Scienta Pro Publica #7 Have Your Say! The Nuffield Council on Bioethics discusses the ethics of ‘personalised’ health care in a consumer age
Jul 09
Posted by: colinhockings

 

What is cancer? Everyone knows that it is a terrifying disease and has some ideas about a mass of cells that grow uncontrollably but I get the feeling that many people don’t quite understand how it actually happens. I think that even from my biochemistry and cell biology lectures I’d still have a very woolly appreciation of what’s important when it comes to cancer. Before I start with the science, I have to recommend “The Hallmarks of Cancer” by Hanahan and Weinberg – it’s a very readable review that neatly organises cancer biology and was written to help usher in a new way of thinking about cancer. 

Cancer can be thought of as being evolution in action. Very simply put: if something replicates faster than its siblings it will dominate its environment, a fact that is as true of cells as it is of rabbits. However, in the human body, with its exquisite regulation of functional tissues and organs, replication is normally kept under control and almost all cells divide very slowly or not at all. Why is this? Because the somatic (i.e. body) cells do not contribute to the next generation, only the germ line cells (which make sperm and eggs) do. Thus there is no evolutionary competition between cells (c.f. ant colonies: the workers are sterile and do not contribute to the next generation, so there’s no evolutionary competition between them and they’ll willingly sacrifice themselves for the colony) – they don’t try to outgrow each other and dominate their organ, because that would be bad for the organism and their genetic material would not be passed on to the next generation. The problem is that evolution is blind so there’s no ‘trying to outgrow’ or foresight involved. If one cell looses the shackles that stop it from replicating it will replicate, causing cancer. It doesn’t ‘know’ that it will only be able to replicate until the organism dies, at which point all its progeny will die too. The effects of natural selection don’t stop there though: one mutation may allow a cell to ignore one signal to stop dividing, but if one of the group of dividing cells acquires another mutation that allows it to divide even faster, then its progeny will come to dominate the tumour.

So what are the changes that cause cancer, and why do they occur? As I’ve just alluded to, we’re talking about mutations – changes to the signal transduction pathways that tell the cells what to do. Mutations happen for all sorts of reasons, most commonly because DNA replication (required for every cell to divide) makes mistakes. Certain things, such as UV light (in sunshine) and many of the components of cigarette smoke also cause mutations and so can increase the likelihood of cancer developing. However, many of the other substances that have been touted as ‘causing cancer’ (c.f. the Daily Mail) have only very mild effects if any.

Simply replicating faster isn’t enough for a cell to become cancerous. Its progeny will still mature and eventually stop growing as they differentiate into skin cells or white blood cells or whatever. In addition, when the body notices the cancer, the immune system will tell the cells to “commit suicide” – i.e. undergo apoptosis. If it forms a lump of cells, there won’t be a blood supply so the ones in the centre will die. After a certain number of divisions, cells slow down and enter ‘senescence’. What I’m trying to say is that one mutation in a single pathway is not enough to create a tumour and kill you. There are several ‘hallmarks’, or characteristics that a potential cancer cell needs to acquire through different mutations in different pathways. These are: 

  • Self-sufficiency in growth signals
  • Insensitivity to anti-growth signals
  • Evading apoptosis (so the cells cannot “commit suicide”)
  • Limitless replicative potential (immortality – most cells can only divide a finite number of times)
  • Sustained angiogenesis (creating a blood supply to the tumour)
  • Tissue invasion and metastasis (this is what kills people, when the tumour invades surrounding areas, bits fall into the blood stream and grow in other parts of the body)

Only once some of the cells of a tumour acquire all these characteristics do you have a full-blown aggressive cancer.

In the following posts on this topic I’ll talk about cancer therapies, leukemia and other types of cancer, as well as the mechanisms of some of the more “popular” cancers (colon, breast, cervical and prostate) and what is meant by predisposition to certain cancers.

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17 Responses to “Understanding Cancer – Part 1”

  1. Nitpicker Says:

    You concentrate on mutations. But mutations are rare and have never been shown to cause cancer. Furthermore that’s not how cancers evolve and that failed theory cannot even explain the existence of non-mutagenic carcinogens such as asbestos.

    Pay more attention to the insightful Peter Duesberg. He has explained in some detail how aneuploidy (loss, gain, or rearrangement of whole chromosomes) does the job, but can take decades to develop from the initial genetic instability of an aneuploid cell into a life threatening aggressive metastasizing cancer.

    What I don’t understand is why a highly effective treatment via transfusion of white blood cells from cancer resistant people into patients with cancer can’t get support to carry out an already approved clinical trial at Wake Forest.

    Where are the major studies of how neutrophil mediated cancer resistance works? Why do we not see in vitro experiments with many kinds of cancer cells with blood from cancer resistant people? Dr. Zheng Cui at Wake Forest Baptist Medical Center can explain how to screen blood donors for cancer resistance.

  2. colinhockings Says:

    You have made several interesting points but seem to have several misconceptions (whether they are common or not I do not know).

    To start with, chromosome aberrations are a form of mutation. They are important in some forms of cancer, especially leukemias, but haven’t been implicated in any other types of cancer as far as I know. I’m going to be working with leukemia for the next five months (starting Monday, I’m very excited!), with a specific chromosome fusion event that creates the fusion protein AML1-ETO so there will be at least one post dedicated to this type of mutation, as well as another on leukemia in general. On this note – and I’m aware that you may take this the wrong way and decide that I’m being evasive – I’m busy packing and making arrangements to move to Frankfurt tomorrow so I don’t have time to find indesputable sources for everything I’m going to say here, or to follow up the work you’ve cited. The next week is going to be fairly hectic, but I’ll try to get back and give you some sources – I don’t want you to simply ‘take my word for it’.

    Assuming that when you say ‘mutations’ you mean ‘point mutations’ (a single base change – a single letter of the DNA code being substituted for something else, deleted, or inserted) I would be extremely interested to find out why you think that they’ve never been shown to cause cancer, and why you think they’re rare. There is no question whatsoever that mutations cause cancer. None at all. Anyone who was able to show otherwise would be heralded as a hero by the scientific community. The fact that cancers evolve is also not under review by any legitimate researchers. The first example that springs to mind is that the progression from a benign neoplasia (a tumour that doesn’t invade neighbouring tissues) to a malignant one. That step requires an additional mutation (often in pathways that regulate the extra-cellular material, so the cells can ‘chew’ their way through tissues) that allows the cells that have it to escape their compartment and replicate further in other parts of the body: a form of evolution. This is not a ‘failed theory’, it’s a fact that is useful to bear in mind when thinking about cancer.

    The only ‘cancers’ that I can think of that do not result from mutations are warts. These are benign neoplasias (which don’t count: no-one would really call a wart ‘cancer’) caused by a virus, HPV, a virus that may be familiar as other strains cause cervical cancer. For the non-invasive mass to become cancer, though, further mutations are needed, and these are common in cervical cells infected with HPV strains 16 and 18 – hence cervical cancer. Again, there will be a post later on viral causes of cancer.

    You are correct in saying that asbestos doesn’t cause mutations, yet causes cancer. Here’s a simplified version of asbestos carcinogenesis (yet again, I may write a post explaining this a little better, especially since one of my lecturers last year died of mesothelioma, a type of cancer that is almost always caused by asbestos): asbestos in the lung consists of small particles that cause a certain degree of damage. The immune system sees this and tries to destroy the ‘invading’ particles but cant. The variety of weapons used by the immune cells causes further damage to neighbouring cells and you enter a vicious cycle. This results in a structure called a granuloma – asbestos particle in the middle, surrounded by dead, dying, and angry immune cells, and a wall of cells and extra-cellular proteins grows around it to stop the damage from spreading (as well as barricading the pathogens that the body thinks are invading). There are lots of growth factors and other signalling molecules floating around thick and fast, and you create an environment where some of the hallmarks (mentioned in the post) are not required to the same extent as usual. Thus it becomes easier for cancer to develop, and given several years, you end up with a vastly increased chance of getting cancer.

    Getting approval for a clinical trial is not difficult as long as you can show that it is safe. If the ladies and gentlemen of Wake Forest cannot get support (i.e. funding, I assume), it is probably because they lack both the evidence that cancer resistance exists, or any kind of plausibility for such a phenomenon, and more importantly, evidence that if one were resistant to one’s own cancer, you could transfer that resistance to anyone else. You must remember that every cancer is unique and is descended from a different source.

    You may not see much research on neutrophils with regard to cancer because they aren’t involved. Neutrophils are immune cells that respond very quickly to acute inflammation. If you get a cut, neutrophils will congregate there within minutes to phagocytose (’eat’) particles/bacteria/viruses that have entered, and to signal to the rest of the immune system that there is a problem. Other types of immune cell, such as NK and Cytotoxic T cells are much more important in defending against cancer, because they find cells that have a problem (i.e. they are cancerous or are infected with a virus) and they tell it to commit suicide (apoptosis). Furthermore, neutrophils are part of the innate immune system: they have no mechanism of resistance or memory. They will respond in the same manner, no matter how many times the problem has occured before.

    I appreciate your comment, because it has helped to highlight certain areas that I want to focus on, and if you have any more queries, I’d be glad to help. From next week, I may even be able to consult bona fide cancer experts, and I will take a look at the work you’ve alluded to when I have the chance

  3. Nitpicker Says:

    Thanks for the long response. Let’s choose the points to discuss in detail as we go along. To avoid a very high incremental cost of participation by each of us and any others who join in I’ll start by addressing only one point.

    Lack of funding might be because there is no monopoly profit to be made. The high expense of conducting an FDA clinical trial serves to preclude approving any treatment other than a new patented drug. No supplements or dietary arrangements need apply. Indeed, it could be valuable to our health to address methods for making much cheaper clinical trials possible.

    Your turn.

  4. Nitpicker Says:

    You say “chromosome aberrations are a form of mutation”, and that is fine. How is asbestos carcinogenic? I claim the method is by physically interfering with the chromosome distribution as a cell divides. Is that not the expected mechanism? Then why is asbestos not mutagenic?

    Notice that virtually all cancers are aneuploid. If cells with a new, different set of chromosomes appears, that is a new species of life. That happens in cancers and even explains sudden resistance to chemotherapeutic agents.

    Mostly the aneuploidy is not about changing the code for one gene though that can happen with random recombination of broken chromosomes. On the other hand losing or gaining an extra copy of an entire chromosome in one blow changes the use of hundreds or thousands of genes. Most such radical changes are harmful to those cells, but sometimes a more effective cell line is born.

    How do we disagree here?

  5. nicholasswetenham Says:

    For a thorough analysis of Peter Duesberg’s claims that aneuploidy is the causative process in cancer, as well as his claims that HIV does not cause AIDS, I highly recommend Seth Kalichman’s “Denying Aids” book as well as his website. Aidstruth.org is also very informative.

    In the interests of balance, if you wish to investigate Peter Duesberg’s views from his own side of the argument, you should google for his website. However, the sources listed above address all of the issues raised and resoundly defend the mainstream scientific consensus. In the case of denying that HIV causes AIDS, his claims are incredibly harmful in the face of evidence.

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