How have some cancers "evolved" to be so aggressive and treatment-resistant?

Question

[In this post, I may ascribe agency to processes, inanimate objects or microorganisms: this is rhetorical, I know they don't "intend" anything. I will also use "evolution" in a fairly loose sense of "learning" (again, rhetorical agency) to overcome obstacles to survival].

Assumptions:

Cancers are caused by mutations of cells, and "successful" cancers are caused by mutations that result in a, sometimes literally, killer combination of

• Suppression of their own apoptosis
• Invisibility to the immune system or resistance to immune attack
• Ability to co-opt biological resources such as bloody supply so they don't starve

The various "types" of cancer that we know and give names to are the end-points of available "mutation pathways" that cells can take to get to such a "successful cancer" state. Because lots of mutations result in cancers that don't "work" for some reason (e.g. immediately shut down by an immune response), they just don't result in a noticeable tumor. Therefore, we end up with a discrete set of "familiar" cancers, each representing a different path, and their frequency related to how likely it is that path is hit (i.e. how many mutations needed, etc).

Some cancers, the malignant ones, happen also to spread very effectively, though this is not specifically required by the above success criteria, so we also see benign tumors which don't spread but still can be said to "succeed" in that the cells survive.

Once mutated, cancers are presumably fairly genetically static within a single case, otherwise we'd see a storm of cancer variants developing within patients over a relatively short period as an evolutionary arms-race took place, much like the race between antibiotics and bacteria.

However:

• Some cancers have quite "advanced" mechanisms for spreading¹
• Some cancers are extremely resistant to human treatment

The question:

How did these "dangerous" cancers becomes so dangerous? A dangerous cancer seems to be "fully capable" of effective spread in the first instance, rather than undergoing a complex evolutionary battle with the host's own anti-cancer abilities or some exogenous treatment.

Furthermore, even cancers that "succeed" can't effectively propagate themselves like bacteria, because they're always in the same body². If anything, cancers that do not kill the host should be selected for, since people with genes "near" dangerous mutation opportunities would be less likely to reproduce effectively³. So (naively, since it's clearly not the case), if people do evolve such that they can get cancer⁴, cancers would tend towards being both benign and generally non-life threatening.

Even if they do somehow "evolve" to spread and threaten the host (as they indeed evidently have), why are they then also often so good at evading non-host treatment?

It seems like two warring armies (host vs. cancer) that have evolved together using hand weapons, evenly matched for centuries. The cancer invents the crossbow (mutates) and starts to win the war. Then, aliens (doctors) suddenly turn up with UAV surveillance and cruise missiles (imaging and treatment) and side with the host, but the cancer still wins much of the time, even though they're facing an Outside Context Problem that by rights they have no innate ability to counter.

So what results in these cancers being so adept at spreading themselves without some adversarial evolutionary process (à la bacteria vs. antibiotics)? Furthermore, how are they so often also resistant to human-directed treatment? Is it just because the human treatment is crude (i.e. not so much aliens but a large but unruly peasant milita that often doesn't really help that much)? Is there more "evolution" going on within a single cancer patient than I imagine?

Expansion in response to comments: if my assumption that the cancer cells are not usually "evolving" once formed is indeed incorrect: is that evolution then usually the cause of treatment escape? And does that mean that treatment-escaping cancers are freely evolving, in that they could take a number of case-dependent paths to escape (as opposed to the original recognizable cancer "type" which took one of a limited number of available mutation pathways through the fairly static environment of human biochemistry to become that cancer in the first place)?

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1. For example, the use of matrix metalloproteases to escape into the bloodstream, the use of cytoskeletal locomotion and various other highly specialized mechanisms that I would normally associate with a long and involved adversarial evolutionary arms race on a far longer timescale than one patient's cancer progression
2. Certain transmissible cancers like in Tasmanian devils notwithstanding
3. The obvious mechanism for this is they die or become critically disabled before having children, but it could also be disadvantageous for elders to die too early, especially for humans, when they assist in rearing their own descendants
4. Perhaps as a by-product of some otherwise-advantageous genetics, like sickle-cell anaemia and malaria resistance, where the occasional lethal downside of in a certain percentage of people is outweighed by the statistical benefits.

Answer 1

Cancer being 'dangerous'

I define 'dangerous' as reduces survival of patient significantly. In my experience, cancers become dangerous, if one can't remove the tumor. This happens if it starts spreading (metastasize) or start infiltrating surrounding tissue. In order to do so, cancer has to 'digest' extracellular matrix (e.g. the stuff that holds cells together as connected tissue).

Each cancer has its own mechanisms, allow me to illustrate this in one example, multiple myeloma: Multiple myeloma degrades surrounding tissue (bone), because doing so directly yields a massive survival benefit. Bone is a huge storage for TGFβ, a growth factor, so myeloma cells get a huge growth boost from mining away bone tissue. To do so, myeloma cells upregulate metalloproteases (MMPs, enzymes that shred proteins). They can do that, since myeloma cells have a mutated form of the NF-κB, a transcription factor that can upregulate a shit-ton of genes (including MMPs, and also growth and survival genes).

So you see, all these mechanisms are focused on maximizing the expression of survival and growth genes. Becoming untreatable in the process (and hence 'dangerous') is simply a "side-effect".

Other cancer types infiltrate surrounding tissue, since their fast increase in size has made them starve for oxygen (hypoxia & angiogenesis). They secrete signals for blood vessels to grow into the tumor and provide oxygen. This can also make a tumor "untreatable" since they cannot be removed, without risking irrepairable blood loss. But you see, this is also just a "side effect" of the tumor maximizing survival.

My point is, the "danger" of a tumor is not a direct consequence of the evolutionary armsrace towards huge growth and survival. It just happens as a side effect, since cells are stupid and can ignore the needs of surrounding tissues.

About Tumor spreading

I got two disagreements. These spreading mechanisms do not have to be "advanced". Sometimes one requires just one dysregulated transcription factor (NF-κB) to induce MMP expression (ref1, ref2). And given their rapid mutation rate, cancer cells populations are very heterogenous and hence provide for a huge functional plasticity, so even 'advanced' mechanisms are possible.

Degrading surrounding tissue does provide a success criterium, like I said, myeloma benefit from mining growth factors (TGFβ) from bone, or from degrading surrounding tissue to provide room for blood supply.

Cancers that do not kill the host should be selected for

Sadly, this is incorrect. Most humans get cancer after the reproductive age. In other words: Cancer happens when you're old and already had children, so it did not prevent you from having children. That's why cancer is not that much of a selective pressure today. It would be, if e.g. a large proportion of teenagers/young adults would get cancer, but that's simply not the case.

About Cancer Resistancy

Cancer resistance to treatment often times is a side-effect of them upregulating survival factors and downregulating apoptosis factors. In other words, the drug is damaging the cancer-cell, but the cancer cell simply doesn't know how to die. Of course, the treatment kills a lot of cancer cells, but resistant ones remain (e.g. using ABC-transporters to pump the drug right out of the cell). And I gotta say: Most classic chemotherapeutics out there are simply very very ineffective.

I hope that I could answer your question somehow. I am sorry for not providing references for each point. If you want some sources on specific points, I can look through my papers and see if I can provide something.