Adipose-derived mesenchymal stem cells promote osteosarcoma proliferation and metastasis by activating the STAT3 pathway

Abstract

Osteosarcoma is the most common primary bone malignancy in children and young adults, but the role of adipose-derived mesenchymal stem cells (ADSCs) in the rapid progression of osteosarcoma is still unclear. Here, we found that ADSCs promoted tumour growth and invasion by increasing matrix metalloproteinase 2/9 (MMP2/9) expression in tumour cells. The persistent activation of signal transducer and activator of transcription 3 (STAT3) has been shown to directly promote tumour growth by mediating a wide spectrum of cellular responses, and STAT3 activation was detected in osteosarcoma cells co-cultured with ADSCs or treated with ADSC-conditioned medium. Furthermore, siRNA-mediated STAT3 inhibition in osteosarcoma cells decreased cell proliferation and invasion and down-regulated MMP2/9 expression. In addition, a nude mouse model of osteosarcoma was established by injecting luciferase-labelled MG63 cells into the tibia. As shown in in vivo bioluminescence images, ADSCs promoted tumour cell proliferation, invasion progression and metastasis. STAT3 inhibition attenuated tumour growth and metastasis and prolonged the survival of these mice. After the siRNA treatment, the MMP2, MMP9 and Ki67 levels decreased. Based on these data, stromal ADSCs promote osteosarcoma progression by increasing STAT3 signalling-mediated MMP2/9 expression.

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…Several studies have confirmed that mesenchymal stem cells promote the proliferation of osteosarcoma cells both in vitro and in vivo [38,[46][47][48][49]. Mesenchymal stem cells, the low differentiated precursor of various cell-types including osteoblast [16], in contrast to differentiated osteoblasts appear unable to communicate with osteosarcoma cells through the establishment of functional gap junctions [50].…”

Adipose Stem Cells and Cancer: Concise Review

“…Studies evaluating OS, a primary malignancy of bone that mostly affects children and young adults, have seen similar effects . Wang et al found that ASCs promote OS growth and metastasis through upregulation of MMP2 and MMP9 through STAT3 activation.…”

“…Wang et al found that ASCs promote OS growth and metastasis through upregulation of MMP2 and MMP9 through STAT3 activation. STAT3 inhibition attenuated these effects, decreased MMP2/9 expression, and prolonged survival in mice . Although the upstream activators of STAT3 were not identified, STAT3 is activated by many of the aforementioned paracrine factors from ASCs.…”

“…ASCs have been shown to express extracellular matrix remodeling proteins as well as upregulate expression of these proteins by cancer cells themselves. Remodeling proteins such as MMP‐2, MMP‐9, and tissue inhibitor metalloprotease 1 (TIMP‐1), are associated with tumor progression and metastasis . Specifically, MMP‐2 and MMP‐9 are proteolytic enzymes that digest type IV collagen, a major constituent of the basement membrane; invasion through the basement membrane is an essential step in metastasis particularly for epithelial tumors (carcinomas) .…”

Pathological and therapeutic aspects of matrix metalloproteinases: Implications in osteosarcoma

“…Wang et al. found that adipose‐derived mesenchymal stem cells (ADSCs) promoted tumor growth and invasion in OS cells by increasing MMP2/9 expression through the activation of signal transducer and activator of transcription 3 (STAT3) pathways . Few studies reported that the expression of MMP‐2 in OS tissues is higher than in other tissues.…”