Systems Biology (Methods in Molecular Biology)

within endogenous network theory. This and other recent devel-

opments strongly suggest that we need to look for new directions,

to diversify our resource away from mutation theory.

3.5 Major Possible
Caveats
in Endogenous
Molecular-Cellular
Network Approach

Ten years ago there were two real and major problems standing on

the way to the development of research program on endogenous

network approach to cancer genesis and progression: first, whether

or not the endogenous network would really exist; and second,

whether or not there would be a functional landscape

corresponding to the nonlinear stochastic dynamics of the network.

After more than 10 years’ effort, the second problem has been

essentially solved: The corresponding functional landscape does

exist, at least in the mathematical and/or theoretical sense. This

second problem has now been replaced by a more practical and

potentially important question: For a given endogenous network,

how can we know for sure that all the major stable functional states

(and all major transition states) would have been found? If not,

some critical information on biology might have been missed. This

will be a challenging problem on the computational side for years

to come.

The first problem has not been solved very satisfactorily. We still

do not know the endogenous network for a given biological system

for sure. This will be a major effort for both experimental (cancer)

biologists and computational modelers now and in the future.

Nevertheless, it is clear that there does appear to have a common

core network for all cancers. This finding forms a workable base for

the further development. Based on the current evident, it is unlikely

that the hypothesized endogenous network would not eventually

be discovered. It may turn out even simpler than we would have

imagined: In biology we have witnessed such solutions several

times. One of the most famous is the discovery of double helix

for heredity processes: Much simpler than biologists would have

been anticipated.

4 Conclusion

Using HCC as an example we have realized the recently proposed

cancer endogenous molecular-cellular network hypothesis. The

working network of the liver was quantified by a set of nonlinear

differentiation equations. We have then demonstrated that the

working network reproduces the main features of the normal liver

and HCC at both the modular and molecular levels, as a first set of

evidence of the validity of the hypothesis. We explicitly obtain two

additional testable predications for the further validation. Specifi-

cally, (1) the potential strategies to cure or relieve HCC may be

inhibiting proliferation and inflammation, and simultaneously

inducing liver differentiation; (2) the genesis and regression of

240 Gaowei Wang et al.