Multicellular life and the origin of cancer

We had an interesting discussion in the mathematical oncology group (co-)founded by David Basanta in the last days. David is interested in studying cancer as an evolutionary disease, knows a lot about the evolutionary aspects of cancer, and drawed our attention to some controversial articles from Paul Davies.

Paul Davies suggested last year that cancer might be an evolutionary throwback to the dawn of multicellular life. This year he has proposed again that cancer may be an throwback to ancient biological age, this time together with Charles Lineweaver. While this has caused refusal and anger, especially among professionals and biologists, some of his ideas are fascinating. Can cancer be considered as an “evolutionary throwback to the dawn of multicellular life, when single cells began cooperating and forming rudimentary aggregations”, as Davies argues in his 2011 article? Is, as Davies suggests in his 2012 article, the fact that “cancer cells thrive in low-oxygen conditions” a sign that they are “reverting to an earlier, albeit less efficient, form of metabolism known as Fermentation” used in the ancient era before multicellular life?

The idea that cancer might be an evolutionary throwback to the dawn of multicellular life sounds odd, but maybe it is not completely wrong. Cancer is a genetic disesase and an evolutionary one. Cancer evolves. It’s obvious that the ability of individual cells to proliferate is essential for life, and any deregulation of this process will have dramatic consequences in form of cancer. It is also clear that there is a certain similarity between early multicellular life, embryonic development and cancer: in all cases a single cell develops into a cluster of multiple ones. So where is the evidence? Well, for one there are many other evolutionary systems as well which are subject to evolution. And we do have these kinds of throwbacks in forms of cultural evolution. I wrote about it earlier here and here. Maybe there are indeed some common grounds between different evolutionary systems. I think that some of the ideas mentioned by Davies are not completely wrong. If we consider cultural evolution, there are indeed cases of ‘cultural cancer’ which are like a backslide, throwback or fall-back to earlier, more primitive forms of organization. Some forms of organized crime for example can arise from the ‘stem cell’ of the family. Fascism can emerge from the ‘stem cell’ of the religious or ideological group (think of the Nazis, WWII, etc.). These forms of organization are more primitive and have a lower degree of Differentiation than the surrounding environment, but also much more aggressive. There are indeed some deep similarities.

We know a lot about cancer and carcinogenesis. We know that it takes 5-7 independent mutations until a tumor develops. One of these mutations for instance often deactivates the tumor suppressor protein p53 or its regulator mdm2 (see picture, p53 controls a certain phase in the cell cycle and acts as a brake which prevents uncontrolled growth and cell Proliferation. This connection between cell cycle and cancer is well known. The p53 Family of proteins is indeed very old, at least 700 million years old). If cancer would be caused simply by a reactivation of ancestral silent genes, then this would have been found out and reported by now. And yet we are powerless against the most aggressive forms of cancer. It would be wonderful if we finally make some progress, especially because the search for a “unified model” of cancer biology has been an elusive goal so far.

The idea that cancer is based on a evolutionary throwback to the dawn of multicellular life, when single cells began cooperating and aggregating, fits also well to the hypothesis of cancer stem cells. Scientists have found some striking parallels between “evil” tumor inducing cancer cells cells and “good” stem cells – both have indefinite potential for self-renewal (see Reya et al. Stem cells, cancer, and cancer stem cells). And both have tremendous power, either to re-create or to destroy the system (since self-rejuvenation and cancer are linked). Cancer stem cells are similar to “selfish” single-celled organisms, as they must have existed at the onset of multicellular life.

Yet some biologists are upset that the solution to one of the most difficult problems is so simple. It is indeed a bit like presenting the name of the problem as its solution: a failure in the regulation of multicellularity is a description and more or less a definition of cancer, but not a solution or cure. And of course the genes for multicellularity are as old as multicellular life itself. Obviously the oldest genes will perform the most fundamental tasks in the cell, such as replication and regulation of multicellular development. Therefore it is not difficult to understand why biologists are angry about Paul Davies, he makes wild speculations and lofty conclusions in their playground, claiming to have identified trivial facts as the root cause of cancer without the willingness to make his hands dirty by formulating a full theory and presenting evidence for it. Somehow his “theory” is a bit like Anne Elke and her brontosaurus theory (which is possibly a parody of Stephen Jay Gould’s “punctuated equilibrium” theory). Yet I like dinosaurs, and most biologists agree that there is indeed a relation or at least a similarity between the evolution of multicellular life, embryonic development and cancer. Cancer belongs to life like explosions to rockets. It is a fundamental property of genes to reproduce and proliferate, just as it the fundamental property of rockets to burn and to explode in a controlled way. If Davies is at least partially right, then “cancers” maybe are the rule, and highly organized biological life-forms are the exception.

Unlike Paul Davies Guadian article from 2011, the Guardian article from 2012 places emphasis on an earlier, less efficient, form of metabolism known as fermentation. Do we have any evidence for an altered metabolism in the majority of cancer cells? This would indicate that some malicious cancers are indeed similar to an alien or ancient life-form based on a distinct type of metabolism. In our discussion, Joe Juliano mentioned a paper from Mark Vincent, Cancer: A de-repression of a default survival program common to all cells which supports this views. According to the hallmarks of cancer paper from Hanahan and Weinberg (2011) the answer seems to be yes: reprogramming of energy metabolism seems to be a hallmark of cancer. It is one of the two new hallmarks proposed by Hanahan and Weinberg to extend the classic hallmarks of cancer, the ‘six organizing principles’: an altered form of metabolism and a kind of immune or defense system.

• Sustaining proliferative signaling
• Evading growth suppressors (insensitivity to anti-growth signals)
• Activating invasion and metastasis
• Enabling replicative immortality (limitless replicative potential)
• Inducing angiogenesis (blood vessel growth)
• Resisting apoptosis (cell death)
• NEW: reprogramming of energy metabolism
• NEW: evading immune destruction (resistance immune system)

Both are typical properties of systems, sub-systems for self-maintenance and self-protection. Will the (evolutionary) system approach be helpful in our attempt to understand cancer? Can evolutionary theory help us to understand the essential aspects of cancer? I think no theory or idea is too weird or too odd if it it helps to fight this terrible disease. At least we should follow every path, even if it turns out to be a blind alley in the end.

Literature

• Douglas Hanahan and Robert A. Weinberg, Hallmarks of Cancer: The Next Generation, Cell Volume 144, Issue 5, 646-674, 4 March 2011
• Mark Vincent, Cancer: A de-repression of a default survival program common to all cells, BioEssays Vol. 34 Issue 1 (2011) 72-82
• Reya et al., Stem cells, cancer, and cancer stem cells, Nature Vol 414 (2001) 105-111
• Paul Davies and Charles Lineweaver, Cancer tumors as Metazoa 1.0: tapping genees of ancient ancestors, Journal of Physical Biology Vol. 8 (2011)
• Kathleen Collins, Tyler Jacks, and Nikola P. Pavletich, The cell cycle and cancer, PNAS 1997 94 (7) 2776-2778
• John W. Pepper et al., Cancer research meets evolutionary biology, Evol Appl. 2009 February; 2(1): 62–70
• Melissa R. Junttila and Gerard I. Evan, p53 – a Jack of all trades but master of none, Nature Reviews Cancer, Vol.9 (2009) 821-829

American Scientist articles:

• Cancer by default, Jan.-Feb. 2000, Vol. 88, Number 1, Page: 1
• Zeroing in on cancer, Sep.-Oct. 2010, Vol. 98, Number 5, Page: 366

Guardian articles by Paul Davies:

• Cancer can teach us about our own Evolution, Nov 2012
• Cancer: The beat of an ancient drum?, Apr 2011

(the Image of the p53 Tumor Suppression protein is from Wikipedia)