Dependence of fibroblast infiltration in tumor stroma on type IV collagen-initiated integrin signal through induction of platelet-derived growth factor
| Autor: | Huan Ching Lin, Sheng Yi Chen, Bei Chang Yang, Jo Shi Lin, Yu Jung Cheng, Yan Shen Shan |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Collagen Type IV
Platelet-derived growth factor Cancer-associated fibroblast Carcinogenesis medicine.medical_treatment Integrin Biology Models Biological Collagen receptor chemistry.chemical_compound Type IV collagen Type IV-α1 collagen Cell Line Tumor Neoplasms medicine Animals Humans Myofibroblasts Fibroblast Protein Kinase Inhibitors Molecular Biology Tumor growth Platelet-Derived Growth Factor Tumor microenvironment Integrin beta1 Growth factor Cell Biology Fibroblasts Molecular biology Cell biology Mice Inbred C57BL medicine.anatomical_structure chemistry Platelet-derived growth factor A Gene Knockdown Techniques biology.protein Ectopic expression Stromal Cells Signal Transduction |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1853:929-939 |
| ISSN: | 0167-4889 |
| DOI: | 10.1016/j.bbamcr.2015.02.004 |
| Popis: | Cancer-associated fibroblasts play a crucial role in accelerating tumor progression, but there is a knowledge gap regarding the chemotactic signal activated in a tumor microenvironment. In this study, the expression of type IV collagen was knocked down using a lentiviral-mediated short hairpin RNA strategy. Although there was no obvious effect on cell growth in vitro, silencing the Col4-α1 gene decreased the tumorigenicity of B16F10 in C57BL/6 mice, which was accompanied by a reduction in the infiltration of alpha-smooth muscle actin-positive (α-SMA+) fibroblasts. Silencing the Col4-α1 gene or disrupting integrin engagement by blocking the antibody reduced the expression of platelet-derived growth factor A (PDGF-A), a potent chemotactic factor for fibroblasts. Furthermore, ectopic expression of the autoclustering integrin mutant significantly stimulated PDGF-A expression in murine B16F10 and human U118MG and Huh7 cells. PDGF-A-specific sh-RNA and neutralizing anti-PDGF-A antibody effectively inhibited the transwell migration of fibroblasts. Adding recombinant PDGF-A back to shCol cell-conditioned media restored the fibroblast-attraction ability indicating that PDGF-A is a major chemotactic factor for fibroblasts in the current study model. The integrin-associated PDGF-A production correlated with the activation of Src and ERK. High type IV collagen staining intensity colocalized with elevated PDGF-A expression was observed in tumor tissues obtained from hepatoma and glioma patients. The integrin signal pathway was activated by collagen engagement through Src and ERK, leading to enhanced PDGF-A production, which serves as a key regulator of fibroblast recruitment. |
| Databáze: | OpenAIRE |
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