XMRV and prostate cancer

Retroviruses like to cause cancer. Its kinda their shtick.

Sometimes the viruses themselves code for oncogenes.

Sometimes the retroviral promoters accidentally upregulate an innate oncogene (the cell doesnt know its supposed to stop replicating).

And sometimes a retrovirus accidentally plops down in the middle of an important regulatory gene, and thats how you get uncontrolled replication.

MLV, murine leukemia virus, is a retrovirus that causes… leukemia… in mice.

It has also been implicated in prostate cancer in humans. This is kinda weird (target is immune cells in mice, but prostate stromal/epithelial cells in humans?), but it would be GREAT news if it were true! Women have HPV shots now to help prevent cervical cancer, and guys could theoretically get MLV shots to prevent prostate cancer!

… Unfortunately, though MLV has been associated with prostate cancer in humans, causality hasnt been established.

And its still not established after this latest paper on the topic:

XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors

XMRV, xenotropic murine leukemia virus-related virus (for real), is what we call a virus that looks like MLV in humans.

These folks, pathologists, got some really nice images of prostate tumors, clearly staining positive for XMLV proteins. Super pictures, well controlled, its nice.

However, as a virologist, I have some issues with this paper.

1. They made an infectious molecular clone of XMLV. First of its kind. But they did very limited analysis of it, and basically just used it to create antibodies they would use for their pictures. They had a cell line that was permissive to XMLV infection, and one that was not, but were apparently uninterested in figuring out the receptor XMLV is using in humans. Knowing this would move their field forward, and give us an easy yes/no as to which human cells are susceptible to XMLV. If normal prostate stromal/epithelial cells dont have the receptor (maybe the receptor is only expressed after transformation), then we can shut this story down now. But they didnt look. What???

2. The images are just beautiful… but they dont look right. MLV has been shown to prefer cell-to-cell transmission. Yet several images in this paper had punctuated infection of cells– a scattering of infected cells, rather than clusters of infected cells. That makes me furrow my eyebrow. It aint right. Especially when we are talking about cancer. If MLV has transformed a cell, then the cancer is clonal, and every cell in the tumor should be making MLV proteins. But in these images, it isnt.

3. Their PCR is shit. For real. Their characterization of their real-time PCR reagents is great, but their reagents are still shit. There is no way that histology is more sensitive than real-time PCR, unless your primer/probes are crap and you need to move them. You cant believe any of the PCR data in this paper, because you know there are a ton of false negatives. *squint eyes* Boo.

This paper is fine, but we still dont know if XMLV can cause prostate cancer in humans.
:(

Comments

  1. #1 zylph
    October 12, 2009

    The cancer is clonal… but that doesn’t mean that production of the virus is clonal. The proviral DNA might be silenced following transformation in some or most of the cancer cells.

    So, yeah, boo on the receptor and the crappy qPCR. But these people are pathologists, it sounds like, and a cDNA substitution study to find the receptor might not have been their thing.

  2. #2 Joshua Zelinsky
    October 12, 2009

    Could you explain for the non-biologists like me what the issue is with their PCR in more detail? I didn’t understand your remarks about that.

  3. #3 D. C. Sessions
    October 12, 2009

    If normal prostate stromal/epithelial cells dont have the receptor (maybe the receptor is only expressed after transformation), then we can shut this story down now. But they didnt look. What???

    Think “minimum publishable unit.”

  4. #4 Sili
    October 12, 2009

    I love how certain you are. It’s beautiful to see someone who knows their field well enough to home in on the problems so easily.

    I don’t think I ever even developed that feel for my own line of work, and these days I just feel stupider by the day.

    I’d imagine that prostate biopsies are nasty, but has noöne done any longitudinal studies yet, getting samples of healthy men, freezing them down and then following them to see who develops enlarged prostates/cancer?

  5. #5 steve s
    October 12, 2009

    man, that umlaut is some serious fail.

  6. #6 steve s
    October 12, 2009

    Sell that bullshit to the toürists.

  7. #7 Sili
    October 12, 2009

    It’s a bloody diæresis. No umlauts here.

  8. #8 Ritchie Annand
    October 13, 2009

    Could I ruin your day by pointing you to David Kirby’s (yes, that David Kirby’s) blether about XMRV on HuffPo?

    It’s tough even tracing who did what in his article, though the institute in question appears to be this one.

    I wouldn’t trust Kirby as far as I could throw him for medical information. Who are these guys, though, and why are they still trying to pin the freaking autism tail on the vaccine?

  9. #9 Ed Yong
    October 13, 2009

    And what are your thoughts on the recent paper linking XMRV to chronic fatigue syndrome?

  10. #10 ERV
    October 13, 2009

    I was gonna write about it tonight– the XMRV CFS paper is pretty dang good. And frankly, I didnt believe in CFS when I started reading it.

    However I got a migraine (PERIODS, YAY! hehehe!), so its not gonna happen till tomorrow :(

  11. #11 Simon
    October 13, 2009

    Ok, the question I have is: ‘why not try to infect cells in culture?’

    Obviously, there must be a reason, I just can’t think of which.

  12. #12 eddie
    October 14, 2009

    From what I read on CFS, it seems to be associated with an actual illness that is properly diagnosed, but the patient continues to feel ill long after their symptoms should have cleared up. And they get seemingly worse over time.
    It occurred to me that there might be a problem with their kidneys’ ability to clean the blood. Not total kidney failure but some dysfunction.
    A way to test this would be dialysis.

  13. #13 eddie
    October 14, 2009

    The info I find on the web relates to peoople already on dialysis developing chronic fatigue, but they already have serious kidney problems.
    My previous comment meant to suggest comparing dialysis ‘sample’ with regular urine sample, but from the above it seems the machines are not comparable to a properly working kidney.

  14. #14 eddie
    October 14, 2009

    I’m sorry but the proposed link between a murine virus and prostate cancer inevitably led me to this: “At a hushed press conference, a hospital spokesman described what happened next. ‘The match ignited a pocket of intestinal gas and a flame shot out the tube, igniting Mr. Tomaszewski’s hair and severely burning his face. It also set fire to the gerbil’s fur and whiskers which in turn ignited a larger pocket of gas further up the intestine, propelling the rodent out like a cannonball.” Snopes said it never happened and I believe them.

  15. #15 ben
    October 14, 2009

    I’m not 100% sure yet but eddie I believe you may be a twat. Might want to look into that.

  16. #16 Richard Wolford
    October 14, 2009

    Off topic I guess, but I have CFS, it is very real, it’s not an uncommon symptom of ankylosing spondylitis, which is my underlying cause. Just thought I’d chime in a bit, great article BTW and I’m glad you can explain it so well, I love this blog.

  17. #17 bonsai4tim
    October 15, 2009

    I tend to agree with comments about CFS regarding some appear to be viral (see Science based Medicine). One of the biggist issues I see is the tendency of some physicians to just accept what the patient tells them, without any critical thinking. I have treated patients who have fatigue, and a very clear history of a well defined viral infection. These patients are “normal people”, and are different from the CHRONIC FATIGUE SYNDROME patients who a) believe they have a disease and b) become extremely angry if you try to discuss with them the obvious psychologic problems that they have. (even when discussing this as “yes I agree you have CFS, but we also need to work on your depression etc).

    As Wallace Sampson writes in SBM, these patients are very defensive, refuse all attempts to treat any psychologic illness, and generally spend huge amounts of time and energy looking for the physical cause of the problem or the “magic pill” that will make them better.

    As noted by Richard (above) chronic fatigue is a symptom of a number of diseases, including auto-immune diseases like AS, RA, Lupus, as well as Multiple Sclerosis, diabetes, pulmonary disease, and some cardiac disease. There is a difference between having a known symptom (fatigue) from a diagnosed medical disease and a diagnosis of CFS

    I believe when this is done, we will find another type of chronic viral infection that causes fatigue as a symptom, and will still have a large group of patients with CFS who test negative for the XMRV virus

  18. #18 Zootfloggin
    October 15, 2009

    ERV-Disagree with your comments about XMRV and chronic fatigue syndrome published in Science. The folks who have praised it in the press (e.g. Coffin, NIH) are not doing themselves any favors.

    Is the study blinded? No. Did the authors use nested PCR? Yes, What is their definition of who has CFS? Dunno. Are any negative controls used in the western blots (Fig 2B)? Nope. Unless the patients are melting from overwhelming viremia, how do you directly detect gag and env proteins at HIGHER levels in patient blood cells than positive control SFFV-infected cells by western blotting using cross-reactive MLV and SFFV antibodies? Apparently, the Whittemore Peterson Institute is some doctor’s office in Incline Village, NV according to its website http://www.wpinstitute.org/about/about_history.html. The WPI has never published a paper before but they certainly hit it out of the park and they are now gearing up to sell blood tests and look at autism and vaccines. Smells like Fulton’s Fish Market, nu? As Eddie said above, “At a hushed press conference, a hospital spokesman…”

  19. #19 ERV
    October 15, 2009

    WAAAAAAAIT!

    Im gonna publish a post on it tonight, promise!

    LOL!!!

  20. #20 Ty
    October 15, 2009

    But I want it NOWWWWWW!!!!

  21. #21 zootfloggin
    October 15, 2009

    Oh yeah, I forgot to mention that these folks show suggest that XMRV is also the possible cause of autism and that it is spread through vaccines http://forums.aboutmecfs.org/showthread.php?t=646. Right.

  22. #22 K
    October 16, 2009

    “Oh yeah, I forgot to mention that these folks show suggest that XMRV is also the possible cause of autism and that it is spread through vaccines. Right.”

    That’s not what I took from it. I thought they said that if you already had XMRV, both infections and vaccines which trigger the immune response somehow activate the XMRV. They are pro vaccine, they say so at the start of this interview here http://www.youtube.com/watch?v=yOdnwPCh-yw

    part 1 is here http://www.youtube.com/watch?v=mzIdpMUunHE
    the speculation about autism starts at 5:12

    I believe Judy Mikovits has a good track record.

  23. #23 GT
    October 16, 2009

    Interesting findings, but literally what i dont understand is that since it is known for more than a decade now that EBV,CMV,HHV6,Coxsackie viruses alone or in different combos can set up chronic latent infections in our bodies and dumpen the stress system responses and affect vast array of neuroendocrine and immune parameters, which built up the picture of CFSid/ME, WHY ON EARTH didnt this institute concentrate on examining patients who have those infections to start with but miraculously was guided to a novel viral agent??

    And what pointed them to this novel viral theory approach?? Was this done solely through the coincidal assumption that since those patients have high RNAse-L activity then they ought to have some common viral strain affecting them all?

    If all CFSID patients had a common viral denominator which according to them is XMRV then how could someone explain the different immune parameters affected amongs patients. Etc some have low T4 counts, others have both T4 and T8 counts depressed, others only T8 counts and NK cells, others T4 counts and B cell line depressed. Its such a complex picture that only multitude and different virulent agents could explain this.

    Last but not least, someone mentioned that CFS can be psychological in nature. This is utterly a joke, maybe some physicians still tend to confuse HPTA axis abnormalities due to incapacitating psychological tress with ME/CFS. The clinical picture is completely different, overactivation/suppression of the HPA systems due to reactive malfunctioning/overfunctioning of LC-sympathetic system-NA has nothing to do with CFS. Dont confuse the word fatigue with CFS here.
    In CFS there is a vast array of symptoms that cannot be caused by any psychological stressor. For example,

    -nonspecific inflammation of terminal small intestine (diagnosed as IBS)
    -chronic persistent lymphadenopathy
    -severe immune manifestations suggestive of cellular immunity depression

    Ok drugs also cause fatigue, antidepressants, stimulants or potent antibiotics have been shown to cause long lasting fatigue (>6 months in duration). These symptoms however, like stress related downregulation of HPA (hypocortisolemia) or tend to improve with time and individuals normalise, in viral onset CFS there is never any normalisation, unless as shown viral antibody titers are brought down.

  24. #24 Mark London
    October 17, 2009

    ERV – I believe a previous study has shown that the XPR1 receptor is used by XMRV:

    http://jvi.asm.org/cgi/content/abstract/JVI.00268-09v1

    My question to you as a virus expert, is what is your opinion of the latest prostate cancer study from Germany, which showed no sign of XMRV, either in the prostate tissue, or in the serum, of their patients? They tested the serum of 146 patients. But acccording to the CFS study, 4% of the US population has been exposed to it, so you would think in Germany, that at least one of their patients would have tested positive (or maybe my conclusion about that is wrong).

    The German study discusses the differences in tests that they used, compared to the ones in the US. As a lay person, I can’t tell if they are implying that the US tests are flawed or not. Can you decipher it for me? See:

    http://www.retrovirology.com/content/pdf/1742-4690-6-92.pdf

    On the other hand, they mention that an unpulished Japanese study claims to have found evidence of XMRV in both prostate cancer patients, and healty people. And then the Germans go on to conclude that perhaps geographic or other health factors, might explain their study’s result. That seems to imply that they are not blaiming their results on test differences. However, given that the CFS researchers claim that 4% of the US has this retrovirus, it’s hard to believe that in European countries, where CFS is also quite prevelant, that none of their patients had a positive serum XMRV antibody test. Obviously, more studies are necessary to explain all of this, but I would appreciate your opinion of the German study. Thanks. – Mark

  25. #25 Eric Johnson
    October 18, 2009

    > If all CFSID patients had a common viral denominator which according to them is XMRV then how could someone explain the different immune parameters affected amongs patients.

    Variation just happens. Most people infected with TB (90%) never face florid growth of the organism and remain asymptomatic. Why? Not known, I think. Many different infections can cause leucopenia, but often they don’t. Syphilis can cause autoimmune cold hemoglobinuria, but usually doesn’t. Moreover, the immunological findings in CFS are not all that spectacular in degree or in sensitivity/specificity. If they were spectacular, CFS would be more validated than it is. Correct me if I’m wrong, but I don’t think you can take natural killer cell counts and separate almost all patients from almost all normals.

  26. #26 Sandy
    October 19, 2009

    Now that General Petraeus is widely known to have prostate cancer, it will bring more needed attention to this form of cancer.

  27. #27 gf1
    October 19, 2009

    @ bonsai4tim

    The Wallace Simpson piece on sciencebasedmedicine is pretty crap. He lies about what the CDC says about CFS recovery rates; lumps CFS in with PTSD and about ten other poorly defined or understood illnesses; seems to have developed his own psychological model for CFS…

    I’m not surprised his CFS patients tend to reject his advice. If anyone lacks insight or clarity of thought, it is him. I’d rather go for reflexology than his version of ‘science based medicine’.

    I don’t know if this XMRV link will turn out to be significant, but we should at least try to criticise it honestly.

  28. #28 Eric Johnson
    October 19, 2009

    Richard Wolford, just FYI – and I’m not an doctor – but you don’t have CFS if your symptoms are explained by AS (whose symptoms I don’t know in detail). CFS is defined as a separate syndrome or disease entity, not simply a description of symptoms. Of course fatigue occurs in lots of immunological diseases and other diseases. Also, I realize it can be under-appreciated by doctors treating, for example, lupus – one doctor expressed, in the canonical reference book “Dubois’ Lupus,” his vague skepticism about the fatigue and incapacity claimed by lupus patients. So, even patients with highly verifiable diseases deal with a certain amount of such skepticism (I’m just noting the phenomenon, without necessarily claiming that such skepticism is usually incorrect). As do, to some extent, normal people claiming one or another sort of minor, specific incapacity or limitation. It’s not exactly unexpected that social organisms dependent on social cooperation would bicker about such things. And would evolve the ability to conclude, probably too readily if anything, that someone is freeloading or malingering.

  29. #29 GT
    October 19, 2009

    Eric, i would say that immunological findings in CFS are extremely spectacular. We are talking about a disease that distorts not only NK cell function, but also causes severe and up to 30-40%(probably even more) drop in CD3+CD4 counts or even CD4+CD8 counts, drops in Monocyte counts and several other abnormalities. It is just a mere fact that most doctors are simply not trained to decipher these changes like vast majority of endocrinologists fail to understand how a drop in 20-30% of HPA function can mean a great deal to a patients metabolic homeostasis and integrity.

    How can someone however misunderstand recurrent atypical pneumonias, ongoing small intestine inflammation (depicted in biopsies) and generalized lymph node enlargements as psychosomatic, this is kind of obsurd.

  30. #30 Eric Johnson
    October 19, 2009

    GT,
    It’s easy to talk the talk. And it’s easy for /me/ to credit your talk about, eg, lymph nodes, because I know the disease is real, just as certainly as I know I’m alive. But to convince a skeptic? You would need literature, and for the most part that literature would have to deal with externally observable matters.

    Can you cite data on the lymph nodes? It’s not something I’ve looked into deeply, but I do happen to recall this publication suggesting that objective abnormalities could not be observed:
    http://pmj.bmj.com/cgi/content/abstract/79/927/59

    Do I know for certain that this investigator was unbiased? I don’t. But for the most part, there’s not much you can do about the possibility of bad faith. And I certainly believe that /most/ of the workers who disconfirmed various reported objective abnormalities in CFS were in fact acting in good faith.

    I do feel that you could find /something/ odd in most severe cases. My case was once quite severe and at the time I had roughly a thousand strong heart palpitations every day, often about ten in a row. Though heart palps are common, I am pretty sure that few if any normal individuals show such a spectacular case of it. I am also pretty sure, though I cannot prove, that you could also find /some/ patients with objectively abnormal lymph nodes. But how would you design a credible study that would take account of a miscellany of odd phenomena in CFS patients? I also had rhinitis noted by a physician, but of course this is nonspecific, and allergic rhinitis can occur alone in the otherwise-hale.

    Can you cite data on the leukocyte abnormalities? I agree that the abnormality in NK function (as opposed to count) is one thing that has been confirmed often and seems likely to be real.

    I agree that it’s /possible/ small differences in HPA function (ie, serum cortisol) could make a significant difference to a patient’s well-being. But even if it does, that /doesn’t/ mean their serum cortisol is necessarily outside the normal range.

  31. #31 Mark London
    October 19, 2009

    How about this study, linking CFS with NF-KB? NF-KB is known to activate XMRV:

    http://www.ncbi.nlm.nih.gov/pubmed/17693978

    “the inflammatory response in CFS is driven by the transcription factor NFkappabeta; c) symptoms, such as fatigue, pain, cognitive defects and the subjective feeling of infection, indicates the presence of a genuine inflammatory response in CFS patients”

  32. #32 Eric Johnson
    October 19, 2009

    That Maes report is highly interesting (as were the other papers published with it). Though I only read the abstracts. But has anyone confirmed it? That’s the thing.

    I just saw that the Gow gene & protein expression paper finally came out last summer – that got past me. This figure should give pause to the doubters – check out the defensin-1 Western blot linked below. Do any of you Western jocks think this is a poor Western?:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716361/figure/F3/

    But this too needs to be independently confirmed.

  33. #33 Eric Johnson
    October 19, 2009

    I would point out that while psychology may have some value, there’s nothing in the whole field that is as clear and objective as the Western blot I just posted. Anyone disagree? It’s not that surprising that most CFS patients don’t want to go off to a psychiatrist to wind up, perhaps, getting further marginalized by the receipt of some psychogenic diagnosis that is /not/ as clear and objective as that Western. A patient with a marked case is /experiencing/ that Western, so to speak – experiencing flu and hangover-like symptoms that are as clear as that Western. He doesn’t have to wonder whether he’s experiencing some vague cycle of defeatist thinking. There’s no way a typical person can give up most of their joy in life and then, while trying to come to terms with that, feel only minimal hostility against those that claim /with operative certainty/ that it is all fake. Of /course/ he feels markedly hostile.

  34. #34 CHA
    October 24, 2009

    For those of you who wonder why an ME/CFS patient may be angered by those who try to say their illness is psycological- take a lesson from the death of Sophia Mirza who was forcibly taken from her home, placed in a psyc ward and died because they refused to acknowledge that she had a physical illness. Grievously, it took an autopsy to prove she was sick. http://www.youtube.com/watch?v=yrBAlKtroBw

  35. #35 sharon
    June 29, 2010

    This blog is not worth reading. When this child gets her PhD and MD then she can inform all of us idiots. Until then, stay in school, keep your little mouth shut, and let the real trained and educated experts do the talking.
    Might try Advil for the period pain.

  36. #36 Stu
    January 3, 2011

    Hey Erv, could you just clarify what you mean about their PCR being shit? I’m writing a paper on the evidence for XMRV being a human pathogen, but I’m a medical student so this PCR stuff isn’t really my thing!

  37. #37 sharon stapleton
    January 27, 2011

    let us remember that Abbie does not have a doctorate. Abbie has never had a real job in the real research world. Abbie knows nothing except to shoot her stupid, nasty little mouth off which she does and the nerdy little grad school boys like.
    Shut up Abbie. Grow up, get your doctorate from that bullshit school, get a real job, publish and then you can speak and attack those that have 30 years real world research/publishing. You are such a nothing.

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