Characteristics and Significance of the Pre-metastatic Niche Yang Liu, Xuetao Cao  Cancer Cell  Volume 30, Issue 5, Pages 668-681 (November 2016) DOI: 10.1016/j.ccell.2016.09.011 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Induction and Formation of the Pre-metastatic Niche TDSFs and EVs induce the mobilization and recruitment of several cell populations to secondary organ sites, including BMDCs such as VEGFR1+ HPCs and CD11b+ myeloid cells, and regulatory/suppressive immune cells including MDSCs, Treg cells, TAMs, and tumor-associated neutrophils (TANs). The interaction among these TDSFs, tumor-recruited cells, and local stroma may create a suitable niche microenvironment for metastatic tumor cell colonization. In addition, hypoxia and ECM remodeling also promote the formation of pre-metastatic niche. Cancer Cell 2016 30, 668-681DOI: (10.1016/j.ccell.2016.09.011) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 2 Characteristics of the Pre-metastatic Niche The pre-metastatic niche that is created by the TDSFs, BMDCs, regulatory/suppressive immune cells, and stromal components in the distant organ can be endowed with six enabling characteristics which promote tumor cell colonization and metastasis. The characteristics of the pre-metastatic niche can be summarized as immunosuppression, inflammation, angiogenesis/vascular permeability, lymphangiogenesis, organotropism, and reprogramming. Cancer Cell 2016 30, 668-681DOI: (10.1016/j.ccell.2016.09.011) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 Role of the Pre-metastatic Niche in the Promotion of Tumor Metastasis (A) In the priming phase, primary tumor cells produce various soluble factors, including TDSFs, EVs, and other molecular components, to trigger the formation of an immature pre-metastatic niche in the secondary organ site or in the same organ outside the primary tumor. (B) In the licensing phase, BMDCs and regulatory/suppressive immune cells are mobilized and recruited into the secondary sites in response to tumor-derived molecular components. The sustained interactions between TDSFs/recruited cells and host stroma alter and fertilize the local microenvironment, and finally establish a mature pre-metastatic niche prepared well for potential seeding and colonization of CTCs. (C) In the initiation phase, CTCs arrive and colonize at the fertile pre-metastatic niche, some of them survive or enter dormancy until the niche environment becomes suitable. The well-prepared pre-metastatic niche can support the seeding, colonization, and outgrowth of tumor cells, resulting in micrometastases. (D) In the progression phase, the pre-metastatic niche can host more migrated tumor cells and directly promote metastatic tumor cells to grow, expand, and progress at the niche, leading to macrometastases. Cancer Cell 2016 30, 668-681DOI: (10.1016/j.ccell.2016.09.011) Copyright © 2016 Elsevier Inc. Terms and Conditions