Why cancer cells waste so much energy

(5) Tissue Invasion.

Solid cells generally sit on a foundation called basement membrane. Tissue invasion means "fuck basement membrane, I'm cutting through it and getting into the sewer pipes (blood vessels) below!"

This actually has two consequences. One is that, well, it's not really cancer until it can escape its original confines - then it's just a pre-cancerous growth. There are a lot of cellular proliferative conditions that will get big, but never go anywhere (e.g., uterine fibromas). These can still cause problems due to displacement of normal tissues, but not of the "I'm all over the body and munching happily away" variety.

The other implication of this step, though, is another type of immortality. Being detached from the basement membrane is one of those cell suicide signals we discussed earlier. So if you can successfully invade the membrane and dig into tissue, the implication is "I'm no longer sensitive to the basement membrane's cell-death signals." These signals overlap and tie into the cell-suicide signals mentioned above. None of these things are completely walled off from the others.

(6) Limitless replicative potential.

Normal cells are limited in their ability to replicate. Every time they do, there is a bit of their DNA that degrades on the ends. In order to compensate, there's a little end-cap, like the plastic aglet on a shoelace, that is there to be sacrificed. Those are called telomeres. Cancers will develop runaway enzymes for restoring those telomeres, so that they never run out of runway for cell replication.

There are other mechanisms in there that make it more complicated, though - we know this because some creatures have much longer telomeres than we do, but not proportionately more cancer (rabbits, if memory serves.)

This also gives rise to some of the weirdness in cancer research. We need immortal cell lines to do standardized research (so everyone is using the same baseline), but by being immortal they are fundamentally abnormal. The HeLa (Henrietta Lacks) cell line of recent fame is one of these immortalized cell lines. (Worth noting: at least in my lab, it wasn't hard to immortalize a cell line if needed. HeLa was unique only in that it was used early enough to become ubiquitous and set a standard - not that there's anything otherwise noteworthy about that particular handful of cells. They're the USB of cells.)

(7) Avoiding immune destruction.

There's overlap between all of these categories. Some of the ways your immune system kills pre-cancer cells are the pathways we broke above: the immune system might trigger apoptosis directly or indirectly, for instance. A cell-killer (CD8+ cytotoxic cell) will attack with an enzyme called 'granzyme', that explicitly tries to trigger apoptosis!

But there are other ways for the immune system to kill, and to be evaded. For instance, cells all express what's called "MHC 1". It's like the inspection sticker on your car. It take samples of intracellular proteins and shoves them up onto the cell surface for inspection by the immune system. If they're unusual, the immune system binds to them and kills the cell. So, not surprisingly, there are some cancers that downregulate MHC 1 - parking your car in your driveway so no one sees the expired sticker. This is common, I believe, in lung cancers. You can also see defects in the machinery that gets proteins to MHC 1; you can increase expression of "come hither" signals for immune suppressing cells (e.g., Regulatory T Cells, and Myeloid-derived suppressor cells); or secretion of immune suppressing molecules directly (e.g., TGF-Beta, IL-10, and VEGF). If VEGF sounds familiar, I should point out it's the signal for growing new blood vessels above.

(That's not a coincidence. Healing a wound requires quieting the inflammation that preceded the healing.)

New research in cancer vaccines is focusing on how to either restore the immunogenic environment, or to use alternative pathways. For instance, the toll-like receptor pathway doesn't usually play much of a role in developing cancer, so it's usually intact - so one of the new strategies that's being worked on is how to activate that pathway in response to cancers. And, we have drugs that target some of the elements here! For instance, those T-Regs express the cell surface marker CD25, which we can hit with a drug called daclizumab (I hope I got that spelled right - small molecule and monoclonal names are all gibberish.)

(8) Tumor-Promoting Inflammation. This wasn't a separate hallmark when I was a wee baby: the inflammatory signals promote cell proliferation, they can make blood vessels leaky, they can make blood vessels dilate (the combination means lots of yummy blood to feed a tumor). Inflammation also brings in lots of tumor-killing signals. "Tumor-promoting inflammation" is basically "everything I described above." So, I don't know, maybe something unique has been found here over time that I missed out on as the field evolved? Or not - all of these have grey areas of overlap.

(9) Genome instability and mutation.

Cancer cells, by virtue of shedding their DNA-protecting mechanism (cell death if the DNA is damaged too much) and going into rapid division, break the absolute shit out of their DNA. Not just the run-of-the-mill "oh, mutations accrue" type of breakage. I mean chromosomes are breaking and reattaching and breaking again, centromeres are all over the place, it's a shit show. This is a normal karyotype (image of the chromosomes as a whole): https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.scienc...

This is the karyotype of a breast cancer cell: https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.resear...

This "genome instability" doesn't just allow for rapid evolution - the fact that it can exist without the cell suiciding is a great big flag that this cell has very serious immortality mechanisms in play already.

(10) Deregulated cellular energy metabolism.

All of the stuff regulated above? It regulates, and is regulated by, cellular energy metabolism (which also feeds into various other type of macromolecule metabolisms - so when energy is dysregulated, it's like saying "our entire supply-side market is broken.") Which means dysregulated growth, dysregulated proliferation, etc. This is also a really core pathway - you can't fuck with such elemental life-or-death metabolic pathways without breaking stuff or killing stuff. By the time a cell can dysregulate these pathways (excess free radical generation by way of energy pathways is one of those cell suicide triggers, for instance), it's already shed a lot of its suicide signals and it's just burning through energy without heed for the tissues around it.

I hope that helps.

Okay, that's what I get for trying to be even slightly witty, username notwithstanding.

Some cells never divide, and so theoretically shouldn't become cancerous. They still happen though: myocardium tumors shouldn't happen, but hey, rhabdomyoma. In that case, it's more likely in youth / congenital, because it had to happen via inherited defect rather than one that accrued through cell replication in your lifetime. It is rare, though, and ridiculously rare in adults. Still, "on a long enough timeline...". I mean geeze, let a guy get a tiny bit poetic.

Other cells don't have DNA and don't reproduce, so they shouldn't be eligible (red blood cells.) They still fall into a grey area though: the RBC itself will be dead soon enough and never leave behind cancerous progeny. On the other hand, your bone marrow can absolutely lose its mind and pump out the equivalent of a red blood cell mass, a condition known as polycythemia. You can also have RBCs turn cancerous before they become fully mature and shed their DNA. The erythroblast stage - the late stage of RBC development, the last stage before it chucks its nucleus and becomes disposable - can develop into a leukemia.

Our reproductive system generally keeps its genetic payload cells in stasis for the lifetime, so it doesn't accrue replication errors, as well as sitting behind a protective wall (e.g., the Blood-Testis Barrier) similar to the one that protects the brain. Even in stasis, though, damage accrues - the age of the parent has a direct impact on the likelihood of various congenital disorders.

I would expect all explicit diets to feature higher mortality, as the correlation with having some sort of health concern (obesity, chronic condition, etc.) is going to be extreme. Skimming the whole study at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555979/ the "compared to what?" question does not appear to be asked or answered. Is it?

Nod to that. Where I'm going is the possibility of comparing people with "normal" diets and low-carb diets, and thus running the risk of comparing people who do not feel compelled to lose weight for health reasons and those who do. Same story as the various vitamin supplementation paradoxes, which can also be influenced by the fact that people supplementing are more likely to have some pre-existing cause to worry about their health.

Well I used to do Cancer research at the NCI before going back to software! :)