Nasopharyngeal carcinoma ecology theory: cancer as multidimensional spatiotemporal "unity of ecology and evolution" pathological ecosystem

Abstract

Nasopharyngeal carcinoma (NPC) is a particular entity of head neck cancer that is generally regarded as a genetic disease with diverse intertumor and intratumor heterogeneity. This perspective review mainly outlines the up-to-date knowledge of cancer ecology and NPC progression, and presents a number of conceptual stepping-stones. At the beginning, I explicitly advocate that the nature of NPC (cancer) is not a genetic disease but an ecological disease: a multidimensional spatiotemporal "unity of ecology and evolution" pathological ecosystem. The hallmarks of cancer is proposed to act as ecological factors of population fitness. Subsequently, NPC cells are described as invasive species and its metastasis as a multidirectional ecological dispersal. The foundational ecological principles include intraspecific relationship (e.g. communication) and interspecific relationship (e.g. competition, predation, parasitism and mutualism) are interpreted to understand NPC progression. "Mulberry-fish-ponds" model can well illustrate the dynamic reciprocity of cancer ecosystem. Tumor-host interface is the ecological transition zone of cancer, and tumor buddings should be recognized as ecological islands separated from the mainland. It should be noted that tumor-host interface has a significantly molecular and functional edge effect because of its curvature and irregularity. Selection driving factors and ecological therapy including hyperthermia for NPC patients, and future perspectives in such field as "ecological pathology", "multidimensional tumoriecology" are also discussed. I advance that "nothing in cancer evolution or ecology makes sense except in the light of the other". The cancer ecology tree is constructed to comprehensively point out the future research direction. Taken together, the establishment of NPC ecology theory and cancer ecology tree might provide a novel conceptual framework and paradigm for our understanding of cancer complex causal process and potential preventive and therapeutic applications for patients.

Keywords: Cancer ecology tree; Ecological pathology; Ecological radiology; Ecological therapy; Multidimensional tumoriecology; Nasopharyngeal carcinoma ecology; Pathological ecosystem; Synthetic cancer ecology; Tumor budding; Tumor microenvironment; Tumor-host interface; Unity of ecology and evolution.

Figure 1

The hallmarks of cancer act as ecological factors of population fitness. Genome instability and mutation lead to the diversity and evolutionary adaptation of population species, other cancer hallmarks affect ecological adaptation of cancer cells through the dynamic change of their survival ability and reproductive capacity in particular.

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.

Figure 3

The “mulberry-fish-ponds model” (top left) to elucidate the dynamic reciprocity of mutualism between (bottom right) cancer cells and TME (e.g. CAFs synthesizing ECM components such as collagen and FN contributes to stromal stiffness, which in turn promotes cancer progression) in cancer ecosystem. Cancer cells and TME work together to build “a community with a shared future” for tumor ecology (ecosystem).

Figure 4

A close analogy of tumor-host interface and budding cells in NPC with the ecological nature. Land/sea transitional zone and isolated islands on earth (A,B). Tumor-host interface as the ecological transition zone, it often takes curved and finger-like shapes (C,D). Tumor buddings are similar to little islands separated from the continent (E, F). (A,B adapted from image.baidu; C-F adapted from our previous studies, Luo WR et al, (Ref.136,229) ).

Figure 5

Human cancer ecology tree. The cancer ecology tree is unprecedentedly constructed to elucidate the framework and research direction of cancer ecology. The nature of human cancer includes NPC is an “ecological and evolutionary unity” disease.