So, this is just a conceptual schema, and not a hard-and-fast rule. It was first published by Robert A. Weinberg in 2000 as "the six hallmarks of cancer", as an attempt to distill down everything we knew about cancer genesis into something we could understand as a model. He's considered the grand high poobah of oncogenetics. There've been people fretting at the details of his model since then, so it's grown a bit.

Also worth noting that this model was basically built on solid tumors. Liquid cancer (cancers of the blood - e.g., leukemia) have a different, more poorly studied path, though the broad brush-strokes seem to be the same.

The original model was: -Evading apoptosis -Self-sufficiency in growth signals -Ignoring anti growth signals -Autonomous, ongoing angiogenesis -Tissue invasion -Limitless replicative potential

The version that I learned in grad school was up to 8 hallmarks. Apparently it's evolved a bit more since then, and the most recent version being bandied about is:

-Evading apoptosis -Self-sufficiency in growth signals -Ignoring anti-growth signals -Autonomous, ongoing angiogenesis -Tissue invasion -Limitless replicative potential -Avoiding immune destruction -Tumor-promoting inflammation -Genome instability and mutation -Deregulated cellular energy metabolism

Honestly, I'm not sure the ten hallmark model really adds anything - I'd argue that the four additions fall neatly under the old six. But whatever - it's just a model, and doesn't change the granular reality at all.

To summarize each of the hallmarks in brief:

(1) Evading Apoptosis. Cells have a number of mechanisms that basically say "something's off here, I should kill myself now."

For instance, when DNA repair enzymes get upregulated, so does p53 - if p53 tips over a key value, it starts setting off the suicide pathway. So, "too much DNA damage" = "cell offs itself rather than propagating damaged DNA." There are actually a bunch of proteins in the cell see-sawing here, in response to internal and external signals, and if the "kill yourself" signal tips the see-saw, the cell dies.

Pretty much any mutation in the cell suicide pathway predisposes to cancer. For instance, an extrinsic trigger of apoptosis is binding of what's called the FAS Ligand to the FAS Receptor (a big part of how immune cells regulate their own suicide, to prevent auto-immunity.) A mutation in FAS Ligand, or FAS Receptor, or anything downstream of them, will predispose to autoimmune disease and cancer.

Another one is the anti-apoptotic protein BCL-2, which you'll find overexpressed in something like half of all cancers.

Since cancer development triggers so many "kill me now!" signals, turning this pathway off is a hallmark of cancer development. The cancer will usually do so through a combination of over-expressing anti-apoptotic proteins, and under-expressing pro-apoptotic proteins.

Do we make use of this knowledge for therapy? Sure do. One therapy is a BCL-2 inhibitor, Venetoclax. Methotrexate, which slows down cell proliferation, also causes adenosine accumulation that can trigger apoptosis. These drugs have varied benefits: when you target the specific broken pathway in the cell, they're excellent (e.g., BCL-2 in CLL). Cancers are good at evolving around these therapies though, so they're not used as mono-therapy.

(2) Self sufficiency in growth signals. Normal cells don't just grow on a whim - they require signaling from cells around them and from distant parts of the body, to ensure things are kept regulated. Once a cell starts generating its own growth signals, though - like an army in revolt, giving its own orders - then you're on the path to cancer. This is one of the key mutations that gives rise to the "atavistic cell" description of cancer - they've thrown off their shackles, and become wild cells again! Well, not really - even wild cells are careful about when to expend the resources to proliferate. Bacteria commonly depend on their neighbors - using whats called quorum sensing molecules - to control their growth. Heedless, runaway growth is not the norm even in 'wild' cells.

(3) Ignoring anti-growth signals. Most everything in the cell is the process of see-saw balances: there are always signals pushing in each direction, compensating biochemical pathways, and shifting balances. Growth is no exception: how the cell acts is in response to a whole bunch of pro- and anti-growth signals, and most of the time it moves in the direction that they're pressured to by the consensus.

Well, if one of the hallmarks of cancer is like an army giving itself orders (independence from external growth signals), another is the active refusal to heed anti-growth signals (shutting down lines of communication with the Joint Chiefs of Staff). This may be because key anti-growth receptors are broken; it may be because something downstream of those receptors is broken. The key is, though, that between "I'll tell myself when to grow" and "I don't care what anyone else says to the contrary," the cell is now positioned to grow and grow and grow.

(4) Autonomous Angiogenesis.

Tissues need oxygen and nutrients and stuff. However, that stuff really only travels a tiny distance from the smallest blood vessels - capillaries - because it has to leave the capillaries via diffusion, and the time for something to travel by diffusion increases as the square of the distance. So, going 4mm will take 4x longer than going 2mm. Forget about feeding tissues 1cm away from a capillary - it's not happening. Usually, outside of embryogenesis, blood vessel construction is rare - it happens when a blood vessel is damaged, and it secretes growth signals to build a new vessel. (In fact, in a well regulated environment, this is often followed by signals to kill some of the new vessels, too - which is why a fresh scar is red and angry, but an old one is pale and avascular. The blood vessels that came in to supply immune cells and fibroblasts actually regress.)

So, anyway, here's our tumor - replicating like wild, if it can, not caring if it grows too far from a capillary. One of the consequences is rampant cell death. Tumors aren't healthy, they're usually riddled with dying cells. Another consequence is shifting to anaerobic metabolism - which, yay, don't need blood supply so much. But it's also massively less energy-efficient than oxygen, so any tumor cells that can make use of oxygen supply will tend to outreplicate those that can't.

So what happens? Almost inevitably, they start secreting stuff like VEGF (vascular endothelial growth factor) to grow their own blood vessels. These vessels are messy and leaky and prone to breaking, but they're so much better than nothing, and our tumor is off to the races.

Do we target angiogenesis in therapy? Yeah, there's a shit-ton of drugs that inhibit angiogenesis (you might have heard about bevacizumab a lot lately - we've also given it to Covid patients at high risk of hospitalization, since nothing in the body ever only has one effect).

I'll continue in another post; I'm not sure if HN has length limits.

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.

Thanks!