How can cancer preventing genes from animals be transferred to humans?

How can cancer preventing genes from animals be transferred to humans?

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I recently read this non-peer reviewed article that states that the prevalence of cancer in crocodiles or elephants is really low, much lower than humans. It is said below

A team of researchers in the US looked closer, and found an abundance of a gene called TP53. This gene is known for its ability to repair damaged DNA and thus halt the spread of cancer, and it's some 20 times more common in elephants than it is in human beings. It appears elephants have developed more of these genes as they've evolved, in part to protect calves born to older mothers

"These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression," says the report, published in the Journal of the American Medical Association.

Naked mole rats are even more miraculous - they never develop cancer, even when scientists try and induce it artificially. What appears to be happening, at least according to a recent study, is that the mole rats are using natural mechanisms to clamp down on the spread of cancer and fight back against the mutation.


So why is it that these genes cannot be transferred from animals to humans? Maybe when the baby is at fetus stage? What are the current problems/limitations and if possible, how would scientists transfer these genes? My logic is that since mice and elephants are both mammals, it should not be too hard to achieve this.

While this research is interesting and might help curing cancer at some point, it's not a ground breaking revelation.

The gene in question here is TP53, coding for the very-well known tumor supressor protein p53. Humans do have this gene, but apparently elephants hav acquired multiple copies of it (~20) during evolution and that might explain why they don't get cancer so easily.

The problem of testing this is not a technical one. Using modern genetic engineering methods it should be fairly easy to multiply the gene in human or mice embryos, or introduce the additional variants from the elephants. Someone might already be planning to do that in mice.

For use on humans however, this is highly unethical. Without proof that these gene copies actually prevent cancer (and one observational study is not a proof), you can't just use a new medical treatment. Secondly this treatment would require genetic modification of an embryo (because its actually cancer prevention, not acute treatment) and that is illegal almost everywhere on earth (even genetic modification of somatic tissue for cancer treatment is just now becoming an experimental therapy).

Cancer in Wild Animals

Cancer seems to affect all animals, from anteaters to zebras. Much less is known about the cancers that affect wild animals, in part because it is hard to study. Animals move around and may not be easily observed for long periods of time. The cancers that have been studied are very interesting and will certainly prove useful in the study of human cancer. As an example, Tasmanian devils have a type of cancer that can be spread from animal to animal by biting!

Cancer in Cats

Cats are susceptible to a variety of cancers. Among the most common are lymphoma, squamous cell carcinoma (skin cancer), mammary cancer, mast cell tumors, oral tumors, fibrosarcoma (soft tissue cancer) , osteosarcoma (bone cancer), respiratory carcinoma, intestinal adenocarcinoma, and pancreatic/liver adenocarcinoma. The disease has become so prevalent that it is now the most common cause of death in cats.4

Certain breeds are more prone to certain cancers than others. Signs and symptoms differ depending on the type and stage of the cancer. Detection and diagnosis requires some detective work. Tumors that are visible and/or detectable by touch are most easily identified. Vets often perform additional tests to make an accurate diagnosis. Along with a physical exam, they may perform blood and urine tests, cytology, imaging and biopsies.

Treatment options vary and include surgery, chemotherapy, radiation, immunotherapy, photodynamic therapy, or a combination of these. In many cases, cancer can be successfully treated. Early detection and diagnosis is critical. Regular visits to the veterinarian can help prevent and manage cancer. The American Veterinary Medical Association recommends twice-a-year wellness exams for all cats.5 Because the causes of cancer in cats are similar to those in humans, risk can be reduced by lowering the animal's exposure to harmful carcinogens, including tobacco smoke.6

Critical Thinking Questions

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    Researchers Advance Findings on Key Gene Related to Cancer Metastasis

    BUFFALO, NY — New evidence reported by researchers at Roswell Park Comprehensive Cancer Center (Roswell Park) lends support to the hypothesis that the SSeCKS/AKAP12 gene is a key inhibitor of prostate cancer metastasis. The data are some of the first to demonstrate this dynamic in transgenic animal models, with promising implications for development of targeted therapies for prostate cancer and perhaps for other solid-tumor cancers.

    A team led by Irwin H. Gelman, PhD, noted that aggressive prostate cancers in humans typically turn off or delete two major regulatory genes, SSeCKS/AKAP12 and Rb. To explore this dynamic, the researchers developed a transgenic animal model to study the effects on prostate cancer progression of deleting these two genes. They report in Cancer Research, a peer-reviewed journal published by the American Association for Cancer Research, that the loss of these two genes and associated protein products leads to early prostate cancer. Moreover, more than 80 percent of the transgenic models in their study developed metastatic lesions in lymph nodes near the prostate.

    “This correlates with our earlier finding that SSeCKS/AKAP12 inhibits the chemotaxis of metastatic prostate tumor cells — that is, their ability to move on to another environment in response to chemical attractants,” said Dr. Gelman, the John & Santa Palisano Chair in Cancer Genetics at Roswell Park. “Thus, our data suggest that SSeCKS plays a role in preventing the early dissemination of prostate cancer cells to metastatic sites. Importantly, we show that humans whose prostate cancers have turned off or deleted the SSeCKS/AKAP12 gene have significantly higher rates of metastasis formation compared to cases where SSeCKS/AKAP12 levels are sustained.”

    While the SSeCKS/AKAP12 gene is deleted in about a third of metastatic prostate cancers, precluding benefit from targeted therapies exploiting this vulnerability, the remaining two-thirds of such tumors may be treatable with drugs that induce the reactivation of SSeCKS/AKAP12 production. Dr. Gelman and colleagues are now looking to identify the genomic signatures controlled by SSeCKS/AKAP12 in the suppression of metastasis pathways — at the level of the tumor cells themselves and in the cells that form the metastatic microenvironment.

    “At least 93 percent of cancer patients die because of complications due to metastatic cancers, yet the vast majority of pathways studied and therapies developed address the biology of primary cancers,” Dr. Gelman noted. “This current research is important in that it addresses specific mechanisms of cancer metastasis, with the result that genetic tests and therapies derived from such studies will have a higher chance of affecting cancer patient survival.”

    Tardigrade protein helps human DNA withstand radiation

    Experiments show that the tardigrade’s resilience can be transferred to cultures of human cells.

    Tardigrades, or water bears, are pudgy, microscopic animals that look like a cross between a caterpillar and a naked mole rat. These aquatic invertebrates are consummate survivors, capable of withstanding a host of extremes, including near total dehydration and the insults of space.

    Now, a paper 1 published on 20 September in Nature Communications pinpoints the source of yet another tardigrade superpower: a protective protein that provides resistance to damaging X-rays. And researchers were able to transfer that resistance to human cells.

    “Tolerance against X-ray is thought to be a side-product of [the] animal's adaption to severe dehydration,” says lead study author Takekazu Kunieda, a molecular biologist at the University of Tokyo. According to Kunieda, severe dehydration wreaks havoc on the molecules in living things. It can even tear apart DNA, much like X-rays can.

    The researchers wanted to know how tardigrades protected themselves against such harsh conditions. So Kunieda and his colleagues began by sequencing the genome of Ramazzottius varieornatus, a species that is particularly stress tolerant. It's easier to study processes within the tardigrade's cells when the animal's genome is inserted into mammalian cells, says Kunieda. So researchers manipulated cultures of human cells to produce pieces of the water bear's inner machinery to determine which parts were actually giving the animals their resistance.

    Eventually, Kunieda and his colleagues discovered that a protein known as Dsup prevented the animal's DNA from breaking under the stress of radiation and desiccation. And they also found that the tardigrade-tinged human cells were able to suppress X-ray induced damage by about 40%.

    Genomic treasure trove

    “Protection and repair of DNA is a fundamental component of all cells and a central aspect in many human diseases, including cancer and ageing,” says Ingemar Jönsson, an evolutionary ecologist who studies tardigrades at Kristianstad University in Sweden.

    This makes the new paper’s findings “highly interesting for medicine”, says Jönsson. It opens up the possibility of improving the stress resistance of human cells, which could one day benefit people undergoing radiation therapies.

    Kunieda adds that these findings may one day protect workers from radiation in nuclear facilities or possibly help us to grow crops in extreme environments, such as the ones found on Mars.

    Bob Goldstein, a biologist at the University of North Carolina at Chapel Hill who helped to sequence the genome of another tardigrade species 2 , says the research is exciting and clever. He also thinks that the study’s authors are correct in predicting that this is probably just the first of many such discoveries.

    “The tardigrade is resistant to a lot of different kinds of extremes,” says Goldstein. And this means that the animals must have many different ways of protecting themselves.

    “We are really just at the beginning of exploring the genetic treasure that the tardigrade genome represents,” says Jönsson.


    Integration of bacterial DNA in the human somatic genome

    Through this extensive analysis of several large human genome sequencing projects, we present evidence supporting LGT from bacteria to the human somatic genome. In terminally differentiated cells, we expect and observe that putative LGTs are detected consistently at low levels. Examination of clonally expanding tumors reveals many more transfers, as we would expect from a rapidly expanding population of cells. In all of the cases examined, the composition of the microbiome across the samples is different from the composition of bacterial DNA integrated into the human genome. When only the regions on the human genome with >4× coverage are examined, a pattern emerges of integration in the mitochondria for LAML and five genes in STAD. Remarkably, in STAD, four of those five genes have previously been shown to be implicated in cancer [54]–[57]. Together we believe this presents a compelling case that LGT occurs in the human somatic genome and that it could have an important role in human diseases associated with mutation.

    While it is possible that these LGT mutations may play a role in carcinogenesis, it is also necessary to consider that they could simply be passenger mutations. The rapidly proliferating tumor cells may be more permissive to LGT from bacteria due to mutations in tumor suppressor genes or down regulation of DNA repair pathways. As a result of clonal expansion, rare mutations may be amplified throughout the tumor. Based on our analysis, it is impossible to determine if the LGTs have a causal role in cancer, or are simply a byproduct of carcinogenesis.

    Likewise, while it is possible that the bacteria are causing mutations that benefit the bacteria, it is equally plausible that this occurs by random chance, or some combination of the two. If the mutations occur by random chance, mutations that induce carcinogenesis will be selected for over time within a local population of cells. This may explain why we observe low levels of LGT across the entire genome with increased coverage in specific genes in the STAD and LAML samples. In contrast, mutations that would benefit the bacteria would include those that create a micro-environment that promotes bacterial growth. This may explain why similar mutations, both in location and bacterial integrant, are observed in multiple individuals (Figure 8).

    Laboratory artifacts

    While the extensive coverage across these putative integrations in multiple samples is strong support for bacterial integration being present in human tumors, we recognize the concern that such bacterial/human read pairs may arise merely from chimeric DNA generated during library construction. We pursued obtaining specimens for validation or establishing collaborations to accomplish this validation with TCGA investigators. Unfortunately, the combination of patient consent and access policy precludes the possibility of experimental validation on these samples by researchers that lack an IRB tied to a grant award from NCI/TCGA. As our funding is from the NIH New Innovator Program this was not possible. Collaborating with current TCGA investigators was also pursued but was found to be explicitly forbidden. However, we anticipate the future successful validation of these results by researchers with access to samples and the proper authorization.

    However, further analyses suggest that these are not laboratory artifacts. If chimeras arise in library construction, they should increase as the prevalence of bacterial DNA/RNA increases. Therefore, we evaluated the possibility of a correlation between the number of read pairs arising from the Pseudomonas-like DNA and putative LGT read pairs for these six STAD samples. The Spearman-rank correlation between these values was not significantly different from zero (P = 0.19), indicating no correlation between the abundance of reads from the bacteria genome and reads supporting integration of Pseudomonas-like DNA in the human genome for these six samples. Overall, no relationship was observed between bacterial integrations and (a) the microbiome composition, (b) human transcript abundance, or (c) mitochondrial transcript abundance.

    Yet, to further examine laboratory artifact chimerism in these samples, the distribution of the insert sizes for paired reads was compared between representative LAML samples, STAD samples, and Neisseria meningitidis whole genome sequencing project samples (Figure S9). The mappings with N. meningitidis were used to establish that ∼0.22–0.29% of reads were outside this distribution when the reads were mapped to the assembled genome for that exact strain. For comparison, 0.94–1.12% of reads were outside this distribution when reads mapped to a divergent genome from the same species (Table S5). The same percentage values for paired reads only mapping to bacteria in the STAD samples ranged from 0.06–0.60% while those for LAML ranged from 0.65–0.87% (Table S5). Given that the database we searched against was limited to only those with complete genomes, it is highly unlikely that the bacterial DNA sequenced through the TCGA is from the same strain that has a genome deposited in RefSeq. Therefore, we anticipate values should lie between 0.22–1.12% as is seen in the N. meningitidis controls. We observed that bacterial read pairs in the TCGA data fell outside the distribution less frequently (0.06%–0.60%). While this percentage is used as a proxy for laboratory artifactual chimerism, bacterial genomes are known to be fluid with genome rearrangements happening in single growths that would result in the same outcome. When these results are taken together, there is no indication that there is a higher level of chimerism in the bacterial DNA of TCGA samples than is normally observed. Furthermore, this level of chimerism would not explain 4× or 150× coverage across the bacterial integrations that are discussed here considering that PCR duplicates were removed. Of note, high coverage chimerism in bacterial samples would lead to an inability to properly assemble the corresponding genomes, which is not observed in microbial genome sequencing projects.

    We note, however, that laboratory artifact chimeras could be detected in TCGA samples with whole genome amplification. As such these samples were eliminated from further analysis beyond what is presented in Table 1. In ovarian cancer, numerous read pairs that would normally support integrations were detected in both tumor and normal samples (Table 1). Upon further examination, all of the putative integrations involved E. coli DNA and are likely chimeras formed during the whole genome amplification used for these samples and that formed between human genomic DNA and small pieces of E. coli DNA introduced with recombinant enzymes.

    Further support that the putative integrations in LAML and STAD samples are not laboratory artifacts comes from the fact that reads supporting integrations were detected 672× and 13.2× more frequently, respectively, in these cancer samples than in representative non-cancer samples (Table 1). This is expected if such mutations were part of the clonally expanding tumor. Across all samples, there are 1,033 reads supporting integrations in the normal samples with 13,392,142,331 read pairs sequenced, yielding an estimated integration frequency of 7.7×10 −8 . In contrast, 690,528 read pairs support integrations in tumor samples out of 42,533,195,146 paired reads sequenced, yielding an integration frequency of 1.6×10 −5 , or 210× higher. Even when compared to the highest integration rate assessed in normal samples, which was 6.02×10 −6 in the Trace Archive data, the aggregate rate across all cancer samples is still >2.5-fold higher.

    While the integration rate in cancers is 210× higher than that in normal samples across the TCGA, this comparison is not directly between matched tumor and normal pairs since normal samples were only present for OV, GBM, and BRCA. However, many different types of normal samples can be used in cancer studies and therefore other comparisons besides matched pairs are quite valid. In fact, no one type of normal sample may be perfect for all experiments. For example, a small piece of adjacent breast tissue determined to be non-cancerous by a pathologist would be considered the normal specimen for breast cancer [58]. These samples are often taken from the margins of tumors when they are resected during surgery. In that case, it's possible they could have cancer characteristics not evident by histology [59], [60]. In OV, blood-derived samples were collected as normal samples from some patients, while others had normal tissue collected. In GBM, only blood-derived samples were collected as normal samples. In other cancer studies, skin tissue from patients prior to treatment may be used [61]. Some blood cancers lack a normal sample because the cancer originates in the bone marrow. Therefore, all of the patient's blood contains cancerous cells [62]. In this instance either blood from healthy individuals [63] or blood taken from the patient once in complete remission [64] may be used as a normal sample.

    Unfortunately, the STAD and LAML samples of greatest interest here for driving the dramatically increased integration rate in the tumor samples also lack normal matched samples in this data release. Given the lack of normal matched samples, and that blood samples from healthy individuals are frequently used as normal samples for studying types of leukemia [63], it is informative to compare LAML to normal samples from OV, GBM, and BRCA or 1000 Genomes data. Of note, the normal samples for OV, GBM, and BRCA have integration rates of 1.1×10 −7 , 2.3×10 −8 , and 1.2×10 −7 (Table 1) respectively, while the integration rate of samples from the 1000 Genomes project was 2.3×10 −6 . Of these, the BRCA mutation rate is most relevant to STAD and LAML as all three are RNA-based sequencing. Comparing these, LAML samples have an integration rate 672× higher than the integration rate for the BRCA normal samples (Table 1). Even if the LAML cancer samples are compared to the normal samples with the highest integration rate, those in the Trace Archive, the integration rate for LAML is still almost 14× higher. While the overall integration frequency of cancer samples is 1.6×10 −5 , or 210× higher than the normal integration rate of 7.7×10 −8 (Table 1), the LAML integration rate is the main driver of the increased frequency. Most tumor types do not have an increased integration rate relative to normal samples (Table 1).

    Another main contributor to the significant increase of integrations in cancer samples is STAD, which has an integration rate of 1.6×10 −6 and is 13.2× higher than the integration rate for the BRCA normal samples (Table 1). Considering STAD is in close proximity to the microbiome, normal stomach tissue would better reflect this exposure to the microbiome, including an increased likelihood of bacterial integration. That means it would be particularly informative if available. Unfortunately, this release of the TCGA lacks STAD normal samples or any other normal samples with constant exposure to the microbiome. This prevents us from determining the rate of integration in non-cancer cells with an abundant microbiome. Further work is needed to resolve differences in the integration rate between normal samples that have constant contact with the microbiome and those that do not.

    Bacterial integration of Acinetobacter-like DNA in mitochondrial genomes

    The majority of the bacterial integrations detected were between an Acinetobacter-like organism and the mitochondrial genome. Acinetobacter spp. are known to invade epithelial cells and induce caspase-dependent and caspase-independent apoptosis [65]. Uptake of apoptotic bodies and caspase-dependant DNA fragmentation is known to facilitate LGT between mammalian cells [66], including LGT of oncogenes [67].

    While we present this as bacterial integration into the mitochondrial genome, it is possible that mitochondrial DNA is integrating into an Acinetobacter-like genome. However, despite the numerous complete Acinetobacter genomes sequenced, mitochondrial DNA has not been detected in the genome of an Acinetobacter isolate.

    Human mitochondria have an essential role in many key cellular processes such as the generation of cellular energy, production of reactive oxygen species, and initiation of apoptosis. The accumulation of somatic mutations in the mitochondrial genome has been implicated in carcinogenesis [68]. For instance, mutations in the mitochondrial cytochrome oxidase subunit I (COI) gene contribute to the tumorigenicity of prostate cancer through an increased production of reactive oxygen species [69]. The LGT from bacteria, such as Acinetobacter, to the mitochondria may be generating novel mutations in the mitochondrial genome and therefore influencing tumor progression.

    Bacterial integration in proto-oncogenes in stomach adenocarcinomas

    The integrations we identified in STAD frequently appear to be in, or near, the untranslated region (UTR) of known proto-oncogenes. In this case, these proto-oncogenes are genes known to be up-regulated in cancers. Despite occurring in or near UTRs, this does not reflect similarity in these sequences. The mappings are specific as observed by both the BWA matches and BLAST searches against NT. While CEACAM5 and CEACAM6 are paralogs, they are sufficiently diverged to be resolved. We postulate that these putative integrations have mutated a repressor binding site and have induced over-expression leading to carcinogenesis. While this is a tempting speculation, it needs to be experimentally verified.

    In chromosome 2, one STAD sample had an integration site in the second exon of thymosin β10 (TMSB10 Figure 8A) while another integration site was found in IGKV4-1. The TMSB10 gene has been shown by SAGE to be up-regulated in gastric tumors and confirmed with Northern blots [54].

    On chromosome 19, integrations were identified in CEACAM5 and CEACAM6 of STAD tumors (Figure 8BC). The same integration site in CEACAM5 was detected in two separate samples while a third sample had a similar integration in CEACAM6. CEACAM proteins were initially identified as prominent tumor-associated antigens in human colon cancer [55]. Approximately 50% of human tumors show over-expression of CEA family proteins [56]. CEACAM5 and CEACAM6 mediate cell adhesion by binding to themselves and other CEACAM family members [55]. Over-expression disturbs ordered tissue formation in 3D tissue culture and leads to increased tumor formation in mice [55].

    On chromosome 5, integration sites were identified in STAD tumors in different portions of CD74 with three samples having an integration in the 5′-end of the gene and one of those samples having a second integration in the 3′-UTR of CD74 (Figure 8D). CD74 initiates antigen presentation as well as signaling cascades that result in cell survival. Therefore it is not surprising that while its regulation is tightly controlled in normal tissues, it has increased expression in many cancers including gastrointestinal carcinomas and precancerous pancreatic lesions [57].

    Importantly, and significantly, we only identified integrations meeting our criteria in these 4 tumor-associated genes and one other immune-related gene. We did not first look at all known oncogenes and try to find bacterial integration with these criteria, nor did we look at oncogenes and try to explain why they are up-regulated. These four oncogenes merely emerged as those having such integrations.

    While there is an association between bacterial DNA integration and up-regulation of these genes, it is important to note that LGT is not associated with the most abundant bacterial transcripts. Such a result would be expected if the read pairs were merely laboratory-based artifactual chimeras generated during library construction. While these human transcripts are up-regulated in the tumors when compared to other tumors, in at least two cases they are not the most abundant transcripts. In fact, in the 143 STAD samples, if we examine the most abundant transcript, it is most frequently annexin A2 (Table 3), which was not identified as having a bacterial integration. Using our search criteria, we find no evidence of human-bacteria chimeras in any of the most abundant transcripts (Table 3) that would suggest such sequences arise from laboratory artifacts. If we, instead, focus only on the abundance of the four up-regulated genes above and on the ten samples where we identified bacterial integration in these genes, we see no clear pattern that would correlate LGT with transcript abundance. In CEACAM5, which has the most bacterial integrations, and CEACAM6, they are >75% less abundant than the most abundant transcript in that sample (Table S6). In addition, there are between 35 and 95 transcripts that are more abundant depending on the sample examined (Table 4).

    Regulation During Development

    The regulation of gene expression is extremely important during the early development of an organism. Regulatory proteins must turn on certain genes in particular cells at just the right time so the individual develops normal organs and organ systems. Homeobox genes are a large group of genes that regulate development during the embryonic stage. In humans, there are an estimated 235 functional homeobox genes. They are present on every chromosome and generally grouped in clusters. Homeobox genes contain instructions for making chains of 60 amino acids called homeodomains. Proteins containing homeodomains are transcription factors that bind to and control the activities of other genes. The homeodomain is the part of the protein that binds to the target gene and controls its expression.


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    A better future thanks to animal research

    These are only a few examples of the countless benefits animal research has brought to people with cancer, but there are thousands of other drugs and treatment techniques that are built on knowledge from tests in animals.

    And it’s not just cancer patients that benefit from animal research. As the Royal Society’s position statement on the use of animals in research points out, ‘virtually every medical achievement in the past century has depended directly or indirectly on research on animals.’

    At Cancer Research UK, animal research is never undertaken lightly – we seek to use alternatives wherever it’s possible, and fund research into alternative methods as well. But this fact remains – millions of people all over the world are alive today thanks to animal research. Much of this knowledge has also been used to tackle diseases that affect animals themselves, including cancer.

    Many people working for and supporting us know first-hand how devastating cancer can be, and all of us are deeply committed to beating the disease. Animal research is, at present, a necessary means to an end: helping people with cancer to survive.

    Dr David Scott, Director of Discovery Research and Research Funding