RESUMO
Breast cancer (BCa) bone metastases cause osteolytic bone lesions, which result from the interactions of metastatic BCa cells with osteoclasts and osteoblasts. Osteoclasts differentiate from myeloid lineage cells. To understand the cell-specific role of transforming growth factor beta (TGF-ß) in the myeloid lineage, in BCa bone metastases, MDA-MB-231 BCa cells were intra-tibially or intra-cardially injected into LysM(Cre)/Tgfbr2(floxE2/floxE2) knockout (LysM(Cre)/Tgfbr2 KO) or Tgfbr2(floxE2/floxE2) mice. Metastatic bone lesion development was compared by analysis of both lesion number and area. We found that LysM(Cre)/Tgfbr2 knockout significantly decreased MDA-MB-231 bone lesion development in both the cardiac and tibial injection models. LysM(Cre)/Tgfbr2 knockout inhibited the tumor cell proliferation, angiogenesis and osteoclastogenesis of the metastatic bones. Cytokine array analysis showed that basic fibroblast growth factor (bFGF) was downregulated in MDA-MB-231-injected tibiae from the LysM(Cre)/Tgfbr2 KO group, and intravenous injection of the recombinant bFGF to LysM(Cre)/Tgfbr2 KO mice rescued the inhibited metastatic bone lesion development. The mechanism by which bFGF rescued the bone lesion development was by promotion of tumor cell proliferation through the downstream mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)-cFos pathway after binding to the FGF receptor 1 (FGFR1). Consistent with animal studies, we found that in human BCa bone metastatic tissues, TGF-ß type II receptor (TßRII) and p-Smad2 were expressed in osteoclasts and tumor cells, and were correlated with the expression of FGFR1. Our studies suggest that myeloid-specific TGF-ß signaling-mediated bFGF in the bone promotes BCa bone metastasis.
Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Células Mieloides/patologia , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Animais , Anticorpos Antineoplásicos , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Linhagem da Célula , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Camundongos , Osteoclastos/patologia , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Receptores de Fatores de Crescimento Transformadores beta/genéticaRESUMO
The development of an cellular inflammatory response secondary to mechanical wounding has not been observed previously in the fetus. The effect of amniotic fluid exclusion on the inflammatory response in fetal rabbits subjected to full-thickness dorsal excisional wounds on day 25 of gestation (term = 31-32) was examined. The fetuses were either returned immediately to the uterus; a silicone cover was sutured over the wound; or a silicone cover with a centrally located hole was sutured over the wound. Seventy-two hours after wounding, uncovered wounds (19 live fetuses) exhibited only occasional inflammatory cells. Covered wounds (14 live fetuses) showed a pronounced cellular inflammatory response. Partially covered wounds (six live fetuses) showed a peripheral, intermediate response. The findings suggest that amniotic fluid contains factors inhibitory to inflammation, which the cover effectively excludes.