TGFβ, released from bone during osteoclastic resorption, plays a central role in stimulating tumor osteolysis by inducing PTHrP in the human breast cancer cell line MDA-MB-231. However, it is unclear whether this is true for other cancer cell lines and whether factors other than PTHrP contribute to the osteolysis. Here, we report that TGFβ also regulates production of VEGF and IL-11 in a variety of osteolytic cancer cell lines. TGFβ signaling to induce PTHrP secretion is both Smad-dependent and -independent in MDA-MB-231 cancer cells. p38 MAP kinase pathway is a major component of Smad-independent signaling, since the combination of p38 inhibition and dominant-negative Smad blockade completely inhibited the TGFβ-induced PTHrP production. Therefore, we determined the role of the MAP kinase pathways in TGFβ regulation of tumor factors implicated in osteolytic metastases. We tested MEK and p38 inhibitors on PTHrP, VEGF, IL-11 and IL-6 secretion by 5 osteolytic cancer lines +/- TGFβ: breast MDA-MB-231, MDA-MB-435S, BT549; prostate PC-3; and lung RWGT2. TGFβ stimulated PTHrP production in all cell lines, and this was reduced by p38 inhibition. Complete blockade was observed in PC-3 cells. p38 inhibition reduced basal PTHrP in MDA-MB-231 and MDA-MB-435S breast cancer. TGFβ stimulated the secretion of VEGF by all cancer lines; this was totally blocked by p38 inhibition in MDA-MB-231. IL-11 was produced by MDA-MB-231, PC-3 and MDA-MB-435s cell lines and was significantly stimulated by TGFβ. p38 inhibition reduced only basal IL-11 secretion in MDA-MB-231 cells. p38 inhibition significantly reduced TGFβ induction of PTHrP and VEGF in most cancer lines, but MEK inhibition reduced only the basal, and not TGFβ stimulation of these factors. All the cell lines studied produced IL-6. TGFβ induced its secretion only in PC-3 and RWGT2 cell lines. These data indicate that the p38 MAP kinase pathway contributes significantly to TGFβ signaling in cancers which cause osteolytic metastases. However, the relative importance of the MAP kinase pathways in the TGFb induction of PTHrP varied among cell lines. The data support a major role for bone-derived TGFβ in stimulating cancer metastasis to the skeleton, in particular by inducing tumor expression of PTHrP, VEGF, and IL-11. p38 MAP kinase signaling pathway regulates the secretion of these factors and may provide molecular targets for anti-osteolytic therapy.
|Original language||English (US)|
|Number of pages||1|
|Journal||Breast Cancer Research and Treatment|
|State||Published - Jan 1 2001|
ASJC Scopus subject areas
- Cancer Research