Cancer Systems Biology: A Robustness-Based Approach - Systems Biology Concepts and Insights - page 447

Chapter 24

Cancer Systems Biology:
A Robustness-Based Approach

Hiroaki Kitano
The Systems Biology Institute, Tokyo, Japan; Okinawa Institute of Science and Technology; Sony Computer Science Laboratories, Inc., Tokyo, Japan;
Department of Cancer Systems Biology, The Cancer Institute, Tokyo, Japan

Chapter Outline
Introduction 469 Mechanisms for Cancer Robustness 471

Cancer as a Robust System 469 Robustness Trade-offs 473

What is Robustness? 469 Theoretically Motivated Therapy Strategies 473

Robustness and Homeostasis 470 A Proper Index of Treatment Efficacy 475

Mechanisms for Robustness 471 Long-Tail Drug 476

Systems Control 471 Open Pharma 477

Fault Tolerance 471 Conclusion 478

Modularity 471 Acknowledgements 478

Decoupling 471 References 478

INTRODUCTION
Cancer as a Robust System
Cancer is a heterogeneous and highly robust disease that
represents the worst-case scenario of entire system failure:
a fail-on fault where malfunction components are protected
by mechanisms that support robustness in normal physi-
ology [1,2] . It involves hijacking the robustness mecha-
nisms of the host. The survival and proliferation capability
of tumor cells are robustly maintained against a range of
therapies, due to intratumoral genetic diversity, feedback
loops for multidrug resistance, tumor

example, bacteria robustly maintain their chemotaxis
circuit's capability against a broad range of perturbations in
external chemical changes and internal fluctuations of
enzyme dosages [4] . Robustness also applies to engineering
systems. For instance, a modern airplane (system) main-
tains its flight path (function) against atmospheric turbu-
lence (perturbations). Specific aspects of the system, the
functions to be maintained, and the types of perturbations
that the system is robust against, must be well defined in
order to make solid deductions.
Robustness is not necessarily identical to homeostasis
or stability. Homeostasis is a term coined by Walter
Cannon, meaning an identical (homo) state (stasis). In
'Wisdom of the body', Cannon describes it as follows:

host interactions,
etc. This chapter examines why cancer is robust against
therapeutic interventions and tries to elucidate possible
options for us to control it.

e

'The everlasting state maintained in the body may be called an
equilibrium state. But, this word has a fairly precise meaning now
since it has been used for a comparatively simple physicochemical
state in which known forces are balanced, namely used for closed
systems. The interrelated physiologic action that maintains the
main portions of stable states in a living body, which contains the
brain, the nerves, the heart, the lungs, the kidneys and the spleen
to fulfill their functions collaboratively, is so complex and unique
that I have been proposing to use a special word of 'homeostasis'

What is Robustness?
Robustness is a property of the system that maintains
a certain function despite external and internal perturba-
tions [3] . It is distinctively a system-level property that
cannot be observed by just looking at components.
Robustness is observed ubiquitously within and among
biological systems; from bacteria to human beings. For