Mathematical modeling in cancer has been growing in popularity and impact since its inception in 1932. The first theoretical mathematical modeling in cancer research was focused on understanding tumor growth laws and has grown to include the competit
ion between healthy and normal tissue, carcinogenesis, therapy and metastasis. It is the latter topic, metastasis, on which we will focus this short review, specifically discussing various computational and mathematical models of different portions of the metastatic process, including: the emergence of the metastatic phenotype, the timing and size distribution of metastases, the factors that influence the dormancy of micrometastases and patterns of spread from a given primary tumor.
Simple ideas, endowed from the mathematical theory of control, are used in order to analyze in general grounds the human immune system. The general principles are minimization of the pathogen load and economy of resources. They should constrain the p
arameters describing the immune system. In the simplest linear model, for example, where the response is proportional to the load, the annihilation rate of pathogens in any tissue should be greater than the pathogens average rate of growth. When nonlinearities are added, a reference value for the number of pathogens is set, and a stability condition emerges, which relates strength of regular threats, barrier height and annihilation rate. The stability condition allows a qualitative comparison between tissues. On the other hand, in cancer immunity, the linear model leads to an expression for the lifetime risk, which accounts for both the effects of carcinogens (endogenous or external) and the immune response.
Objective: Interstitial fluid flow through vascular adventitia has been disclosed recently. However, its kinetic pattern was unclear. Methods and Results: We used histological and topographical identifications to observe ISF flow along venous vessels
in rabbits. By MRI in alive subjects, the inherent ISF flow pathways in legs, abdomen and thorax were enhanced by paramagnetic contrast from ankle dermis. By fluorescence stereomicroscopy and layer-by-layer dissection after the rabbits were sacrificed, the perivascular and adventitial connective tissues (PACT) along the saphenous veins and inferior vena cava were found to be stained by sodium fluorescein from ankle dermis, which coincided with the findings by MRI. By confocal microscopy and histological analysis, the stained PACT pathways were verified to be the fibrous connective tissues and consisted of longitudinally assembled fibers. By usages of nanoparticles and surfactants, a PACT pathway was found to be accessible for a nanoparticle under 100nm and contain two parts: a tunica channel part and an absorptive part. In real-time observations, the calculated velocity of a continuous ISF flow along fibers of a PACT pathway was 3.6-15.6 mm/sec. Conclusion: These data further revealed more kinetic features of a continuous ISF flow along vascular vessel. A multiscale, multilayer, and multiform interstitial/interfacial fluid flow throughout perivascular and adventitial connective tissues was suggested as one of kinetic and dynamic mechanisms for ISF flow, which might be another principal fluid dynamic pattern besides convective/vascular and diffusive transport in biological system.
A theoretical model based on the molecular interactions between a growing tumor and a dynamically evolving blood vessel network describes the transformation of the regular vasculature in normal tissues into a highly inhomogeneous tumor specific capil
lary network. The emerging morphology, characterized by the compartmentalization of the tumor into several regions differing in vessel density, diameter and necrosis, is in accordance with experimental data for human melanoma. Vessel collapse due to a combination of severely reduced blood flow and solid stress exerted by the tumor, leads to a correlated percolation process that is driven towards criticality by the mechanism of hydrodynamic vessel stabilization.
The CVS is composed of numerous interacting and dynamically regulated physiological subsystems which each generate measurable periodic components such that the CVS can itself be presented as a system of weakly coupled oscillators. The interactions be
tween these oscillators generate a chaotic blood pressure waveform signal, where periods of apparent rhythmicity are punctuated by asynchronous behaviour. It is this variability which seems to characterise the normal state. We used a standard experimental data set for the purposes of analysis and modelling. Arterial blood pressure waveform data was collected from conscious mice instrumented with radiotelemetry devices over $24$ hours, at a $100$ Hz and $1$ kHz time base. During a $24$ hour period, these mice display diurnal variation leading to changes in the cardiovascular waveform. We undertook preliminary analysis of our data using Fourier transforms and subsequently applied a series of both linear and nonlinear mathematical approaches in parallel. We provide a minimalistic linear and nonlinear coupled oscillator model and employed spectral and Hilbert analysis as well as a phase plane analysis. This provides a route to a three way synergistic investigation of the original blood pressure data by a combination of physiological experiments, data analysis viz. Fourier and Hilbert transforms and attractor reconstructions, and numerical solutions of linear and nonlinear coupled oscillator models. We believe that a minimal model of coupled oscillator models that quantitatively describes the complex physiological data could be developed via such a method. Further investigations of each of these techniques will be explored in separate publications.