Review Articles A Systems Biology Approach to Cancer: Fractals, Attractors, and Nonlinear Dynamics Simona Dinicola, 1 Fabrizio D’Anselmi, 2 Alessia Pasqualato, 3 Sara Proietti, 1 Elisabetta Lisi, 4 Alessandra Cucina, 2 and Mariano Bizzarri 1 Abstract Cancer begins to be recognized as a highly complex disease, and advanced knowledge of the carcinogenic process claims to be acquired by means of supragenomic strategies. Experimental data evidence that tumor emerges from disruption of tissue architecture, and it is therefore consequential that the tissue level should be considered the proper level of observation for carcinogenic studies. This paradigm shift imposes to move from a reductionistic to a systems biology approach. Indeed, cell phenotypes are emergent modes arising through collective nonlinear interactions among different cellular and microenvironmental components, generally de- scribed by a phase space diagram, where stable states (attractors) are embedded into a landscape model. Within this framework cell states and cell transitions are generally conceived as mainly specified by the gene-regulatory network. However, the system’s dynamics cannot be reduced to only the integrated functioning of the genome– proteome network, and the cell–stroma interacting system must be taken into consideration in order to give a more reliable picture. As cell form represents the spatial geometric configuration shaped by an integrated set of cellular and environmental cues participating in biological functions control, it is conceivable that fractal-shape parameters could be considered as ‘‘omics’’ descriptors of the cell–stroma system. Within this framework it seems that function follows form, and not the other way around. Paradigm Instability A central feature of the prevailing interpretative paradigm for carcinogenesis is the underlying notion that cancer originates at the cellular level of organization. This approach roots in the work of Theodor Boveri and Ernest Tyzzer, who first used the term ‘‘somatic mutation’’ connect- ing it with cancer (Boveri, 1914; Wunderlich, 2007). The so- matic mutation theory (SMT) posits that cancer is related in a deterministic fashion to a point-mutation of a proto-oncogene and results from a progressive accumulation of mutations in somatic cells that lead to the ‘‘cancer phenotype,’’ charac- terized by ‘‘specific,’’ both molecular and functional (gene expression, metabolic phenotype), features (Fearon and Vogelstein, 1990; Hahn et al., 1999). The acquired trans- formation is thought to confer some kind of ‘‘selective ad- vantage’’ and is then transmitted to cell progeny. Tumor progression is therefore explained as a sort of microevolu- tionary Darwinian process leading to different and more malignant phenotypes (Michor er al., 2004). The implicit assumption underlying the above-mentioned paradigm considers that the overall information is embedded into the gene, and the gene is able to govern cellular functions through a linear and deterministic process. However, we cannot anymore define a ‘‘gene’’ as a unitary component of the genome: every genomic element interacts either directly or indirectly with many other genomic and nongenomic com- ponents (proteins and RNA). Thus, the idea that any cellular or organismal character, as being ‘‘determined’’ by a single region of the genome, has no logical connection with our knowledge of biogenesis (Noble, 2008). Genomic functions are inherently interactive in that isolated DNA is virtually inert: ‘‘DNA can- not replicate or segregate properly to daughter cells or tem- plate synthesis of RNA by itself. This fundamental biochemical reality alone would invalidate the central dogma’’ (Shapiro, 2009). In addition, a large amount of data suggests gene ex- pression is fundamentally a stochastic process (Elowitz et al., 2002). Cells expressing the same phenotype and placed in homogenous environments should always express the same genes if they are controlled by a tight determinist mechanism. 1 Department of Experimental Medicine, Sapienza University, Roma, Italy. 2 Department of Surgery ‘‘Pietro Valdoni,’’ Sapienza University, Roma, Italy. 3 Department of Basic and Applied Medical Science, University ‘‘G. D’Annunzio,’’ Chieti-Pescara, Italy. 4 Department of Biology, ‘‘Roma Tre’’ University, Roma, Italy. OMICS A Journal of Integrative Biology Volume 15, Number 3, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/omi.2010.0091 93