Untitled

Abstract

Endogenous growth factors and cytokines are known to have a major influence on the progression, motility and invasiveness of tumor cells. We have reported previously that conditioned media from mouse fibroblasts increases the motility of breast cancer cells. Further, we determined that keratinocyte growth factor (KGF) was an active factor from mouse fibroblasts responsible for most of the motility response in breast cancer cells. The present study examined the effect of Human KGF on the motility of estrogen receptor (ER)-positive and ER-negative human breast cancer cell lines in culture using time-lapse videomicroscopy to quantify cell motility. In the present study we observed that recombinant human KGF enhanced several parameters of cellular motility in ER-positive cells but not in ER-negative cell lines. Further, we observed that the level of KGF receptor (KGFR) expression in ER-positive cells was much greater than in the ER-negative cell lines. The motility response to KGF was found to be both dose-and time-dependent. Of the three ER-positive breast cancer cell lines tested. MCF-7 cells were the most responsive to KGF stimulation. Finally, MCF-7 cells grown in estrogen-depleted media did not respond to KGF. These results suggest that KGF from stromal tissue surrounding a primary tumor mass can enhance tumor cell motility and may be an early signal in the progression of breast cancer cells to a more motile and metastatic phenotype. Thus, KGF, KGFR and/or the KGF signaling pathway may be important therapeutic targets for the treatment or prevention of breast cancer metastasis.

Silencing of Keratinocyte Growth Factor Receptor Restores 5-Fluorouracil and Tamoxifen Efficacy on Responsive Cancer Cells

“…The same wound-healing assay was also performed on MCF-7 breast cancer cells, known to be responsive to KGF in terms of motility [15], with similar results (Fig. 4C).…”

“…In some cases, such increased expression seems to be associated with cell transformation and, perhaps, malignant progression [14]. Moreover, KGF administration has been shown to increase cell motility in estrogen receptor (ER)-positive breast tumor cells [15], [16], to be potentially involved in breast cancer progression and metastasis [17] and to enhance the invasive potential of gastric carcinoma derived cell lines overexpressing KGFR [18].…”

Keratinocyte Growth Factor Stimulates Macrophage Inflammatory Protein 3α and Keratinocyte‐derived Chemokine Secretion by Mouse Uterine Epithelial Cells

“…35,36 The production of KGF by stromal fibroblasts as well as the mitogenic, morphogenic, and motogenic effects of KGF on epithelial cells suggests that KGF functions as a paracrine mediator of stromal fibroblast–epithelial cell interactions. 39,48–50,95 Others have shown that uterine and vaginal epithelial cell proliferation increases approximately 5-fold in neonatal mice following treatment with KGF. 38 In the lung, KGF has been shown to influence epithelial cell secretory function.…”

E2F1 Drives Breast Cancer Metastasis by Regulating the Target Gene FGF13 and Altering Cell Migration

“…S3, Vegfa 41 , Hbegf 42 , Hspb1 43 , Flt1 44 , L1cam 45 , and Plaur 46 had significantly lower expression (p < 0.05) in E2F1 −/− tumors and have all previously been shown to regulate breast cancer metastasis in vivo . Additionally, there were genes with significantly lower expression in E2F1 −/− tumors that had been shown to have in vitro invasion or migration function such as Areg 47 , Tead1 48 , Coro1C 49 , Lama5 50 , Tgm2 51 , and Fgf 7 52 (p < 0.05, Fig. S4).…”

“…In addition to hypoxia response, E2F1 −/− tumors had significantly lower expression of genes previously associated with metastasis. In vitro studies have demonstrated that Areg 47 , Tead1 48 , Coro1C 49 , Lama5 50 , Tgm2 51 and Fgf 7 52 are involved in cell migration and invasion features of tumor cells. The reduced expression of these genes involved in invasion phenotypes may provide additional mechanistic information to explain our previous finding that E2F1 −/− tumors had possible invasion/intravasation problems indicated by a reduction in circulating tumor cells 11 .…”