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2018 ; 8
(ä): 133
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Transforming Growth Factor-? Signaling Plays a Pivotal Role in the Interplay
Between Osteosarcoma Cells and Their Microenvironment
#MMPMID29761075
Verrecchia F
; Rédini F
Front Oncol
2018[]; 8
(ä): 133
PMID29761075
show ga
Osteosarcomas are the most frequent form of primary bone tumors and mainly affect
children, adolescents, and young adults. Despite encouraging progress in
therapeutic management, including the advent of multidrug chemotherapy, the
survival rates have remained unchanged for more than four decades: 75% at 5?years
for localized disease, but two groups of patients are still at high risk:
metastatic at diagnosis (overall survival around 40% at 5?years) and/or poor
responders to chemotherapy (20% at 5?years). Because these tumors are classified
as "complex genomic," it is extremely difficult to determine the signaling
pathways that might be targeted by specific therapies. A hypothesis has thus
emerged, stating that the particular microenvironment of these tumors may
interfere with the tumor cells that promote chemoresistance and the dissemination
of metastases. The stroma is composed of a large number of cell types (immune
cells, endothelial cells, mesenchymal stromal cells, etc.) which secrete growth
factors, such as transforming growth factor-? (TGF-?), which favors the
development of primary tumors and dissemination of metastases by constituting a
permissive niche at primary and distant sites. Rather than targeting the tumor
cells themselves, which are very heterogeneous in osteosarcoma, the hypothesis is
instead to target the key actors secreted in the microenvironment, such as
TGF-?s, which play a part in tumor progression. In the last decade, numerous
studies have shown that overexpression of TGF-? is a hallmark of many cancers,
including primary bone tumors. In this context, TGF-? signaling has emerged as a
crucial factor in the cross talk between tumor cells and stroma cells in
poor-prognosis cancers. Secretion of TGF-? by tumor cells or stroma cells can
effectively act in a paracrine manner to regulate the phenotype and functions of
the microenvironment to stimulate protumorigenic microenvironmental changes.
TGF-? can thus exert its protumorigenic function in primary bone tumors by
promoting angiogenesis, bone remodeling and cell migration, and by inhibiting
immunosurveillance. This review focuses on the involvement of TGF-? signaling in
primary bone tumor development, and the related therapeutic options that may be
possible for these tumors.