. Mechanistically, increased production of the mouse chemokine ligand 9 (CCL9/MIP-1γ) was found in the PSGL-1 -deficient mice, and the macrophages are likely the major source of macrophage inflammatory protein-1 gamma (MIP-1γ). Studies in vitro demonstrated that macrophage-derived MIP-1γ promoted colorectal cancer tumor cell growth through activating NFκB signaling. Conversely, restoration of the PSGL-1 signaling via bone marrow transplantation reduced MIP-1γ production and attenuated the ability of Apc <superscript>Min/+</superscript> ; PSGL-1 <superscript>-/-</superscript> mice to generate intestinal tumors. In human colorectal cancer clinical specimens, the presence of PSGL-1 -positive cells was associated with a favorable tumor-node-metastasis staging and decreased lymph node metastasis. Implications: PSGL-1 deficiency and inflammation render intestinal tissue more vulnerable to develop colorectal tumors through a MIP-1γ/NFκB signaling axis. Mol Cancer Res; 15(4); 467-77. ©2017 AACR .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Adenoma metabolism
Animals
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms metabolism
Female
HCT116 Cells
Humans
Macrophage Activation
Macrophages metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neoplasm Invasiveness
Signal Transduction
Chemokines, CC metabolism
Colorectal Neoplasms pathology
Macrophage Inflammatory Proteins metabolism
Macrophages pathology
Membrane Glycoproteins deficiency
NF-kappa B metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3125
- Volume :
- 15
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 28108624
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-16-0309