Irradiated fibroblast-induced bystander effects on invasive growth of squamous cell carcinoma under cancer-stromal cell interaction

Cancer Sci. 2008 Dec;99(12):2417-27. doi: 10.1111/j.1349-7006.2008.00978.x. Epub 2008 Nov 17.


The irradiated fibroblast-induced response of non-irradiated neighboring cells is called 'radiation-induced bystander effect', but it is unclear in non-irradiated human squamous cell carcinoma (SCC) cells. The present study shows that irradiated fibroblasts promoted the invasive growth of T3M-1 SCC cells, but not their apoptosis, more greatly than non-irradiated fibroblasts, using collagen gel invasion assay, immunohistochemistry and Western blot. The number of irradiated fibroblasts decreased to about 30% of that of non-irradiated fibroblasts, but irradiated fibroblasts increased the growth marker ki-67 display of SCC cells more greatly than non-irradiated fibroblasts. Irradiated fibroblasts did not affect the apoptosis marker ss-DNA expression of SCC cells. Irradiated fibroblasts enhanced the display of the following growth-, invasion- and motility-related molecules in SCC cells more greatly than non-irradiated fibroblasts: c-Met, Ras, mitogen-activated protein kinase (MAPK) cascade (Raf-1, MEK-1 and ERK-1/2), matrix metalloproteinase-1 and -9, laminin 5 and filamin A. Irradiated fibroblasts, but not non-irradiated ones, formed irradiation-induced foci (IRIF) of the genomic instability marker p53-binding protein 1 (53BP1) and expressed transforming growth factor-beta1 (TGF- beta1). Irradiated fibroblasts in turn enabled SCC cells to enhance 53BP1 IRIF formation more extensively than non-irradiated fibroblasts. Finally, effects of irradiated fibroblasts on growth and apoptosis of another HEp-2 SCC cell type were similar to those of T3M-1. These results suggest that irradiated fibroblasts promotes invasion and growth of SCC cells by enhancement of invasive growth-related molecules above through TGF- beta1-mediated bystander mechanism, in which irradiated fibroblast-induced genomic instability of SCC cells may be involved.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bystander Effect / radiation effects*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Dose-Response Relationship, Radiation
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fibroblasts / radiation effects
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen / metabolism
  • Mice
  • Mouth Neoplasms / metabolism
  • Mouth Neoplasms / pathology
  • NIH 3T3 Cells
  • Neoplasm Invasiveness
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Stromal Cells / metabolism*
  • Stromal Cells / pathology


  • Ki-67 Antigen