However, the initial theory has been extended by the concept of pre-metastatic niche formation: prior to the dissemination of tumor cells, the primary tumor can induce the formation of a supportive and receptive tissue microenvironment via the production of tumor-derived secreted factors VEGF-A, tumor necrosis factor α (TNF-α) and TGF-β. Here, TGFB1 is linked to neoplasm.