Abstract
Crosstalk between cancer cells and the surrounding cancer associated fibroblasts (CAFs) plays an illusive role in cancer radiotherapy. This study investigated the effect of cancer cell-cancer associated fibroblasts crosstalk on the proliferation and survival of irradiated cervical cancer cells. A pretreatment with conditioned medium from a mixed culture of CAF and HeLa cells (mixCAF) had a stronger effect on enhancing the proliferation and survival of irradiated HeLa cells compared to pretreatment with CAF conditioned medium alone. In addition, pretreatment with a mixed culture of CAF and HeLa cells conditioned medium reduced the levels of two major radiation-induced genes, GADD45 and BTG2, and phosphorylation of p38. Profiling of the growth and survival factors in the conditioned medium revealed PDGF and VEGF, and IGF2, EGF, FGF-4, IGFBPs and GM-CSF to be specifically secreted from HeLa cells and CAFs, respectively. This study demonstrated radiation protective effects of CAF-cancer cell crosstalk, and identified multiple growth factors and radiation response genes that might be involved in these effects.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinoma, Squamous Cell / pathology*
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Cell Communication*
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Cell Division / radiation effects
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Coculture Techniques
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Culture Media, Conditioned / pharmacology
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Epithelial Cells / metabolism
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Epithelial Cells / pathology*
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Epithelial Cells / radiation effects
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Female
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Fibroblasts / metabolism
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Fibroblasts / pathology*
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Gene Expression Regulation, Neoplastic / radiation effects
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HeLa Cells / metabolism
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HeLa Cells / radiation effects
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HeLa Cells / transplantation
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Humans
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Immediate-Early Proteins / biosynthesis
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Immediate-Early Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neoplasm Transplantation
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Phosphorylation / radiation effects
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Protein Processing, Post-Translational / radiation effects
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Radiation Tolerance
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Real-Time Polymerase Chain Reaction
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Stromal Cells / metabolism
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Stromal Cells / pathology*
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Tumor Microenvironment*
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Tumor Stem Cell Assay
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
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Uterine Cervical Neoplasms / pathology*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Cell Cycle Proteins
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Culture Media, Conditioned
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GADD45A protein, human
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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Neoplasm Proteins
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Nuclear Proteins
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Tumor Suppressor Proteins
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BTG2 protein, human
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p38 Mitogen-Activated Protein Kinases