Advocating the need of a systems biology approach for personalised prognosis and treatment of B-CLL patients

The clinical course of B-CLL is heterogeneous. This heterogeneity leads to a clinical dilemma: can we identify those patients who will benefit from early treatment and predict the survival? In recent years, mathematical modelling has contributed significantly in understanding the complexity of diseases. In order to build a mathematical model for determining prognosis of B-CLL one has to identify, characterise and quantify key molecules involved in the disease. Here we discuss the need and role of mathematical modelling in predicting B-CLL disease pathogenesis and suggest a new systems biology approach for a personalised therapy of B-CLL patients

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

ATM in focus:a damage sensor and cancer target

The ability of a cell to conserve and maintain its native DNA sequence is fundamental for the survival and normal functioning of the whole organism and protection from cancer development. Here we review recently obtained results and current topics concerning the role of the ataxia-telangiectasia mutated (ATM) protein kinase as a damage sensor and its potential as therapeutic target for treating cancer. This monograph discusses DNA repair mechanisms activated after DNA double-strand breaks (DSBs), i.e. non-homologous end joining, homologous recombination and single strand annealing and the role of ATM in the above types of repair. In addition to DNA repair, ATM participates in a diverse set of physiological processes involving metabolic regulation, oxidative stress, transcriptional modulation, protein degradation and cell proliferation. Full understanding of the complexity of ATM functions and the design of therapeutics that modulate its activity to combat diseases such as cancer necessitates parallel theoretical and experimental efforts. This could be best addressed by employing a systems biology approach, involving mathematical modelling of cell signalling pathways

Sense and response in the cell

Almost a century ago, Paul Ehlrich proposed the concept of the ‘receptors’ as sensing components of cellular signaling pathways for the mediation of downstream response in context of toxin action. Since then, we have come a long way in describing the signal transduction through dynamic sense & response in various domains of cell physiology studies, beyond the static ‘receptor-ligand’ mechanism. A multi-nodal characteristic of such signaling modules generates an enriched version of temporal signals responsible for a fine-tuned cellular response based on the identity and severity of stimulus. Here, we review diverse modes of dynamic signal transduction mechanism for efficient cellular response.&nbsp