What Causes Cancer? What is Cancer?

There is some frustration in the literature.

Fifty years into the war on cancer, what have we learned and gained? We do not have a general cure, though we have a few cures and a lot of treatments. We have a lot of understanding, but no comprehensive theory or guide to practice. While some treatments are pin-point specific to certain proteins and even certain mutated forms of those proteins, most treatments remain empirical, even crude, and few provide more than a temporary respite. Cancer remains an enormous challenge, clinically and intellectually.

Recently, a prominent journal ran a provocative commentary about the origins of cancer, trashing the reigning model of "Somatic Mutation Theory", or SMT. Which is the proposition that cancer is caused by mutations that "drive" cell proliferation, and thus tumor growth. I was surprised at the cavalier insinuations being thrown around by these authors, their level of trash talk, and the lack of either compelling evidence or coherent alternative model. Some of their critiques have a fair basis, as discussed below, but to say, as the title does, that this is "The End of the Genetic Paradigm of Cancer" is simply wrong.

"It is said that the wise only believe in what they can see, and the fools only see what they can believe in. The latter attitude cements paradigms, and paradigms are amplified by any new-looking glass that puts one’s way of seeing the world on steroids. In cancer research, such a self-fulfilling prophecy has been fueled by next-generation DNA sequencing."

"However, in the quest for predictive biomarkers and molecular targets, the cancer research community has abandoned deep thinking for deep sequencing, interpreting data through the lens of clinical translation detached from fundamental biology."

Whew!

The main critique, once the gratuitous insults and obligatory references to Kuhn and Feynman are cleared away, is that cancer does not resemble other truly clonal disease / population processes, like viral or bacterial infections. In such processes, (which have become widely familiar after the COVID and HIV pandemics), a founder genotype can be identified, and its descendants clearly derive from that founder, while accumulating additional mutations that may respond to the Darwinian pressures, such as the immune system and other host defenses. While many cancers are clearly driven by some founding mutation, when treatments against that particular "driver" protein are given, resistance emerges, indicating that the cancer is a more diverse population with a very active mutation and adaptation process. 

Additionally, tumors are not just clones fo the driving cell, but have complex structure and genetic variety. Part of this is due to the mutator phenotypes that arise during carcinogenesis, that blow up the genome and cause large numbers of additional mutations- many deleterious, but some carrying advantages. More significantly, tumors arise from and continue to exist in the context of organs and tissues. They can not just grow wildly as though they were on a petri plate, but must generate, for example, vascular structures and a "microenvironment" including other cells that facilitate their life. Similarly, metastasis is highly context-dependent and selective- only very few of the cells released by a tumor land in a place they find conducive to new growth. This indicates, again, that the organ setting of cancer cells is critically important, and accounts in large part for this overall difference between cancers and more straightforward clonal processes. 

Schematic of cancer development, from a much more conventional and thorough review of the field.

Cancer cells need to work with the developmental paradigms of the organism. For instance, the notorious "EMT", or epithelial-mesenchymal transition is a hallmark of de-differentiation of many cancer cells. They frequently regress in developmental terms to recover some of the proliferative and self-repair potential of stem cells. What developmental program is available or allowed in a particular tissue will vary tremendously. Thus cancer is not caused by each and every oncogenic mutation, and each organ has particular and distinct mutations that tend to cause cancers within it. Indeed, some organs hardly foster any cancers at all, while other organs with more active (and perhaps evolutionarily recent) patterns of proliferation (such as breast tissue, or prostate tissue) show high rates of cancer. Given the organ setting, cancer "driver" mutations need not only unleash the cell's own proliferation, but re-engineer its relations with other cells to remove their inhibition of its over-growth, and pursuade them to provide the environment it needs- nutritionally, by direct contact, by growth factors, vascular formation, immune interactions, etc., in a sort of para-organ formation process. It is a complicated job, and one mutation is, empirically, rarely enough.

"Instead, cancer can be broadly understood as “development gone awry”. Within this perspective, the tissue organization field theory is based on two principles that unite phylogenesis and ontogenesis."

"The organicist perspective is based on the interdependency of the organism and its organs. It recognizes a circular causal regimen by closure of constraints that makes parts interdependent, wherein these constraints are not only molecules, but also biophysical force."

As an argument or alternative theory, this leaves quite a bit to be desired, and does not obviate the role of  initiating mutations in the process.

It remains, however, that oncogenic mutations cause cancer, and treatments that address those root causes have time and again shown themselves to be effective cancer treatments, if tragically incomplete. The rise of shockingly effective immunotherapies for cancer have shown, however, that the immune system takes a more holistic approach to attacking disease than such "precision" single-target therapies, and can make up for the vagaries of the tissue environment and the inflammatory, developmental, and mutational derangements that happen later in cancer development. 

In one egregious citation, the authors hail an observation that certain cancers need both a mutation and a chemical treatment to get started, and that the order of these events is not set in stone. Traditionally, the mutation is induced first, and then the chemical treatment, which causes inflammation, comes second. They state: 

"The qualitative dichotomy between a mutagenic initiator that creates ’cancer cells’ and the non-genetic, tissue-perturbing promoter that expands them may not be as clear-cut. Indeed, the reverse experiment (first treatment with the promoter followed by the initiator) equally produces tumors. This result refutes the classical model that requires that the mutagenic (alleged) initiator must act first."

The citation is to a paper entitled "The reverse experiment in two-stage skin carcinogenesis. It cannot be genuinely performed, but when approximated, it is not innocuous". This paper dates from 1993, long before sequencing was capable of evaluating the mutation profiles of cancer cells. Additionally, the authors of this paper themselves point out (in the quote below) a significant assymetry in the treatments. Their results are not "equal":

"The two substances showed a reciprocal enhancing effect, which was sometimes weak, sometimes additive, and sometimes even synergistic, and was statistically most significant when the results were assessed from the time of DMBA application. Although the reverse experiment was not in any way innocuous it always resulted in a lower tumor crop than the classical sequence of DMBA followed by a course of TPA treatment. 

However, the lower tumor crop in the reverse experiment cannot be used to prove a qualitative difference between initiators and promoters."

(DMBA is the mutagen, while TPA is the inflammatory accelerant.)

So chemical treatment can prepare the ground for subsequent mutant generation in forming cancers in this system, while being much less efficient than the traditional order of events. This is not a surprise, given that this chemical (TPA) treatment causes relatively long-term inflammation and cell proliferation on its own.

"An epistemic shift towards a biological theory of cancer may still be an uphill battle in the current climate of thought created by the ease of data collection and a culture of research that discourages ’disruptive science’. Here, we have made an argument for dropping the SMT and its epicycles. We presented new and old but sidelined theoretical alternatives to the SMT that embrace theory and organismal biology and can guide experiments and data interpretation. We expect that the diminishing returns from the ceaselessly growing databases of somatic mutations, the equivalent to Darwin’s gravel pit, may soon reach a pivot point."

One rarely reads such grandiloquent summaries (or mixed metaphors) in scientific papers! But here they are truly beating up on straw men. In the end, it is true that cancer is quite unlike clonal infectious diseases, and for this, as for many other reasons, has had scientists scratching their heads for decades, if not centuries. But rest assured that this chest-thumping condescension is quite unnecessary, since those in the field are quite aware of these difficulties. The various nebulous alternatives these authors offer, whether the "epigenetic landscape", the "tissue organization field theory", or the "biological theory of cancer" all have kernels of logic, but the SMT remains the foundation-stone of cancer study and treatment, while being, for all the reasons enumerated above and by these authors, only part of the edifice, not the whole truth.

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