**3.1 TDE in upregulation of inflammatory molecules and premalignant niche formation**

Tumor development and metastasis are aided by chronic inflammation. As a result, one of the most important variables in the establishment of a pre-metastatic niche is the local inflammatory microenvironment. Tumor cells can be induced to create TDSFs such as vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), transforming growth factor (TGF-β), and interleukin-2 by the local inflammatory microenvironment. These TDSFs then exert a paracrine effect on myeloid cells, initiating their migration to potential pre-metastatic niche formation sites [18]. Host stromal cells in the pre-metastatic niche may upregulate the expression of inflammatory factors in response to TDSF activation. The recruitment of BMDCs or immune cells to the pre-metastatic niche speeds up the release of inflammatory factors. Exo from tumors also transport inflammatory substances into the bloodstream, where they reach the pre-metastatic niche. In the pre-metastatic niche, an inflammatory milieu supportive to tumors is eventually generated [18].

In a study conducted by Hoshino, he showed that the proinflammatory cytokine s100 was upregulated up to four folds when Kupffer cells were treated with integrin intact Exo, as compared to those treated with integrin knocked out Exo. Hoshino speculated that the activation of Src, and its phosphorylation might be a causative pathway [19].
