Abstract
BackgroundOsteosarcoma (OS) is the representative primary malignant bone tumor with the highest incidence. It is known that malignant phenotypes of OS, such as proliferation, invasion, and metastasis, are significantly influenced not only by characteristics of the tumor itself, but also by the surrounding microenvironment. In other words, OS is considered to utilize cells in the vicinity of the tumor by changing the characteristics of these cells. Direct intercellular contact is believed to be important for this phenomenon. In the present study, we hypothesized that an interaction mediated by a humoral factor, requiring no cellular contact, might play a significant role in the progression of OS.MethodsWe developed a new co-culture model, using OS cells and mesenchymal stem cells (MSCs) without cellular contact, and found that both cell types expressed IL-8 at a high level, and FAK in OS cells was phosphorylated leading to an increase in the metastatic potential of the tumor in the co-culture condition.ResultsIt was revealed that OS cells formed a loop of signal cross-talk in which they released IL-8 as a paracrine factor, stimulating MSCs to express IL-8, and received IL-8 released by MSCs to accelerate IL-8 expression in OS cells. Administration of anti-IL-8 antibody resulted in the inhibition of FAK expression, its downstream signaling, and the invasive potential of the OS cells, resulting in decrease in metastatic lesions.ConclusionThe present study might lead not only to the clarification of a new molecular mechanism of invasion and metastasis of OS, but also to the development of a new therapeutic strategy of blocking IL-8 in OS.
Highlights
Osteosarcoma (OS) is the representative primary malignant bone tumor with the highest incidence
We further found that the paracrine factor IL-8 formed a signaling loop between OS cells and human mesenchymal stem cells (hMSCs), leading to the tumor progression and metastatic spread
The array analysis showed that the expressions of 6542 mRNAs in OS cells were significantly changed in comparison with that in hMSCs
Summary
Osteosarcoma (OS) is the representative primary malignant bone tumor with the highest incidence. Normal cells adjacent to tumors are believed to be under the influence of the tumor cells via direct contact. It has been demonstrated by use of various malignant tumors that mesenchymal stromal cells surrounding the tumor are affected by the tumor to aid tumor proliferation [1, 2]. The interaction is considered to occur primarily between the tumor cells and directly contacting cells [3] If this interaction is mediated by a humoral factor that can disperse to a wide range, it might be remarkably advantageous for the environmental.
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