Tumor progression — time for a new paradigm?

Ernberg I.

I. Ernberg, MD, PhD, Professor of Tumor Biology

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm SE-17177, Sweden

Ingemar.Ernberg@ki.se

Around the millennium three decades of successful research into the biology of cancers were concluded in the most cited review on cancer ever “Hallmarks of Cancer” (Hanahan and Weinberg, Cell, 2000). It marked the end of the era when oncogenes and suppressor genes were discovered en masse, and when tumor progression at the level of cell and tissue pathology could be linked with molecular steps like that of the pioneering description by Bert Vogelstein of colon cancer progression (“The Vogelgram”). We then understood that cancer was indeed a disease of cells and depended on mutations of some ten genes. Tumor progression, when tumors “go from bad to worse”, could be viewed as an evolutionary, Darwinistic process at the tumor cell population level, with sequences of mutation, improved cell survival, selection, another mutation etc. This seemed so transparent and logically sound that the scientific community at large believed it had understood the biology of cancer. Now we only needed to trace these mutated genes and eliminate their erroneous behaviour one way or another. It also gave a strong impetus to “personalized cancer medicine”, now we only needed the genome of individual tumors for designing the cure. One impressive major extrapolation was that all the 200 different forms of cancer develop through a similar mechanism. With this modern paradigm of cancer biology (or the Hanahan — Weinberg — Vogelstein/HWV-paradigm) as a basis, ten years later it was clear that the success rate in exploiting its implications for cancer treatment was quite low.

During the same time the understanding of cell and tissue biology took quantum leaps in new directions, which clearly exposes the HWV-paradigm as totally insufficient and oversimplified, although not directly wrong. The conclusions are two: we do not really understand cancer biology, and cancer is a very complex disease reflected by the enormous complexity of its “host” — the cell. Major findings have been: epigenetic deregulation is as important as mutations, cancer tissues are highly heterogenous with cell hierarchies (including stem-cell like cells) and a participating stroma, microRNAs represent a large new set of regulatory genes, low level chronic inflammation is a key component in early carcinogenesis, there are not only some ten mutations in cancer cells but rather several thousands, and cancer cells usually switch metabolism from oxidative glycolysis to fermentation (the Warburg effect).

How can we comprehend all these significant findings in our understanding of cancer biology? Firstly we should be humble. Secondly we should explore new tools and technologies in interdisciplinary initiatives to adopt an approach that accommodates complex or complicated features of biological systems like cancer. This will be a long and uncertain way. Meanwhile it must be perfectly motivated to continue to develop treatments based on trial-and-error without sufficient information about the enemy.

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