gradient-based control, irrespective of the presence, or absence, of
genetic mutations in cancer cells, during the initial neoplastic pro-
cess. Basically, we can say that the architecture of normal tissue is a
3-D organizing system that, like morphogenetic fields, carries posi-
tional and historical information. Both association patterns and cell
types change as tissues and organs are formed. In addition, the
immune system was shown to play more important roles than
identified genetic alterations [27–33].
The stochastic evolution of cancer, by definition, makes it
impossible to establish direct causal relationships with specific
genetic or epigenetic features. Reconstructing discrete stages is
difficult, and attributing the origin of cancer to a unique intracellu-
lar molecular component or specific exogenous factor seems impos-
sible. During the neoplastic process the molecular components are
mainly unvaried, buttheir functional activitychanges, due to inter-
nal and external factors that eventually involve multiple
DNA-damaging events as well. Such change is considered
dis-functional as far as it does not respond to the normal regulative
factors properly (e.g., aberrant differentiation) and brings about a
change of the subsystems as well (e.g., genetic instability). From
this point of view cancer can be considered a disease of the
on-going systemic organization of an organism, of its natural dyna-
mism. Parts lose their integrated functional properties and become
more rigid falling into apparently functional states that mainly
require a lower level of energy to be maintained. This perspective
is also interpretive of the numerous studies showing that cancer
cells can return to normality when placed in a normal microenvi-
ronment and maintain their ability to undergo apparently correct
differentiation, despite genetic defects [34–37]. The changes in the
genome would then be causally specific only in the context of
global destabilization of gene expression (seeNote 4).
Ageing and cancer appear as deeply related. Some data on the
role of stem cells in ageing suggest that stem cells age as a result of
the alteration of processes that, over the course of life, work to
prevent the onset of the neoplastic phenotype. Not only cellular
factors that are inheritable through cell duplication (e.g., damage of
the DNA), but also alterations in the niches that support stem cells,
can contribute to the processes of ageing in mammals [38]. The
results of embryonic stem cell research have deepened our under-
standing of the mechanisms involved in the generation and assem-
bly of tissues and organisms, including those related to ageing and
tumorigenesis (seeNote 5). Some authors even started to envisage a
unified theory of development, ageing, and cancer [40, 41].
Similarities between carcinogenesis and ontogenesis have paved
the way for unified studies of their pathways and protein patterns. A
simple example comes from studies of the WNT family proteins
whose members—secreted glyco-proteins modified by covalent
bonds to lipids—are involved in embryogenesis, adult tissue
homeostasis, and carcinogenesis. But if tumorigenesis and
Conceptual Challenges in Systems Biology 9