Niche inheritance: a cooperative pathway to enhance cancer cell fitness through ecosystem engineering

Abstract

Cancer cells can be described as an invasive species that is able to establish itself in a new environment. The concept of niche construction can be utilized to describe the process by which cancer cells terraform their environment, thereby engineering an ecosystem that promotes the genetic fitness of the species. Ecological dispersion theory can then be utilized to describe and model the steps and barriers involved in a successful diaspora as the cancer cells leave the original host organ and migrate to new host organs to successfully establish a new metastatic community. These ecological concepts can be further utilized to define new diagnostic and therapeutic areas for lethal cancers.

Keywords: diaspora; dispersal filters; genetic instability; metastasis; niche construction; tumor cell heterogeneity.

Fig 1

Cancer cells as ecological engineers. Ecosystem engineers construct and modify their niche to create environmental conditions that favor their survival. Cancer cells, for example, function as engineers as they secrete matrix metalloproteinases that physically alter their environment, attract the formation of new vasculature, change the architecture, pH, and interstitial pressure of the organ host ecosystem in which they live. This fundamentally changes the growth patterns of host cell species as well as changes the flow of nutrients and information in the forms of cytokines, chemokines, hormones, and exosomes as they traffic through the ecosystem. Tumor cell heterogeneity is promoted through inherent genetic instability as well as the ecological inheritance through adaptive selection.

Fig 2

Modeling ecological inheritance. Niche construction by a species fundamentally changes the ecosystem in which it establishes. The theory of ecological inheritance describes the inheritance, via an external environment, of one or more natural selection pressures previously modified by the ecological engineer species. Ecological inheritance depends on a niche existing across multiple generations of a species, that is, the next generation of the species is born into the engineered environment. This engineered environment can then speed the process of the selection of genetic and epigenetic factors that increase a species’ chances of survival. Gene pool 1 reflects the amount of tumor cell heterogeneity that is a result of the intrinsic genetic instability of cancer cells. Gene pool 2 reflects the increased amount and rate of genetic instability as a result of the malignant niche environment created by the ecological engineering of the cancer cells. Ultimately, this results in increased fitness of the species as cancer cell clones are generated that have the attributes necessary for survival and metastasis.

Fig 3

The cancer diaspora. The diaspora paradigm takes into account and models several variables in the metastatic cascade. A diaspora is started by unfavorable conditions in a homeland, leading to the voluntary or forced eviction of a population. The nutrient poor and hypoxic environment of the evolving primary tumor microenvironment reflects this. The diaspora concept also accounts for the fitness of individual cancer cell migrants and migrant populations. Since diaspora communities remain in contact with their homeland, it also describes and models the bidirectional movement of cancer and host cells between cancer sites (including between primary and metastases as well as between metastases). By describing the receptivity of the new hostland for the arriving migrants, the diaspora also models the quality of the target microenvironments to establish metastatic sites (adapted from Pienta et al., 2013).

Fig 4

Cancer metastasis as a form of ecological dispersal. Once a cancer successfully establishes a niche in the primary organ, it invariably metastasizes. Disseminated cancer cells use the blood stream to undergo jump dispersal and if they are able to surpass dispersal and niche filters they can act as an invasive species and establish a foothold in distant sites. Eventually they may proliferate and act as ecological engineers to form a new niche in the target organ.