Cancer modelling: Getting to the heart of the problem

Paradoxically, improvements in healthcare that have enhanced the life expectancy of humans in the Western world have, indirectly, increased the prevalence of certain types of cancer such as prostate and breast. It remains unclear whether this phenomenon should be attributed to the ageing process itself or the cumulative effect of prolonged exposure to harmful environmental stimuli such as ultraviolet light, radiation and carcinogens (Franks and Teich, 1988). Equally, there is also compelling evidence that certain genetic abnormalities can predispose individuals to specific cancers (Ilyas et al., 1999). The variety of factors that have been implicated in the development of solid tumours stems, to a large extent, from the fact that ‘cancer’ is a generic term, often used to characterize a series of disorders that share common features. At this generic level of description, cancer may be viewed as a cellular disease in which controls that usually regulate growth and maintain homeostasis are disrupted. Cancer is typically initiated by genetic mutations that lead to enhanced mitosis of a cell lineage and the formation of an avascular tumour. Since it receives nutrients by diffusion from the surrounding tissue, the size of an avascular tumour is limited to several millimeters in diameter. Further growth relies on the tumour acquiring the ability to stimulate the ingrowth of a new, circulating blood supply from the host vasculature via a process termed angiogenesis (Folkman, 1974). Once vascularised, the tumour has access to a vast nutrient source and rapid growth ensues. Further, tumour fragments that break away from the primary tumour, on entering the vasculature, may be transported to other organs in which they may establish secondary tumours or metastases that further compromise the host. Invasion is another key feature of solid tumours whereby contact with the tissue stimulates the production of enzymes that digest the tissue, liberating space into which the tumour cells migrate. Thus, cancer is a complex, multiscale process. The spatial scales of interest range from the subcellular level, to the cellular and macroscopic (or tissue) levels while the timescales may vary from seconds (or less) for signal transduction pathways to months for tumour doubling times The variety of phenomena involved, the range of spatial and temporal scales over which they act and the complex way in which they are inter-related mean that the development of realistic theoretical models of solid tumour growth is extremely challenging. While there is now a large literature focused on modelling solid tumour growth (for a review, see, for example, Preziosi, 2003), existing models typically focus on a single spatial scale and, as a result, are unable to address the fundamental problem of how phenomena at different scales are coupled or to combine, in a systematic manner, data from the various scales. In this article, a theoretical framework will be presented that is capable of integrating a hierarchy of processes occurring at different scales into a detailed model of solid tumour growth (Alarcon et al., 2004). The model is formulated as a hybrid cellular automaton and contains interlinked elements that describe processes at each spatial scale: progress through the cell cycle and the production of proteins that stimulate angiogenesis are accounted for at the subcellular level; cell-cell interactions are treated at the cellular level; and, at the tissue scale, attention focuses on the vascular network whose structure adapts in response to blood flow and angiogenic factors produced at the subcellular level. Further coupling between the different spatial scales arises from the transport of blood-borne oxygen into the tissue and its uptake at the cellular level. Model simulations will be presented to illustrate the effect that spatial heterogeneity induced by blood flow through the vascular network has on the tumour’s growth dynamics and explain how the model may be used to compare the efficacy of different anti-cancer treatment protocols

Stochastic resonance in a suspension of magnetic dipoles under shear flow

We show that a magnetic dipole in a shear flow under the action of an oscillating magnetic field displays stochastic resonance in the linear response regime. To this end, we compute the classical quantifiers of stochastic resonance, i.e. the signal to noise ratio, the escape time distribution, and the mean first passage time. We also discuss limitations and role of the linear response theory in its applications to the theory of stochastic resonance.Comment: 17 pages, 5 figures, approved for publication in PR

Periodic Modulation Induced Increase of Reaction Rates in Autocatalytic Systems

We propose a new mechanism to increase the reactions ratesin multistable autocatalytic systems. The mechanism is based upon the possibility for the enhancement of the response of the system due to the cooperative behavior between the noise and an external periodic modulation. In order to illustrate this feature we compute the reaction velocities for the particular case of the Sel'Kov model, showing that they increase significantly when the periodic modulation is introduced. This behavior originates from the existence of a minimum in the mean first passage time, one of the signatures of stochastic resonance.Comment: Submitted to J. Chem. Phy

Cancer disease: integrative modelling approaches

Cancer is a complex disease in which a variety of phenomena interact over a wide range of spatial and temporal scales. In this article a theoretical framework will be introduced that is capable of linking together such processes to produce a detailed model of vascular tumour growth. The model is formulated as a hybrid cellular automaton and contains submodels that describe subcellular, cellular and tissue level features. Model simulations will be presented to illustrate the effect that coupling between these different elements has on the tumour's evolution and its response to chemotherapy

Mathematical modelling of angiogenesis and vascular adaptation

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From invasion to latency: intracellular noise and cell motility as key controls of the competition between resource-limited cellular populations

In this paper we analyse stochastic models of the competition between two resource-limited cell populations which differ in their response to nutrient availability: the resident population exhibits a switch-like response behaviour while the invading population exhibits a bistable response. We investigate how noise in the intracellular regulatory pathways and cell motility influence the fate of the incumbent and invading populations. We focus initially on a spatially homogeneous system and study in detail the role of intracellular noise. We show that in such well-mixed systems, two distinct regimes exist: In the low (intracellular) noise limit, the invader has the ability to invade the resident population, whereas in the high noise regime competition between the two populations is found to be neutral and, in accordance with neutral evolution theory, invasion is a random event. Careful examination of the system dynamics leads us to conclude that (i) even if the invader is unable to invade, the distribution of survival times, PS(t), has a fat-tail behaviour (PS(t)∼t−1) which implies that small colonies of mutants can coexist with the resident population for arbitrarily long times, and (ii) the bistable structure of the invading population increases the stability of the latent population, thus increasing their long-term likelihood of survival, by decreasing the intensity of the noise at the population level. We also examine the effects of spatial inhomogeneity. In the low noise limit we find that cell motility is positively correlated with the aggressiveness of the invader as defined by the time the invader takes to invade the resident population: the faster the invasion, the more aggressive the invader

3D modelling of angiogenesis and vascular tumour growth

This paper was presented at the 3rd Micro and Nano Flows Conference (MNF2011), which was held at the Makedonia Palace Hotel, Thessaloniki in Greece. The conference was organised by Brunel University and supported by the Italian Union of Thermofluiddynamics, Aristotle University of Thessaloniki, University of Thessaly, IPEM, the Process Intensification Network, the Institution of Mechanical Engineers, the Heat Transfer Society, HEXAG - the Heat Exchange Action Group, and the Energy Institute

Precision Measurement of the Radiative B\Beta Decay of the Free Neutron

The standard model predicts that, in addition to a proton, an electron, and an antineutrino, a continuous spectrum of photons is emitted in the $\beta$ decay of the free neutron. We report on the RDK II experiment which measured the photon spectrum using two different detector arrays. An annular array of bismuth germanium oxide scintillators detected photons from 14 to 782~keV. The spectral shape was consistent with theory, and we determined a branching ratio of 0.00335 $\pm$ 0.00005 [stat] $\pm$ 0.00015 [syst]. A second detector array of large area avalanche photodiodes directly detected photons from 0.4 to 14~keV. For this array, the spectral shape was consistent with theory, and the branching ratio was determined to be 0.00582 $\pm$ 0.00023 [stat] $\pm$ 0.00062 [syst]. We report the first precision test of the shape of the photon energy spectrum from neutron radiative decay and a substantially improved determination of the branching ratio over a broad range of photon energies

Measurement of the proton electric to magnetic form factor ratio from \vec ^1H(\vec e, e'p)

We report the first precision measurement of the proton electric to magnetic form factor ratio from spin-dependent elastic scattering of longitudinally polarized electrons from a polarized hydrogen internal gas target. The measurement was performed at the MIT-Bates South Hall Ring over a range of four-momentum transfer squared $Q^2$ from 0.15 to 0.65 (GeV/c)$^2$. Significantly improved results on the proton electric and magnetic form factors are obtained in combination with previous cross-section data on elastic electron-proton scattering in the same $Q^2$ region.Comment: 4 pages, 2 figures, submitted to PR

Investigation of the conjectured nucleon deformation at low momentum transfer

We report new precise H$(e,e^\prime p)\pi^0$ measurements at the $\Delta(1232)$ resonance at $Q^2= 0.127$ (GeV/c)$^2$ using the MIT/Bates out-of-plane scattering (OOPS) facility. The data reported here are particularly sensitive to the transverse electric amplitude ($E2$) of the $\gamma^* N\to\Delta$ transition. Analyzed together with previous data yield precise quadrupole to dipole amplitude ratios $EMR = (-2.3 \pm 0.3_{stat+sys} \pm 0.6_{model})$ and $CMR = (-6.1 \pm 0.2_{stat+sys}\pm 0.5_{model})$ and for $M^{3/2}_{1+} = (41.4 \pm 0.3_{stat+sys}\pm 0.4_{model})(10^{-3}/m_{\pi^+})$. They give credence to the conjecture of deformation in hadronic systems favoring, at low $Q^2$, the dominance of mesonic effects.Comment: 4 pages, 1figur