Devil Dispatch: MHC the Key to Contagious Cancer Vaccine?

28 April 2013 by Anne-Marie Hodge, posted in Uncategorized

The contagious cancer currently ripping through Tasmanian devil (Sarcophilus harrisii) populations has captivated public attention and imagination. The reasons for this are understandable. First, in a world where cancer kills 7.6 million people every year, just the idea of tumor cells that can be passed along between individuals like a cold or flu is a horrific notion to contemplate—a concept straight out of a cheap thriller novel. Also, the irascible Tasmanian devil has a sort of anti-charisma—fearsome temper, frightening countenance (even before infection with deadly facial tumors), and a name with sinister connotations . . . how can we help but love it?

Tasmanian devil suffering from DFTD

About a year and a half ago, I wrote about devil facial tumor disease (DFTD), the transmissible cancer that is pushing the Tasmanian devil closer and closer to the edge of extinction (see that post for a detailed discussion about the biology of contagious cancer). In the mean time, scientists have continued to press onward in pursuit of a way to stop DFTD’s spread and attempt to prevent the extinction of this unique and endangered marsupial. Last month, a fascinating and promising new discovery about DFTD was published in the Proceedings of the National Academy of Sciences (Siddle et al. 2013), and it looks as though there may actually be a light at the end of the tunnel for those who have worked so hard to understand and beat the disease—and for the devils themselves, of course.

As you might remember from my earlier post, there are two known transmissible cancers, DFTD and canine transmissible venereal tumor (CTVT), a sexually transmitted strain of cancer found in dogs and a few wild canids. Although DFTD is invariably fatal, CTVT rarely kills its hosts. Why? This question was a key starting point for Siddle and colleagues as they embarked on this new study. The researchers reasoned that the vast difference in mortality rate between the two diseases indicates that there must be something different about how the DFTD cells and CTVT cells interact with host immune systems.

Before we dive farther into the study, let’s have a very basic refresher course on mammalian immune responses. In order to recognize non-self cells (ie, those resulting from an infection or another foreign source), the immune system’s T-cells rely upon signals from the major histocompatibility complex (MHC) molecules that are displayed on the outside of the cell walls. These are the signals that tell the animals’ body, “this cell is mine, let it go about its business in peace,” or “Invader! Attack!” The expression of MHC molecules is controlled by a dizzying array of transcription factors, cytokines, DNA promoter elements, and epigenetic changes that occur over the course an organism’s development. Through their control of MHC activity, these factors influence the ability of the immune system to recognize “non-self” cells that need to be isolated and destroyed.

The progression of CTVT infection is interesting from an MHC perspective. For the first couple of months after an animal is infected, its CTVT cells don’t express MHC—the tumors fly under the immunological radar. Starting three to nine months after infection, however, the cells finally begin to express the MHC signals, and this allows lymphocytes to recognize the tumor cells as a problem and go in for the attack (Pérez et al. 1998; Hsiao et al. 2008). This is likely why CTVT is nowhere near as fatal as DFTD.

Now, it had long puzzled researchers that DFTD cells can be grafted between individuals with no rejection effect whatsoever—the animal’s body cannot tell that the tumor came from another devil. This is not due to extreme genetic similarity between devils—they have sufficient genetic variation that their immune systems should recognize a cell from another individual. (Sidebar: One often-told story is that cheetahs are famously so genetically homogenous that captive animals fail to reject skin grafts from other cheetahs, even without anti-rejection drugs . . . but newer research on wild cheetahs has shown that although there is indeed very low MHC variation, they are not as immunologically vulnerable as once thought).

So, back to devils. We have a transmissible cancer with a 100% mortality rate, and with cells that can be shuffled around between individuals with no alarm from the immune system…it seems clear that we needed a better understanding of exactly what is going on with the MHC molecules on DFTD cells.

Siddle and colleagues proceeded to isolate three cell lines from DFTD tumors, using a devil fibroblast cell line as a control. They cultured these cell lines in the lab, and conducted a series of tests to look at the activity of genes regulating MHC expression. They also checked to see if the DFTD cells exhibit structural abnormalities that could affect MHC recognition.

Siddle et al. (2013) show that DFTD cells do not express MHC molecules on their cell surfaces—in other words, they act like Trojan horses for the cancer, with no signal to the immune system that the tumor cells are a cause for concern. It turns out that DTFD cells down-regulated genes that are required for antigen processing, ultimately leading to a lack of MHC expression on the outside of the tumor cells. Without that signal from the MHC molecules, the immune system is oblivious to this sinister presence, and the cancer proliferates until it has killed the animal—explaining why this disease has a 100% mortality rate. The loss of gene expression was due to epigenetic modifications of the regulatory units, not to structural abnormalities of the tumor cells themselves.

Yes, this is quite upsetting news for a devil.

The discoveries didn’t stop there. Siddle’s group also tried treating the tumor cells with two substances: an antifungal drug called Trichostatin A, which is known to affect the activity of genes involved in MHC regulation, and a cytokine called interferon gamma, which had previously been shown to limit the growth of CTVT tumors. Both treatments resulted in a reactivating of the MHC gene activity, allowing the DFTD cells to be labeled as cause for alarm.

The upshot of this is intriguing: the authors suggest that the new discovery could yield a vaccine against DFTD. If devils can be inoculated with DFTD cells that have their MHC machinery reactivated, we may have finally found a way to allow the devils’ immune systems to fight off the tumor cells.

There is still much work to be done before this solution becomes a reality, of course. There are other ways the DFTD cells try to evade the immune system, and further research is needed to determine the best way way to strip the tumors of as many defenses as possible. Still, this is an exciting advance. For a species as close to the extinction abyss as the Tasmanian devil, good news can be scarce, and this study is definitely a cause for hope.

 

 

ResearchBlogging.org

 

 

 

Hsaio YW, et al. (2008). Interactions of hos IL-6 and IFN-gamma and cancer-derived TGF-beta1 on MHC molecule expression during tumor spontaneous regression. Cancer Immunology, Immunotherapy, 57 (7), 1091-1104.

Pérez J, Day MJ, Mozoz E. (1998). Immunohistochemical study of hte local inflammatory infiltrate in spontaneous canine transmissible venereal tumour at different stages of growth. Veterinary Immunology and Immunopathology, 64 (2), 133-147.

Siddle HV, Kreiss A, Tovar C, Yuen CK, Cheng Y, Belov K, Swift K, Pearse AM, Hamede R, Jones ME, Skjødt K, Woods GM, & Kaufman J. (2013). Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer. Proceedings of the National Academy of Sciences of the United States of America, 110 (13), 5103-8 PMID: 23479617

 

All images sourced from Wikimedia Commons.


35 Responses to “Devil Dispatch: MHC the Key to Contagious Cancer Vaccine?”

  1. Khalil A. Cassimally Reply | Permalink

    That first picture of the Tassie Devil makes me real sad but the research detailed here is promising. I do wonder why it took this long for scientists to realise that the evading mechanism was because of the non-expression of MHC though.

    More importantly, considering the that devil's numbers is constantly shrinking, the need for a cure/vaccine is very important. I do hope that we can find something for them before they reach critically low numbers.

    • Daduweb Reply | Permalink

      Really, the first picture got me. I think we must find a cure for this disease. So other tasmanian can be saved and not got this disease too. Maybe this time we can try to slow the spread and lets hope the population of this animal is rising :)

  2. Peter Vásárhelyi Reply | Permalink

    while i don't know much Hard Science, i do remember a show on either Nat Ge0, OR Disc. channel, that addressed the issue regarding the 'Devil's being on the Verge of Extinction .. .. i do seem to recall, from said show as well, that they'd managed to capture a Live Specimen, one WITHOUT the TFDT, and that they were looking into finding a Mate for it .. .. alas, i think it's a year or 2 ago i saw that show
    many things may have happened since then, tho', and this wellwritten article, is
    definitely newer .. .. while i'm as sorry for the li'l Bugger's, as everyone else with a
    Heart for Animal's, it did leave me kinda heartened to read this Article

    Peter

    p.s. thx to Miss/Mrs. Hodge for posting it :)

  3. Chris Noble Reply | Permalink

    Very nicely written article, however just one thing I don't understand.

    You say that treating the tumor cells with Trichostatin or interferon gamma, resulted in a reactivating of the MHC gene activity.

    It's not clear to me however why inoculating the devils with treated DFTD cells is the answer.

    1. Why not simply inject devils suffering from DFTD with trichstatin or interferon?

    2. How does inoculating with treated DFTD cells has any effect on stopping a subsequent DFTD infection since the new DFTD presumably won't express MHC.

  4. Rebekah Reply | Permalink

    Really enjoyed reading; you made this understandable for the non-science majors, like myself. :]
    Also, I had not known of "research blogging" until seeing this (saw it on Reddit). Awesome.

  5. webseobuy.com Reply | Permalink

    Thank you, I've been seeking for info about this subject matter for ages and yours is the best I have discovered so far.

  6. agen ibcbet Reply | Permalink

    If you love betting then visit at at http://arenabetting.com and become one of gamblers all over the country and receive some bonuses. We also give tips on how to play especially for newbies.

  7. Jobsloud.com Reply | Permalink

    I have bookmarked you to check out new stuff of your blog. A must read!!!!

  8. Jasa Seo Murah Reply | Permalink

    Did you understand that one of the most number regarding independent organizations of education inside the U. Azines. A come in Hawaii. Additionally it is home to be able to four key schools which can be completely self-sufficient.
    Visit : https://www.distributorseo.co.id

  9. Visaan Rao Reply | Permalink

    Oh ye, I need to create more good elements. I am in the quotes industry and wonder how much that will help. And oved the post the other day about content conversion and this one is equally awesome! http://khelomcx.com/

  10. Goatripsindia Reply | Permalink

    The Tasmanian devil is a carnivorous marsupial and the Tasmanian devil is therefore distantly related to kangaroos and wombats.

  11. velorina tasha Reply | Permalink

    Iam really impressed with your writing abilities and also with
    the structure in your weblog. Is that this a paid subject matter or
    did you customize it yourself? Anyway stay up the excellent high quality writing, it
    is uncommon to peer a nice weblog like this
    one these days..

    http://vipbet88.com | http://npselalu.net

  12. dewa poker Reply | Permalink

    Keep up the great piece of content, I read several posts on this site and I think that your web blog is truly attention-grabbing and
    also contains plenty of outstanding information.

    http://rajajudi.biz

  13. velorinaaaa Reply | Permalink

    Hello! I could have sworn I’ve been to this site before but after reading through some of the post I realized it’s
    new to me. Anyways, I’m definitely glad I found it and I’ll
    be book-marking and checking back often!

    http://skor88.com

  14. veveaa Reply | Permalink

    Hello my friend! I wish to say that this post is amazing, nicely written along
    with contain almost all significant information. I’d
    like to see more posts such as this.

    http://agenbola1.com

  15. Obat aborsi Reply | Permalink

    Obat aborsi 2 bulan ini bisa kita namakan obat penggugur kandungan untuk usia 2 bulan Paket no.2 ,jadi jika anda ingin memesan tinggal sebutkan saja paket obat usia no. 2Bulan Obat menggugurkan kandungan terampuh ini sangat manjur dan terbukti merangsang haid atau melunturkan telat datang bulan dari umur 1 minggu hingga 5 6 7 8 MINGGU Pastinya seperti obat aborsi usia 2 bulan ini pun tidak menimbulkan sakit atau perih di perut,karena obat penggugur kandungan yang kami jual ini dipakai oleh dokter-dokter luar Negeri yang sudah maju di sana,tentunya telah teruji klinis untuk cara menggugurkan kandungan.

    OBAT ABORSI USIA 2 BULAN
    Untuk anda yang masih belum tahu usia kehamilan janin yang anda kandung, cara menghitung usia kehamilan dari terakhir menstruasi anda bulan dan tanggal berapa. Jadi Anda bisa membedakan obat aborsi mana yang cocok dengan usia kehamilan anda.

    obat aborsi ini sangat aman dengan ramuan alami dan tradisional,tidak menimbulkan rasa sakit atau efek samping. Telah terbukti puluhan orang di indonesia dan luar negeri, Kasiatnya benar-benar bagus dan ampuh. jadi Anda tidak perlu kiret dan tak perlu ragu.

    Hasil racikan dokter-dokter pakar dalam bidang Genealogy.yang mana tahu betul seluk dalam hal cara aborsi menggunakan obat menggugurkan kandungan.

    setelah anda minum obat penggugur janin ( obat aborsi aman ) ini,pelan-pelan darah haid anda akan keluar,dari vagina anda akan keluar bercak-bercak darah yang mana ini buktinya telah berhasil dengan menggunaka obat penggugur kandungan ini,keluar seperti orang haid / menstruasi biasa.

    OBAT ABORSI USIA 2 BULAN

    DAFTAR HARGA OBAT RACIKAN DOKTER PFIZER

    Paket Standar 2 Bulan : Rp.1.000.000,- (cytotec/obat cyrux pendorong janin)
    Paket Tuntas 2 Bulan : Rp.1.300.000,- (cytotec/obat anti nyeri/ cyrux pendorong janin)
    Cara pakai dan tips penggunaan sudah ada di dalam kemasan

    Bila anda sudah haid,otomatis kehamilan akan gugur dan batal hamil,Artinya,sukses!!! Di Tempat kami tidak memberikan garansi dalam wujud apapun. Produk kami telah teruji dan terbukti puluhan orang. Jadi anda tidak perlu khuwatir lagi tentang khasiat nya. Asalkan diminum sesuai intruksi yang diberikan,dan nantinya kami berikan obat aborsi untuk membersihkan rahim agar hasilnya menjadi kembali baik dengan sempurna.

  16. veveaa Reply | Permalink

    Hello! I could have sworn I’ve been to this site before but after reading through some of the post I realized it’s
    new to me. Anyways, I’m definitely glad I found it and I’ll
    be book-marking and checking back often!

    http://dwlive88.com | http://bgselalu.com

  17. ranjang pasien murah Reply | Permalink

    Goodd day! Do you use Twitter? I'd like to follow you if that would be ok. I'm absolutely enjoying your site and look forward to new updates.

  18. ranjang pasien murah Reply | Permalink

    Goodd day! Do you use Twitter? I'd like to follow you if that would be ok. I'm absolutely enjoying your blog and look forward to new updates.

Leave a Reply


+ six = 11