**3. Pre-metastatic niche formation**

The complex and heterogeneous microenvironment of both primary or metastatic tumor is comprised of a network of cellular and acellular constituents. The cellular compartment consists of tumor cells and assorted non-transformed cells, such as cancer-associated fibroblasts (CAFs), macrophages, and endothelial cells. The noncellular part is formed by secreted factors and components of the ECM. The tumor microenvironment modulates tumor progression by providing inhibitory or stimulatory growth signals [17]. Thus pre-metastatic niche refers to the microenvironment, that is primed to allow tumor cells to colonize in and disseminate to distant sites. The main machineries of the premetastatic niche formation include tumor-derived secreted factors (TDSFs), EVs bone marrow-derived cells (BMDCs), suppressive immune cells and host stromal cells [4], and inflammation. Chronic inflammation is a driving force for tumor development and metastasis. Thus, the local inflammatory microenvironment is one of the essential factors for the pre-metastatic niche formation and driving force for metastasis.
