Imatinib Mesylate Inhibits Proliferation and Exerts an Antifibrotic Effect in Human Breast Stroma Fibroblasts

Abstract

Tumor stroma plays an important role in cancer development. In a variety of tumors, such as breast carcinomas, a desmoplastic response, characterized by stromal fibroblast and collagen accumulation, is observed having synergistic effects on tumor progression. However, the effect of known anticancer drugs on stromal cells has not been thoroughly investigated. Imatinib mesylate is a selective inhibitor of several protein tyrosine kinases, including the receptor of platelet-derived growth factor, an important mediator of desmoplasia. Recently, we have shown that imatinib inhibits the growth and invasiveness of human epithelial breast cancer cells. Here, we studied the effect of imatinib on the proliferation and collagen accumulation in breast stromal fibroblasts. We have shown that it blocks the activation of the extracellular signal-regulated kinase and Akt signaling pathways and up-regulates cyclin-dependent kinase inhibitor p21 WAF1 , leading to the inhibition of fibroblast proliferation, by arresting them at the G 0 /G 1 phase of the cell cycle. Imatinib inhibits more potently the platelet-derived growth factor -mediated stimulation of breast fibroblast proliferation. By using specific inhibitors, we have found that this is due to the inhibition of the Akt pathway. In addition, imatinib inhibits fibroblast-mediated collagen accumulation. Conventional and quantitative PCR analysis, as well as gelatin zymography, indicates that this is due to the down-regulation of mRNA synthesis of collagen I and collagen III-the main collagen types in breast stroma-and not to the up-regulation or activation of collagenases matrix metalloproteinase 2 and matrix metalloproteinase 9. These data indicate that imatinib has an antifibrotic effect on human breast stromal fibroblasts that may inhibit desmoplastic reaction and thus tumor progression. (Mol Cancer Res 2008;6(5):706 -14)

Stiff Collagen Matrices Increase Tumorigenic Prolactin Signaling in Breast Cancer Cells

“…Moreover, a recent report suggests that PRL may act directly on tumor-associated fibroblasts (76) in addition to enhancing collagen realignment in stiff matrices as reported herein. Tyrosine kinase inhibitors, which block activation of ERK1/2 and AKT, inhibit both proliferation and collagen synthesis in tumor-associated fibroblasts (77). In light of the ability of PRL to potently cooperate with growth factors to activate these signaling pathways (15,16), these interactions deserve further investigation.…”

Imatinib mesylate inhibits the proliferation-stimulating effect of human lung cancer-associated stromal fibroblasts on lung cancer cells

“…The findings indicate that Imatinib treatment decreased the concentration of some soluble growth stimulants secreted by CAFs in the conditioned media, resulting in a decrease of proliferative activity of lung cancer cells. We suspect that the decrease was mainly due to the reduced number of CAFs because of blocking PDGF signaling by Imatinib, based on the findings that Imatinib inhibited DNA synthesis in CAFs (28) and increased the incidence of apoptosis in CAFs (29). However, we have not yet been able to identify the soluble growth stimulants secreted by CAFs and involved in the increase of proliferation of lung cancer cells.…”

“…Fibroblasts are a major component of tumor stroma in many solid tumors. It is suggested therefore that inhibition of fibroblast activity could lead to suppression of tumor development and progression (28)(29)(30)(31).…”

“…In CML, the molecular target of Imatinib is c-Abl tyrosine kinase, a Bcr-Abl fusion protein, caused from t(9;22) chromosomal translocation, and in GIST the target is c-Kit tyrosine kinase constitutively activated by gain-of-function mutation (23)(24)(25). Furthermore, Imatinib inhibits the tyrosine kinase activity of PDGFR; it is also reported that treatment with Imatinib can suppress the PDGF-mediated growth of cancer cells and CAFs in in vitro and in vivo experiments (26)(27)(28)(29)(30).…”

Sunitinib mesylate inhibits proliferation of human colonic stromal fibroblasts in vitro and in vivo

“…Several studies have been carried out to target stromal fibroblasts using tyrosine kinase inhibitor, such as dasatinib or imatinib (Mueller et al, 2007a;Gioni et al, 2008;Haubeiss et al, 2010). Mueller et al (2007a) showed that imatinib inhibits proliferation and modulates cytokine expression of human cancerassociated fibroblasts from colorectal metastases.…”