A Multi-Scale Approach to Colorectal Cancer: From a Biochemical- Interaction Signaling-Network Level, to Multi-Cellular Dynamics of Malignant Transformation. Interplay with Mutations and Onco-Protein Inhibitor Drugs

L.      Tortolina; N.      Castagnino; C.      De Ambrosi; E.      Moran; F.      Patrone; A.      Ballestrero; S.      Parodi

Abstract

This review article is part of a special Current Cancer Drug Targets issue devoted to colorectal cancer and molecularly targeted treatments. In our paper we made an attempt to connect more basic aspects with preclinical, pharmacological / therapeutic and clinical aspects. Reconstruction of a Molecular Interaction Map (MIM) comprising an important part of the G0 – G1 – S cell cycle transition, was a major component of our review. Such a MIM serves also as a convenient / organized database of a large set of important molecular events. The frequency of mutated / altered signaling-proteins indicates the importance of this signaling-network region. We have considered problems at different scale levels. Our MIM works at a biochemical-interaction level. We have also touched the multi-cellular dynamics of normal and aberrant colon crypts. Until recently, dynamic simulations at a biochemical or multi-cellular scale level were considered as a sort of esoteric approach. We tried to convince the reader, also on the basis of a rapidly growing literature, mostly published in high quality journals, that suspicion towards simulations should dissipate, as the limitations and advantages of their application are better appreciated, opening the door to their permanent adoption in everyday research. What is really required is a more interdisciplinary mentality and an interdisciplinary approach. The prize is a level of understanding going beyond mere intuition.

Keywords: Colorectal cancer, colon crypts, dynamic simulations, ErbB-family, oncogene mutations, signaling-network, TGFbeta, WNT