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| Pregnant woman (Ivory Coast, West Africa) |
Recently I’ve mentioned a few cases of transmissible tumors — that is, cases where tumors actually spread from their original host, to other individuals. The two most dramatic transmissible tumors are Canine Transmissible Venereal Tumor (CTVT) and Tasmanian Devil Facial Tumor (TDFT), where the original tumor can spread widely throughout the entire species. (See this post, this one, and this one, for more detail.) There’s also at least one case of a tumor that accomplished a single transmission, from the original patient to the surgeon who operated on him. 1
Tumors aren’t supposed to be able to spread in this way, because they’re essentially foreign transplants — they should be rapidly rejected, as if they were, say, a skin graft between two random people. In this post I talked about how CVTV and TDFT might have arisen. (There are also a number of cases of tumors that spread to immuno-suppressed individuals, such as after organ transplants, but those cases are easier to understand from an immunologic viewpoint.)
When checking up on references for the last post, I ran across a set of transmissible tumors I hadn’t known about: Vertically transmitted tumors, in which tumors spread from a pregnant mother to the fetus in utero.2
This also, I’m glad to say, seems to be very rare, as you’d expect. Even though mother and child are partially tissue-matched, and even though pregnancy is a very special situation, immunologically, the parent and her child are not genetically identical, and should reject grafts from each other pretty efficiently. (Transplants from parent to child still require immune suppressive treatment.) The review I ran across lists a total of 14 cases of vertical spread of tumors, from 18663 to 2002.4 Although they do note that:
Given the lag time between birth and diagnosis in several of the infants, cases of maternal–fetal transmission may not be as rare as the literature would suggest, and the number of cases could be higher as the detection of metastatic tumor in the fetus may go undetected in cases of abortion or maternal–fetal demise. 2
Malignancy during pregnancy isn’t all that uncommon (0.1% of pregnancies, it says here), so the handful of cases with actual spread of the tumor to the fetus are “numerically inconsequential”. What was different about these 14 cases? We don’t really know, in general. Almost all of the described cases are earlier than 1965,5 predating the molecular era of medicine. Perhaps some, or many, of the infants were immune compromised, as the authors note:
Fetuses with a congenital immunodeficiency are likely to be at an even higher risk for the engraftment of such tumor cells.6 Other factors that may affect the likelihood of tumor cells entering the fetal circulation include maternal homozygosity for one of the fetal HLA haplotypes,7 metastatic potential of the maternal tumor, and a high maternal blood and/or placental tumor load. 2
The outcome of this transmission was very poor; only 3 of the 14 children survived the disease.
I don’t really have any lesson to draw from these cases. Without an extensive molecular workup that isn’t available for almost all of these cases, I don’t know that we can learn much about tumor transmission. Still, these stories are worth keeping in mind when thinking about mechanisms of tumor transmission.
- Gartner HV, Seidl Ch, Luckenbach C, et al. Genetic analysis of a sarcoma accidentally transplanted from patient to a surgeon. N Engl J Med 1996;335:1494–1496.[↩]
- Tolar J, & Neglia JP (2003). Transplacental and other routes of cancer transmission between individuals. Journal of pediatric hematology/oncology : official journal of the American Society of Pediatric Hematology/Oncology, 25 (6), 430-4 PMID: 12794519[↩][↩][↩]
- Friedreich N. Beitrage zur pathologie des Krebses. Virchows Arch 1866; 36:465–477.[↩]
- Tolar J, Coad JE, Neglia JP. Transplacental transfer of small cell carcinoma of the lung. N Engl J Med 2002; 346:1501–1502.[↩]
- Not saying the molecular medicine abruptly switched on in 1965, it’s just a convenient cutoff[↩]
- Pollack MS, Kirkpatrick D, Kapoor N, et al. Identification by HLA typing of intrauterine-derived maternal T cells in four patients with severe combined immunodeficiency. N Engl J Med 1982; 307:662–666.[↩]
- Osada S, Horibe K, Oiwa K, et al. A case of infantile acute monocytic leukemia caused by vertical transmission of the mother’s leukemic cells. Cancer 1990; 65:1146–1149.[↩]
Thanks for the reference about the surgeon!
It’s very interesting that maternal-fetal transmission of tumors has been reported. I didn’t know that!
A colleague in my department has done some work on maternal-fetal microchimerism. It turns out that maternal cells migrate more or less routinely across the placenta and take part in the formation of many different tissues. I don’t know for how long the maternally derived cells persist, but it probably means that the fetus is in principle immunologically “able” to harbour maternal cancer cells as well.
For reviews on microchimerism, see e.g.
Bharath et al, Journal of Pediatrics. 142(1):31-35
Nelson, Trends in Molecular Medicine, Volume 8, Issue 3, 1 March 2002, Pages 109-113, doi:10.1016/S1471-4914(01)02269-9
One interesting element of vertical transmission of tumors is the lack of HLA expression on many tumors. In fact, I’m surprised we don’t see MORE vertical transmission of tumors because they are poor immunologic targets, the infant’s immune system is inherently deficient (most antibody is maternally derived for the first few months of life, and those antibodies should not mediate tumor rejection), and maternal cells readily cross the placenta and persist in the fetal/infant circulation for some time post-natally.
A related, also very interesting topic is twin/twin transmission of malignancy, predominantly leukemias. There is a big literature on this topic, especially as it relates to questions about the origins of childhood leukemia.
One interesting element of vertical transmission of tumors is the lack of HLA expression on many tumors.
It’s variable depending on tumor type, but compelte loss of HLA on tumors is rather unusual — the most I’ve seen is about 35% for one tumor type (I can’t remember which one, though), with 5 – 20% being much more typical figures for complete loss. A partial loss, whether loss of heterozygosity or even isoform-specific mutations, is much more common, and that would leave much of the tissue-transplant-rejection aspect still functional. What’s more, those tumors that have completely deleted HLA, should be good targets for NK cells. I suspect this is telling us that a large component of tumor success is the specific immune suppression, in the form of TRegs and suppresssive antigen-presenting cells, associated with the tumor mass, and that this immune suppression does not cross the placenta.
Still, I agree that it’s a little surprising that vertical transmission isn’t more common, especially given the rate of maternal chimerism, as you and Song both point out.
Hi Ian,
Nice post.
I selected it as one of my “picks of the week” of posts aggregated at RB in molecular biology, over at my blog http://amontenegro.blogspot.com/2009/08/bacterial-freeloaders-early-metastasis.html
Cheers,
-A