Tumor and the microenvironment: a chance to reframe the paradigm of carcinogenesis?

Mariano Bizzarri,Alessandra Cucina

doi:10.1155/2014/934038

Abstract

The somatic mutation theory of carcinogenesis has eventually accumulated an impressive body of shortfalls and paradoxes, as admittedly claimed by its own supporters given that the cell-based approach can hardly explain the emergence of tissue-based processes, like cancer. However, experimental data and alternatives theories developed during the last decades may actually provide a new framework on which cancer research should be reframed. Such issue may be fulfilled embracing new theoretical perspectives, taking the cells-microenvironment interplay as the privileged level of observation and assuming radically different premises as well as new methodological frameworks. Within that perspective, the tumor microenvironment cannot be merely considered akin to new “factor” to be added to an already long list of “signaling factors”; microenvironment represents the physical-biochemical support of the morphogenetic field which drives epithelial cells towards differentiation and phenotype transformation, according to rules understandable only by means of a systems biology approach. That endeavour entails three fundamental aspects: general biological premises, the level of observation (i.e., the systems to which we are looking for), and the principles of biological organization that would help in integrating and understanding experimental data.

Highlights

From the ‘‘Cancer Hallmarks’’ to the ‘‘Shortfalls’’ of the Somatic Mutation Theory of CarcinogenesisCancer is commonly thought as the result of progressive accumulation of random mutations and increased deregulation of key molecular pathways [1]
Despite the expectations raised by “the Ame’s axiom (“substances act as carcinogens because they have mutagenic activity”), it shortly turned out that most powerful carcinogens are not mutagen”; “but —as Weinberg candidly admits— I and others were not derailed by discrepant facts.”
Thereby, as we are unable to grasp such overwhelming complexity, we are unable to set a reliable theory of biological organization [13]. This is especially true in the field of carcinogenesis, where both experimental modelling and theoretical framework have been for a long time dominated by the SMT [14, 15]

Summary

Introduction

From the ‘‘Cancer Hallmarks’’ to the ‘‘Shortfalls’’ of the Somatic Mutation Theory of Carcinogenesis. Cancer is commonly thought as the result of progressive accumulation of random mutations and increased deregulation of key molecular pathways (somatic mutation theory of carcinogenesis, SMT) [1]. This statement utterly relies on a tacit premise that assumes that the pathogenetic process depends on alterations in a discrete number of signalling pathways, thought to carry “instructive” biological “information.” That paradigm prompted the pharmaceutical industry to focus on development of drugs targeting specific molecular components, funding basic research, and technological applications in line with those premises, strengthening a bottom-up reductionist approach. Passing the buck like this is an enormously liberating experience.”

Thinking of Cancer as a Tissue-Based Disease

Carcinogenesis Theory May Be Rebuild upon the Tumor Microenvironment Paradigm

Physical Cues Drive Cells Differentiation and Fate

Microenvironment and Cancer

Conclusions