Infectious cancer
Mikhail Gelfand, "Nature" No. 2, 2016
Published on the website "Elements"
When people talk about cancer as an infectious disease, they usually mean viruses that provoke its development.
In the Russian-language medical literature, cancer means only malignant neoplasms from epithelial tissue. According to English medical terminology, cancer is any malignant tumor, and the one that develops from epithelial tissue is a carcinoma. In this article, for simplicity, the word "cancer" also means any malignant neoplasms.
Among the most famous examples are human papilloma viruses of the 16th and 18th types (causing cervical cancer), Epstein–Barr virus, or human herpes virus of the 4th type (Burkitt's lymphoma), and Raus sarcoma virus (malignant tumors of connective tissue in birds). Cancer can also be provoked by some parasitic flatworms, such as cat fluke (Opisthorchis felineus) and schistosoma (Schistosoma) [1].
However, there are diseases that are carried by the cancer cells themselves. Once in a new organism, they become the progenitors of the tumor. Thus, we are dealing with a classic infectious agent that uses the host for reproduction and further transfer to another organism. Although only a few such cases are known, their list is gradually growing – and it seems that what was previously considered an exception may well turn out to be the rule. The study of such cancers (in particular, the elucidation of their evolutionary history and epidemiological studies) has made significant progress in the last few years thanks to the sequencing of tumor cell genomes.
With bucky
One of these types of cancer is transmissible venereal sarcoma of dogs (Canine Transmissible Venereal Tumor – CTVT). This is a tumor of the external genitalia of canids, known as a separate disease for more than 200 years [2]. In 1876, the Russian veterinarian M. A. Novinsky demonstrated the transmission of the disease by transferring cancer cells from a sick dog to a healthy one [3]. Although the tumor looks terrible, in most cases it can be completely cured with chemotherapy, and sometimes even disappears after a few months.
The genome of this tumor, or rather, two genomes – tumors of a purebred American Cocker spaniel from Brazil and a dog of Australian aborigines, were sequenced in 2014 [4]. The number of mutations in each of the genomes was about 100 times higher than the number of mutations in other cancers, reflecting a long history of accumulation of these changes. More than 10 thousand genes – slightly less than half – have mutations that completely destroy more than 600 genes. The spectrum of observed nucleotide substitutions resembles some types of human cancer; in particular, mutations caused by ultraviolet radiation are clearly visible.
From comparison with the genomes of modern dogs, it turned out that a representative of the canine family, in which the tumor originated, lived about 11 thousand years ago and most of all resembled the Alaskan malamute. It was a medium or large–sized dog, black or two-colored - dark on most of the body and lighter on the belly, paws. Some of the genes associated with domestication had alleles characteristic of wolves, which reflects the antiquity and some primitiveness of the breed. At the same time, the sequenced genomes of the two tumors diverged less than 500 years ago. This may mean that transmissible venereal sarcoma was introduced to Australia by dogs of the first European settlers.
It also turned out that the ancient dog came from a small, genetically homogeneous population. Perhaps this affected the first stages of the emergence of a pathogenic clone: since dogs were close relatives, the cells of one individual after infection with another were not destroyed by its immune system.
Tasmanian Devils
Cells of another type of infectious cancer – the Tasmanian devil Facial Tumor (Devil Facial Tumor Disease – DFTD) – are a young pathogen, unlike the cells of venereal sarcoma of dogs. Tasmanian devils are the largest predators among marsupial mammals living on the island of Tasmania. In 1996, the beginning of epizootics was noted in the north-west of the island. The disease, which manifests itself in large and often metastasizing tumors of the muzzle and oral cavity, spreads rapidly and threatens the existence of the species.
It quickly became clear that the disease is spread due to the transmission of cancer cells during bites (and Tasmanian devils are quite aggressive) [5]. Some features of the gene expression of these cells indicate that they originate from the neural crest – probably from Schwann cells, which normally form the myelin sheaths of nerve fibers.
In 2012, the genomes of two healthy individuals of the Tasmanian devil and two DFTD patients from geographically remote areas were sequenced. Analysis of phylogenetic trees based on mitochondrial genomes; absence of traces of tumor cells in museum samples collected in 1941-1989; high contagiousness and conspicuous external manifestations – all these factors make it unlikely that the disease existed unnoticed for a long time in the population of Tasmanian devils [6]. Counting the number of differences between two tumor genomes and comparing them with the genomes of normal cells allowed us to estimate the rate of accumulation of mutations and the pressure of natural selection, and also showed that the read cancer genomes diverged shortly after the appearance of the ancestral tumor cell. At the same time, the same set of preferred types of substitutions is present in both cancer genomes (which nucleotide is replaced by which most often), which indicates some kind of molecular defect in the mechanism of replication or repair in a common ancestor. Additional genotyping of 69 more sick animals allowed us to assume not only the time, but also the place of appearance of the ancestral clone on the Forestier peninsula, and also confirmed the rapid spread of one of the genetic variants of the tumor that is happening now.
One of the assumptions about how facial tumor cells avoid a reaction from the immune system of a new host was based on the relatively small genetic diversity of Tasmanian devils. Two genetically different cell types were found in several diseased individuals, i.e. these animals were infected with pathogenic cells at least twice. It turned out, however, that healthy Tasmanian devils develop a normal rejection reaction when transplanting tissue from another individual. Later it was found out that the cells of the facial tumor do not express the genes of the main histocompatibility complex and, apparently, thus avoid the attack of the immune system [7].
The strategy of saving the species is understandable, although sad: it is necessary to isolate a sufficient number of individuals of the Tasmanian devil to preserve genetic diversity and repopulate the area after the extinction of wild animals – carriers and victims of the disease. Modern scientists have a unique opportunity to observe an explosive epidemic of infectious cancer, and their primary task is to collect as many samples as possible for further study.
Bivalves
However, is the epizootic of the Tasmanian devil's facial tumor unique? It turns out that a similar rapidly spreading disease affects bivalves on the Atlantic coast of North America. For the first time, the development of the disease was noticed in the 1970s in the edible mollusks Mya arenaria [8]. It is expressed in uncontrolled cell division of the immune system and resembles lymphoma.
High expression of the reverse transcriptase gene, characteristic of viruses and mobile elements of the genome, was found in cancer cells. The source of this increased expression turned out to be a new retrotransposon (a mobile element of the genome that propagates in it through an intermediate stage of the RNA molecule) – Steamer. Naturally, it was assumed that the cause of cancer was genomic instability caused by retrotransposon [9]. However, a more detailed analysis showed that in cancer cells of different individuals, the sites of retrotransposon insertion into the genome coincide and at the same time differ from the positions of Steamer in the genomes of the hosts [10]. Nevertheless, the multitude of copies of the retrotransposon in the genome of cancer cells (150-300 pieces, as opposed to 2-10 in normal cells) and the fact that most of the integration sites coincide in different copies of the tumor suggest that Steamer played a role in the primary transformation of cells.
Similar tumors have been observed in other bivalves: mussels, oysters, scallops [11]. Interestingly, in Pacific mussels (Mytilus trossulus), cancer cells of different individuals have the same set of polymorphisms. This may also be evidence of the common origin of tumors and, therefore, the infectious pathway of cancer [12]. Invertebrates do not have the main histocompatibility complex – the main defender against the introduction of foreign cells – and therefore there is no way to prevent the expansion of infectious tumor clones. Hopefully, understanding the mechanism of the spread of infectious shellfish cancer will help to find new examples among other invertebrates.
Person
A person can get cancer during organ transplantation if there was an unnoticed tumor clone in the transplanted tissues [13]. There is also a case when a surgeon who injured his arm during surgery became infected with sarcoma [14]. But perhaps the most amazing (and, alas, tragic) story happened to a forty-year-old man from Colombia, a patient with acquired immunodeficiency syndrome [15].
During the initial examination, it turned out that he was infected with dwarf tapeworm (Hymenolepis nana), but the main thing, of course, was not this, but numerous neoplasms in the lungs and in the lymph nodes. The neoplasms consisted of atypical cells of small size, although some were large and contained multiple abnormal nuclei with a large number of nucleoli.
As the authors of the publication write, this case was a diagnostic nightmare. On the one hand, clinically, the tumor behaved like a cancer – it captured neighboring tissues, the cells were the same and looked like stem cells (a high ratio of the volumes of the nucleus and cytoplasm). On the other hand, the small size of the cells indicated an infection caused by an unknown, possibly single–celled eukaryotic pathogen. Cells with multiple nuclei resembled slime mold cells. The possibility of helminthic invasion was considered, but was rejected due to the primitive, undifferentiated type of cells and the complete absence of cytological signs characteristic of parasitic worms.
The exact diagnosis was made only 72 hours before death, when, due to kidney failure, the patient's condition was already so bad that there was no point in using specific treatment. Sequencing of the genome of tumor cells showed that their source was the same dwarf tapeworm, and cancer cells underwent multiple genomic rearrangements, as often happens with conventional types of cancer. It is known that in patients with a suppressed immune system, the development of a tapeworm often follows an abnormal path – with the formation of giant, poorly formed organisms. Apparently, normal development requires interaction with the host's immune system. However, cases of neoplasia are also known in free-living flatworms. Thus, it seems that there is nothing exceptional in cancer caused by the degeneration of parasite cells.
HeLa Cells
The disease of Henrietta Lacks, who was born in 1920 and died at the age of 31 from cervical cancer, which gave numerous metastases, was diagnosed shortly before the woman's death. The diagnosis of "epidermoid carcinoma" turned out to be incorrect – in fact, it was an adenocarcinoma of the cervix. However, this mistake, which was common at that time, would still not have affected the treatment – radiotherapy using a radiation source sewn into the body. A sample of tumor tissue obtained during the operation was placed at the disposal of Dr. George Otto Gey. He discovered that the cells of the sample are able to divide indefinitely. This is how the "immortal" human cell line HeLa (named after the tumor carrier) was created, which is still used in thousands of biological experiments and with which a polio vaccine was produced on an industrial scale after it was developed by virologist Jonas Salk.
However, the viability of HeLa cells has bad consequences. Already in the 1960s, it was discovered that many laboratory cell lines were infected with HeLa; as of today - 10-20% [16, 17]. Thus, the HeLa line behaves almost like a pathogen, only its host is not an organism, but cells cultured in laboratories.
In March 2013, the genome of one of the sublines of HeLa cells was published, but at the request of G. Lacks' relatives, access to it was closed [18]. In August of the same year, an agreement was reached according to which studies using the HeLa cell genome should be conducted exclusively for medical purposes, and the results should be placed in a single database [19]. Access to it is regulated by a special committee consisting of biologists, bioethicists and members of the G. Lacks family. At the same time, the second version of the HeLa cell genome and data on rearrangements in several more sublines were published [20]. The reason for the transformation that led to the fatal illness of the famous patient was the integration of the type 18 papilloma virus, which caused the activation of the MYC proto-oncogene.
So, it seems that cancer clones sometimes behave like independent single-celled pathogenic organisms. They overcome immunological barriers when they weaken or in a situation of low antigenic diversity in the hosts. It is natural to assume that the known examples do not exhaust the existing variety of infectious types of cancer. It is approximately clear where to look for new ones – in relatively large, but genetically homogeneous populations. The existence of such cancers indicates one of the possible reasons for the appearance of tissue incompatibility genes (which now interfere so much with organ transplantation) – the evolutionary advantage they gave could be just protection from infectious tumor clones.
***
During the preparation of this article for publication, literally in the last days of 2015, a publication was published about the second clone of the Tasmanian devil facial tumor – DFT2 [21]. The tumors caused by this clone are externally indistinguishable from those caused by the first DFT1 clone described. Externally, but not histologically or cytogenetically! In particular, the DFT2 clone has a Y chromosome, which means that its ancestor was a male, while DFT1 cells originate from a female. There are also differences in the lengths of microsatellites (short tandem DNA repeats) and in the alleles of the main histocompatibility complex. Probably, an article about the DFT2 genome will be published soon, which, hopefully, will allow us to hypothesize about the mechanisms of the origin of these clones. Although the authors suggest that Tasmanian devils, for some reason, are particularly prone to generating tumor clones, it is difficult to explain why then this species has not yet become extinct, given the hurricane nature of the current epidemic. As a very wild hypothesis, we can assume that the DFT2 clone still comes from DFT1 cells that have experienced (partial?) hybridization with the cell of an infected individual. Indeed, the history of transmissible venereal sarcoma in dogs includes horizontal transfer of the mitochondrial genome from the host to the tumor [22]. Something similar could have happened in the case of the Tasmanian devil's facial tumor. This will be clear after determining the genomic sequence of DFT2, while no common specific markers have been found in the two clones. However, if hybridization has led to a complete replacement of genetic material, it is not very clear how to detect it by existing methods today.
The work was supported by the Russian Science Foundation (project 14-24-00155).
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About the author
Mikhail Sergeevich Gelfand – Doctor of Biological Sciences, Professor, Member of the European Academy, Deputy Director of the A. A. Harkevich Institute of Information Transmission Problems of the Russian Academy of Sciences, Professor of the Faculty of Bioengineering and Bioinformatics of Lomonosov Moscow State University. Research interests – bioinformatics, molecular evolution, systems biology, comparative and functional genomics, metagenomics.
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