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.
Highlights
Osteosarcoma, the most common malignant bone tumour in children and adolescents, invades and destroys bone and adjacent soft tissues, and approximately 15% to 20% of patients will have clinically detectable metastases at presentation [1, 2]
We performed EdU and CCK-8 proliferation assays using OS cells that had been treated with adipose-derived stem cells (ADSCs) or ADSC-conditioned medium for 4 days to evaluate the ability of ADSCs to induce OS cell proliferation
Adipose tissue has been increasingly recognized as the largest endocrine organ in the body, and adipose tissue-derived cells, such as cancer-related adipocytes and ADSCs, are recruited to cancer microenvironments to enhance protumour effects [22,23,24]
Summary
Osteosarcoma, the most common malignant bone tumour in children and adolescents, invades and destroys bone and adjacent soft tissues, and approximately 15% to 20% of patients will have clinically detectable metastases at presentation [1, 2]. In addition to oncogenes and tumour suppressor genes, cross talk between tumour cells and their microenvironment facilitates tumour growth and metastasis [3]. Stromal cells of haematopoietic or mesenchymal origin, together with the extracellular matrix and soluble factors, constitute a tumour microenvironment (TME) capable of facilitating tumour growth, angiogenesis, inflammation, and metastasis [4]. Cytokines, and chemokines secreted by ADSCs have been linked to cancer development and progression and result in more aggressive tumour behaviours [6, 7]. ADSCs make important contributions to the TME through a variety of mechanisms, but few studies have examined sarcomas originating from bone, cartilage, and muscle [8]
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