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. Author manuscript; available in PMC: 2021 Jul 28.
Published in final edited form as: Trends Cancer. 2021 Jan 26;7(7):624–634. doi: 10.1016/j.trecan.2020.12.014

Figure 4. Microenvironmental Signals Promote Survival and Outgrowth at Metastatic Sites Through the Activation of Stem Cell Programs.

Figure 4.

After migration from the primary tumor site, cancer cells must colonize the new, hostile tissue. Cancer cells can signal to neighboring immune cells and fibroblasts to prime and condition the metastatic niche. These microenvironmental cells, such as tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and cancer-associated fibroblasts (CAFs), in turn provide signals that promote the survival and self-renewal of cancer cells through the activation of stem cell pathways. TAM-secreted cytokines and neutrophil extracellular traps (NETs) produced by TANs mediate inflammation in the niche and promote survival and metastatic colonization. Microenvironmental signals can also promote metastatic outgrowth by modulating cancer stem cell metabolism or enhancing survival in the context of therapy. Cancer cells enriched for stem cell signals may also avoid immune-mediated killing by innate natural killer (NK) cells or cytotoxic CD8+ T cells at the metastatic site by downregulating NK ligands or upregulating immune checkpoints.