title: Tumor morphological evolution: directed migration and gain and loss of the self-metastatic phenotype.
abstract: BACKGROUND
  Aside from the stepwise genetic alterations known to underlie cancer cell creation, the microenvironment is known to profoundly influence subsequent tumor development, morphology and metastasis. Invasive cluster formation has been assumed to be dependent on directed migration and a heterogeneous environment--a conclusion derived from complex models of tumor-environment interaction. At the same time, these models have not included the prospect, now supported by a preponderance of evidence, that only a minority of cancer cells may have stem cell capacity. This proves to weigh heavily on the microenvironmental requirements for the display of characteristic tumor growth phenotypes. We show using agent-based modeling that some defining features of tumor growth ascribed to directed migration might also be realized under random migration, and discuss broader implications for cause-and-effect determination in general.
  
  
  RESULTS
  Considering only the properties of random migration in tumors composed of stem cells and committed cells, we are able to recapitulate a characteristic clustering feature of invasive tumor growth, a property we attribute to "self-metastatic" growth. When the additional influence of directed migrations under chemotactic environments are considered, we find that tumor growth and invasive morphology are supported while the tumor is distant from the source, but are progressively discouraged as the tumor converges about that source.
  
  
  CONCLUSIONS
  We show that invasive clustering can derive from basic kinetic assumptions often neglected in more complex models. While higher-order mechanisms, e.g. directed migration upon chemotactic stimuli, may result in clustering growth morphologies, exclusive attributions of this phenotype to this or other structured microenvironments would be inappropriate, in light of our finding these features are observable in a homogeneous environment. Furthermore, directed migration will result in loss of the invasive phenotype as the tumor approaches the attractor source.
  
  
  METHODS
  This article was reviewed by Mark Little and Glen Webb.
authors.affiliation: Center of Cancer Systems Biology, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
authors.forename: Heiko
authors.initials: H
authors.lastname: Enderling
authors.forename: Lynn
authors.initials: L
authors.lastname: Hlatky
authors.forename: Philip
authors.initials: P
authors.lastname: Hahnfeldt
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*; D010641:Phenotype
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