Figure 2.

A novel ecological dispersal model of tumor multidirectional progression in NPC is proposed. During this process, ① NPC cells with CSCs characteristics undergo spindle-like phenotypes through EMT (mainly adapt to the selective pressure from the remodeling microenvironment) to dissociate from tumor-host interface (e.g. budding cells) and interplay with the various stroma components (local primary ecosystem); intravasate into the circulation (through either ② lymphangion or ③ blood vessels), survive the stresses of the circulating process, and extravasate to a metastatic site (lymph node or distant organ) (circulating ecosystem); enter slow-cycling states for dormancy, escape immune predation, engineer organ-specific niches to colonize micro/macro-metastases and later spread (distant metastatic ecosystem); Self-seeding of ④ CTCs or ⑤ metastatic tumor cells at distant sites, or their releasing soluble factors such as exosomes, cytokines and chemokines (self-feeding), or host cells include CAFs and immune cells (self-accomplice) return to primary tumor (multidirectional ecosystem) ; Additionally, metastatic cancer cells at ⑥ distant organ or ⑦ lymph node can produce the new populations in the second distant site.