The theory of tumor ecosystem

Abstract

Cancer cells can be conceived as "living organisms" interacting with cellular or non-cellular components in the host internal environment, not only the local tumor microenvironment but also the distant organ niches, as well as the immune, nervous and endocrine systems, to construct a self-sustainable tumor ecosystem. With increasing evidence for the systemic tumor-host interplay, we predict that a new era of cancer therapy targeting the ecosystemic vulnerability of human malignancies has come. Revolving around the tumor ecosystem scoped as different hierarchies of primary, regional, distal and systemic onco-spheres, we comprehensively review the tumor-host interaction among cancer cells and their local microenvironment, distant organ niches, immune, nervous and endocrine systems, highlighting material and energy flow with tumor ecological homeostasis as an internal driving force. We also substantiate the knowledge of visualizing, modelling and subtyping this dynamically intertwined network with recent technological advances, and discuss ecologically rational strategies for more effective cancer therapies.

Keywords: ecological therapy; neuroendocrine system; onco-sphere; pre-metastatic niche; tumor ecosystem; tumor immunity; tumor microenvironment; tumor-host interplay.

FIGURE 1

The hierarchy of tumor ecosystem. Taking breast cancer as an example, the patient's systemic environment can be perceived as an integral ecosystem and scoped at three different levels: primary (cancerous breast), regional (metastatic lymph node) and distal (metastatic brain, lung, liver or bone) onco‐spheres. The material and energy flow throughout the systemic onco‐sphere are largely ascribed to its metabolic function within the host macroenvironment. Besides internal factors, food and nutrient, microorganisms (e.g., viruses and bacteria) and therapeutic interventions (e.g., irradiation) serve as external stimuli that also shape the tumor ecosystem. Abbreviations: Tregs, Regulatory T cells; MDSCs, myeloid‐derived suppressor cells.

FIGURE 2

Intertwined interactions within the tumor ecosystem. The material and energy flow arising from tumor metabolism and intercellular communication (central) runs through the host macroenvironment, linking tumor microenvironment (upper) to distant organ niches (right), immune (bottom) as well as the nervous and the endocrine systems (left). Such tumor‐specific metabolic and other non‐metabolic hallmarks are intertwined to form a dual cause‐effect relationship that constitutes an evolving systemic onco‐sphere. Abbreviations: ATP, adenosine triphosphate; CXCL12, C‐X‐C motif chemokine ligand 12; CXCR4, C‐X‐C motif chemokine receptor4; IL‐6, interleukin‐6; IL‐8, interleukin‐8; MDSCs, myeloid‐derived suppressor cells; OXPHOS, oxidative phosphorylation; PPP, pentose phosphate pathway; ROS, reactive oxygen species; SNS, sympathetic nervous system; TCA, tricarboxylic acid; Treg, Regulatory T cells.