Physicochemical modeling of tumorigenic homeorhesis: a system-dynamics interpretation of computer simulations

Abstract

Midway through this duology, we present an emergent system-dynamical interpretation of the evolution of malignant tumors (carcinomas) into stromal invasion events and possible metastases based on the macroscopic 'mechano-metabolomics' model described in the prequel. The theoretico-computational model predicts spatio-temporal exergy or adenosine triphosphate (ATP) generation rates, cell number densities, mechanical stress–strain fields, and tumor growth patterns characteristic of Gompertzian kinetics (S-curve) and steady state far-from-equilibrium physics observed in biotic or living systems. Perturbation simulations track the homeorhesis of the tumor–membrane system—a nonlinear transition from one homeostatic steady state to another. The conjecture that neoplasia-induced cavitation of a pathologically-softened basement membrane (BM) precedes cancer invasion continues to need validation, as in the preceding article, owing to the availability of only circumstantial ex vivo evidence of cancer invasion in the literature. The simulations appear consistent with clinico-experimental observations of oncogenesis and illuminate the physical mechanisms at play during the breaching of BMs and stromal invasion. A system-dynamics interpretation of comparative simulations provides a tissue-level feedback control perspective, which we call 'histodynamics', and noteworthy insights: at the outset, we assumed that pressure inhibits cell proliferation via mechanotransduction. When the BM is stiff (normal), it inhibits the proliferation of an increasingly crowded tumor cell population. When it is softer (pathological), the BM initially inhibits the proliferation of crowded tumor cells in a similar way, but is unable to sustain this resistance. It stretches out, allowing continued proliferation and tumor expansion. The additional outstretching increases the likelihood of cavitation or tensile yielding in the membrane and stress-localized changes to the adhesome (e.g. a cadherin-switch, biomolecular ruptures). The stiffness of the membrane thus determines whether it participates in negative autoregulation (NAR) or a positive autoregulation (PAR) at long times. This discovery could play a critical role in both early cancer diagnoses and, ultimately, better prognoses.