Why havent we cured cancer yeeeeeet?

A neat paper was just published in Nature, where they did complete genome sequencing of the prostate cancer tumors from seven advanced/aggressive prostate cancer patients.

The genomic complexity of primary human prostate cancer

Why did they want to do this? They hoped to identify some new features of aggressive prostate cancer that could be exploited for treatment purposes. A mutation obliterates Gene X? Maybe administering Protein X helps. A chromosomal rearrangement plops a strong promoter in front of Gene A? Maybe administering inhibitor of Protein A helps. Heck, maybe everyone has a little mutation or deletion or something going on at a particular region that doesnt make a bit of difference until youve got 'cancer' set into motion, so we could figure out some 'you need to watch out for...' genetic tests in the future.

Yeah, its fishing, but they were going to learn something, whether it translated into any immediate help for prostate cancer patients or not.

I dont know about you all-- Maybe Orac has a better hold on 'cancer' conceptually than I do-- but I always kinda thought that "First there are some mutations, and that causes some mistakes in genome replication, and then there is some messy chromosomal rearrangements and such, which make the whole thing worse--> cancer."

I figured genomes got pretty messy in tumors, but I dont think I fully comprehend the magnitude of the chromosomal train-wreck of 'prostate cancer'.

There were: 53, 67, 90, 213, 133, 156, 43 chromosomal rearrangements.

43, yeah, okay, I would believe that. Thats "a lot" to me. But 213??? HOLY CRAP. Look at this! Its like 'cancer' just took these folks genomes and shuffled em like a deck of cards. On average, there were ~108 chromosomal abnormalities in these folks tumors. Not even getting to the mutations, just gross chromosomal shuffling.

O.o

And we arent talking a mutation here, a tiny deletion there-- we are talking huge chunks of DNA in the wrong place. Different spot on the 'right' chromosome, different chromosome all together... As one of the authors put it:

If the genome was a book, instead of just looking for out-of-place letters or misspelled words, whole genome sequencing looks for whole paragraphs that are in the wrong place.

Man. What a mess.

And people wonder why we havent cured 'cancer' yet. *rolleyes*

On a side note, please note the lulz in that Yahoo article: gratuitous reference to 'JUNK DNA!', Creationist excited about gratuitous reference to 'JUNK DNA!', woo-er giving medical advice on how we wouldnt have cancer if everyones blood was at the right pH, and a man-jerk bitching about how much money boob cancer gets. Awesome. LOL.

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Have you Googled "Antineoplastic activity of cannabinoids"?

IIRC there was a study last year or thereabouts on the amount of mutation in melanoma. Bind moggling.

I'm curious, though, for anyone who can make better sense of this kind of thing than I do: does a cell line go off the rails and then head out to sea or does it float away first? In other words, how much of the genetic change happens before the cell line starts multiplying aggressively and how much results from wiring down the safety valves after the original ancestor goes rogue?

By D. C. Sessions (not verified) on 11 Feb 2011 #permalink

I'm curious, though, for anyone who can make better sense of this kind of thing than I do: does a cell line go off the rails and then head out to sea or does it float away first? In other words, how much of the genetic change happens before the cell line starts multiplying aggressively and how much results from wiring down the safety valves after the original ancestor goes rogue?

Cancer requires certain functional abnormalities to occur at certain points in the process (e.g. angiogenesis must occur before a certain tumor mass and often before metastasis is possible otherwise tumors necrotize internally and collapse), but the big one is getting around the telomere problem. See, if a cell just starts proliferating rapidly it will reach the M1 Hayflick Limit, and if it keeps proliferating it will reach the M2 crisis limit.

Actually, speaking of the M2 limit, breakage-fusion-bridges might account for some of the crazy chromosomal abnormalities this study found.

Anyway, cancer cell lines must either re-activate telomerase or activate ALT pathways fairly early in the game to keep cell death mechanisms off their back, after that though they basically have free run of the place and can play around and mutate. One of the major 'safety valves' is what prevents cells from multiplying aggressively. This is why,as I have written about before, I am always a little skeptical about those plans to reactivate telomerase to prevent aging...

And that's without the epigenetic changes, the alterations to the local microenvironment and consequently altered paracrine signaling, systemic effects, immune and inflammatory cell recruitment, and all the other joys of a cancer researcher's life. The amazing thing is that we can cure any cancers - not that we can't cure them all.

What is amazing to me is how that stuff can still stay alive. Even after trying to whack it with all manner of toxins and even radiation.

It seems to me the worst case would have been had the tumors' genomes been so close to normal that there was nothing to target. IOW, had it turned out that cancer was virtually normal tissue that could turn cancerous in any of a variety of small ways, not necessarily genetic. The fact that the genome is a train wreck creates some leverage for therapies that work only against train wrecks. We just have to figure out what those are...

Thing is - like you said - how much chromosomal rearrangement is there in "normal" tissue? Did they sequence non-cancerous genomes from the same patient? I don't think we really have a handle yet on how much somatic mutation goes on.

That said, and assuming the assemblies are good, these are pretty damn screwed up.

The reason cancer cures are vanishingly rare is our collective unwillingness to hold our egos and research monies in check. The giants of the past 100 years in curing cancers hold the answers. Let's invest money to systematically look at Cooley, Hoxsey, Beard, Livingston, Gerson and others. If we don't I guarantee we'll be seeing posts like this 10 years from now - still no further from cures, billions of dollars down a rathill of worthless research, with the answers still ignored or disparaged.

It's a damn shame.

Telomerase is not oncogenic. Cancer causes massive overexpresion of telomerase by mutation over expression recombination etc etc etc. Cancer causes the over expression of telomerase not the other way around. Be skeptical all you like in 5 years you'll say you knew it all along...

By Anonymous (not verified) on 12 Feb 2011 #permalink

#10: Well, yes, what you wrote is true, but as Caudoviral pointed out, cancer cell lines have to figure out how to activate telomerase in order to survive in the long run (or use an alternate way of lengthening telomeres). Activating telomerase for them just gives them a leg up. Any "rejuvenation" that you give a patient also helps the (pre-)cancerous cells.

#10

...eh, yes and no. Mostly no. For a cell line to proliferate to the point of causing disease, it really helps to have a way to make itself immortal, and telomerase is a really easy way to do that.

...what is #9 going on about? :S

@Charl: #9 is referring to some alternative doctors with some, shall we say, not entirely evidence-based treatments.

S/he is asserting that those people have, in fact, come up with serious breakthroughs in the understanding and treatment of cancer, but that "big pharma" researchers are too egotistical to actually pay attention and learn the truth.

The Hoxsey Therapy article on Wikipedia has some citations regarding the evidence for that treatment:
http://en.wikipedia.org/wiki/Hoxsey_Therapy#Studies_by_major_medical_bo…

Review of 71 Canadian patients: >50% mortality or progression of cancer. 25% *no clear evidence they had cancer to begin with*. One single patient had improved; surgical excision would have also worked and would have been less disfiguring.

So, yeah, not very convinced.

By Gopiballava (not verified) on 14 Feb 2011 #permalink

@14, that wiki sucked me in. I remember the whole Starchild fiasco. I was 18 at the time, all I could think was that I was so glad my parents hadn't named me Starchild and had given me a firm grip on reality and the truth of science.

The genetic abnormalities in cancers of the hematopoietic/immune cell system, my old area of diagnostic expertise, are sometimes simpler. My guess is that, as cells that can already circulate, they become clinically significant at an earlier genetic stage, because they don't have to evolve the ability to metastasize. Some of them actually are more like solid tissue tumors in genetics at incidence, and some become that way with progression, and this is always a very unfavorable development.

At a broad level, it is very much mutation and natural selection that drive cancer.

In a multicellular organism, cells must exquisitely differentiate.

Metastatic cancer cells can be conceptualized as losing the "ability" to differentiate normally, and instead differentiating into cells that behave much like a population of unicellular parasites or infectious agents, but with the added ability to form local masses and provoke dysfunctional tissue responses like fibrosis.

Within the cancer cell population, those cells with abnormalities that best allow them to outcompete normal cells for resources are selected for.

The genomes in this article may look like crazy random jumbles, but remember that there are probably 10^13 or so, give or take large degrees of uncertainty, cells in the human body. Many tissues experience vast numbers of mitotic events every day, and the opportunities for somatic mutations to arise are innumerable. Those crazy looking genomes are the result of many cycles of cellular reproduction, probably with both abnormally high mutation rate, and certainly with ability to compete with normal cells for resources, selected for.

In the end, cancer cells always go extinct, except if they are preserved as a cell culture. They are either successfully excised or killed with drugs, or they destroy their own world, the body of the person with cancer.

Also - although many types of cancer are well-associated with environmental predisposers, and although certain types of good advice are obvious (don't smoke cigarettes, exercise, eat vegetables and fruit), there is no know environment that allows for zero risk of cancer. Furthermore, some environmental factors can cut both ways. Sunlight exposure increases the risk of some skin cancers (all of which can be detected early with regular skin exams, except in very rare cases), but decreases the risk of a number of other types of cancer.