RESUMEN
BACKGROUND: Toxicology testing is frequently used as a means of gathering objective data about substance use in pregnancy, but little is known about the clinical utility of testing in the peripartum setting. OBJECTIVE: This study aimed to characterize the utility of obtaining maternal-neonatal dyad toxicology testing at the time of delivery. STUDY DESIGN: We performed a retrospective chart review of all deliveries in a single healthcare system in Massachusetts between 2016 and 2020, and identified deliveries with either maternal or neonatal toxicology testing at delivery. An unexpected result was defined as a positive test for a nonprescribed substance that was not known on the basis of clinical history, self-report, or previous toxicology testing within a week of delivery, excluding results for cannabis. We evaluated the characteristics of maternal-infant dyads with unexpected positive results, unexpected positive results by rationale for testing, changes in clinical management after an unexpected positive test, and maternal outcomes in the year after delivery using descriptive statistics. RESULTS: Of the 2036 maternal-infant dyads with toxicology tests performed during the study period, there were 80 (3.9%) with an unexpected positive result. Diagnosis of substance use disorder with active use in the last 2 years was the clinical rationale for testing that yielded the greatest number of unexpected positive results (10.7% of total tests ordered for this rationale). Inadequate prenatal care (5.8%), maternal use of medication for opioid use disorder (3.8%), maternal medical indications such as hypertension or placental abruption (2.3%), history of substance use disorder in remission (1.7%), or maternal cannabis use (1.6%) yielded lower rates of unexpected results compared with a recent substance use disorder (within the last 2 years). Solely on the basis of findings from unexpected test results, 42% of dyads were referred to child protective services, 30% of dyads had no documentation of maternal counseling during delivery hospitalization, and 31% did not receive breastfeeding counseling after an unexpected test; 22.8% had monitoring for neonatal opioid withdrawal syndrome. Postpartum, 26 (32.5%) were referred to substance use disorder treatment, 31 (38.8%) attended a postpartum mental health visit, and only 26 (32.5%) attended a postpartum visit. Fifteen individuals (18.8%) were readmitted in the year after delivery, all for substance-related medical complications. CONCLUSION: Unexpected positive toxicology results at delivery were uncommon, particularly when tests were sent for frequently used clinical rationales for testing, suggesting a need to revisit guidelines surrounding appropriateness of indications for toxicology testing. The poor maternal outcomes in this cohort highlight a missed opportunity for maternal connection to counseling and treatment in the peripartum period.
Asunto(s)
Síndrome de Abstinencia Neonatal , Trastornos Relacionados con Opioides , Lactante , Recién Nacido , Niño , Embarazo , Humanos , Femenino , Periodo Periparto , Estudios Retrospectivos , Placenta , Síndrome de Abstinencia Neonatal/diagnóstico , Trastornos Relacionados con Opioides/diagnóstico , Trastornos Relacionados con Opioides/epidemiología , Trastornos Relacionados con Opioides/tratamiento farmacológicoRESUMEN
One of the cornerstones of effective cancer treatment is early diagnosis. In this context, the identification of proteins that can serve as cancer biomarkers in bodily fluids ("liquid biopsies") has gained attention over the last decade. Plasma and serum fractions of blood are the most commonly investigated sources of potential cancer liquid biopsy biomarkers. However, the high complexity and dynamic range typical of these fluids hinders the sensitivity of protein detection by the most commonly used mass spectrometry technology (data-dependent acquisition mass spectrometry (DDA-MS)). Recently, data-independent acquisition mass spectrometry (DIA-MS) techniques have overcome the limitations of DDA-MS, increasing sensitivity and proteome coverage. In addition to DIA-MS, isolating extracellular vesicles (EVs) can help to increase the depth of serum/plasma proteome coverage by improving the identification of low-abundance proteins which are a potential treasure trove of diagnostic molecules. EVs, the nano-sized membrane-enclosed vesicles present in most bodily fluids, contain proteins which may serve as potential biomarkers for various cancers. Here, we describe a detailed protocol that combines DIA-MS and EV methodologies for discovering and validating early cancer biomarkers using blood serum. The pipeline includes size exclusion chromatography methods to isolate serum-derived extracellular vesicles and subsequent EV sample preparation for liquid chromatography and mass spectrometry analysis. Procedures for spectral library generation by DDA-MS incorporate methods for off-line peptide separation by microflow HPLC with automated fraction concatenation. Analysis of the samples by DIA-MS includes recommended protocols for data processing and statistical methods. This pipeline will provide a guide to discovering and validating EV-associated proteins that can serve as sensitive and specific biomarkers for early cancer detection and other diseases.
Asunto(s)
Vesículas Extracelulares , Neoplasias , Humanos , Biomarcadores de Tumor/metabolismo , Proteómica/métodos , Proteoma/metabolismo , Espectrometría de Masas/métodos , Neoplasias/diagnóstico , Neoplasias/metabolismo , Vesículas Extracelulares/metabolismoRESUMEN
MHC-I and MHC-II molecules are critical components of antigen presentation and T cell immunity to pathogens and cancer. The two monoclonal transmissible devil facial tumours (DFT1, DFT2) exploit MHC-I pathways to overcome immunological anti-tumour and allogeneic barriers. This exploitation underpins the ongoing transmission of DFT cells across the wild Tasmanian devil population. We have previously shown that the overexpression of NLRC5 in DFT1 and DFT2 cells can regulate components of the MHC-I pathway but not MHC-II, establishing the stable upregulation of MHC-I on the cell surface. As MHC-II molecules are crucial for CD4+ T cell activation, MHC-II expression in tumour cells is beginning to gain traction in the field of immunotherapy and cancer vaccines. The overexpression of Class II transactivator in transfected DFT1 and DFT2 cells induced the transcription of several genes of the MHC-I and MHC-II pathways. This was further supported by the upregulation of MHC-I protein on DFT1 and DFT2 cells, but interestingly MHC-II protein was upregulated only in DFT1 cells. This new insight into the regulation of MHC-I and MHC-II pathways in cells that naturally overcome allogeneic barriers can inform vaccine, immunotherapy and tissue transplant strategies for human and veterinary medicine.
Asunto(s)
Neoplasias Faciales , Marsupiales , Animales , Neoplasias Faciales/genética , Neoplasias Faciales/veterinaria , Neoplasias Faciales/patología , Antígenos de Histocompatibilidad Clase II , Péptidos y Proteínas de Señalización Intracelular , Marsupiales/genéticaRESUMEN
The identification of practical early diagnostic biomarkers is a cornerstone of improved prevention and treatment of cancers. Such a case is devil facial tumor disease (DFTD), a highly lethal transmissible cancer afflicting virtually an entire species, the Tasmanian devil (Sarcophilus harrisii). Despite a latent period that can exceed one year, to date DFTD diagnosis requires visual identification of tumor lesions. To enable earlier diagnosis, which is essential for the implementation of effective conservation strategies, we analyzed the extracellular vesicle (EV) proteome of 87 Tasmanian devil serum samples using data-independent acquisition mass spectrometry approaches. The antimicrobial peptide cathelicidin-3 (CATH3), released by innate immune cells, was enriched in serum EV samples of both devils with clinical DFTD (87.9% sensitivity and 94.1% specificity) and devils with latent infection (i.e., collected while overtly healthy, but 3-6 months before subsequent DFTD diagnosis; 93.8% sensitivity and 94.1% specificity). Although high expression of antimicrobial peptides has been mostly related to inflammatory diseases, our results suggest that they can be also used as accurate cancer biomarkers, suggesting a mechanistic role in tumorous processes. This EV-based approach to biomarker discovery is directly applicable to improving understanding and diagnosis of a broad range of diseases in other species, and these findings directly enhance the capacity of conservation strategies to ensure the viability of the imperiled Tasmanian devil population.
Asunto(s)
Vesículas Extracelulares , Neoplasias Faciales , Marsupiales , Animales , Péptidos Catiónicos Antimicrobianos , Detección Precoz del Cáncer , Vesículas Extracelulares/patología , Neoplasias Faciales/diagnóstico , Neoplasias Faciales/veterinaria , CatelicidinasRESUMEN
Devil facial tumour disease (DFTD) is a transmissible cancer that has circulated in the Tasmanian devil population for >25 years. Like other contagious cancers in dogs and devils, the way DFTD escapes the immune response of its host is a central question to understanding this disease. DFTD has a low major histocompatibility complex class I (MHC-I) expression due to epigenetic modifications, preventing host immune recognition of mismatched MHC-I molecules by T cells. However, the total MHC-I loss should result in natural killer (NK) cell activation due to the 'missing self'. Here, we have investigated the expression of the nonclassical MHC-I, Saha-UD as a potential regulatory or suppressive mechanism for DFTD. A monoclonal antibody was generated against the devil Saha-UD that binds recombinant Saha-UD by Western blot, with limited crossreactivity to the classical MHC-I, Saha-UC and nonclassical Saha-UK. Using this antibody, we confirmed the expression of Saha-UD in 13 DFTD tumours by immunohistochemistry (n = 15) and demonstrated that Saha-UD expression is heterogeneous, with 12 tumours showing intratumour heterogeneity. Immunohistochemical staining for the Saha-UD showed distinct patterns of expression when compared with classical MHC-I molecules. The nonclassical Saha-UD expression by DFTD tumours in vivo may be a mechanism for immunosuppression, and further work is ongoing to characterise its ligand on immune cells.
RESUMEN
The iconic Tasmanian devil (Sarcophilus harrisii) is endangered due to the transmissible cancer Devil Facial Tumour Disease (DFTD), of which there are two genetically independent subtypes (DFT1 and DFT2). While DFT1 and DFT2 can be differentially diagnosed using tumour biopsies, there is an urgent need to develop less-invasive biomarkers that can detect DFTD and distinguish between subtypes. Extracellular vesicles (EVs), the nano-sized membrane-enclosed vesicles present in most biofluids, represent a valuable resource for biomarker discovery. Here, we characterized the proteome of EVs from cultured DFTD cells using data-independent acquisition-mass spectrometry and an in-house spectral library of > 1500 proteins. EVs from both DFT1 and DFT2 cell lines expressed higher levels of proteins associated with focal adhesion functions. Furthermore, hallmark proteins of epithelial-mesenchymal transition were enriched in DFT2 EVs relative to DFT1 EVs. These findings were validated in EVs derived from serum samples, revealing that the mesenchymal marker tenascin-C was also enriched in EVs derived from the serum of devils infected with DFT2 relative to those infected with DFT1 and healthy controls. This first EV-based investigation of DFTD increases our understanding of the cancers' EVs and their possible involvement in DFTD progression, such as metastasis. Finally, we demonstrated the potential of EVs to differentiate between DFT1 and DFT2, highlighting their potential use as less-invasive liquid biopsies for the Tasmanian devil.
Asunto(s)
Biomarcadores de Tumor/sangre , Vesículas Extracelulares/metabolismo , Neoplasias Faciales/clasificación , Neoplasias Faciales/diagnóstico , Marsupiales/metabolismo , Proteoma/análisis , Tenascina/sangre , Animales , Diagnóstico Diferencial , Neoplasias Faciales/sangre , Espectrometría de Masas , Proteoma/metabolismoRESUMEN
PURPOSE: Downregulation of MHC class I (MHC-I) is a common immune evasion strategy of many cancers. Similarly, two allogeneic clonal transmissible cancers have killed thousands of wild Tasmanian devils (Sarcophilus harrisii) and also modulate MHC-I expression to evade anti-cancer and allograft responses. IFNG treatment restores MHC-I expression on devil facial tumor (DFT) cells but is insufficient to control tumor growth. Transcriptional co-activator NLRC5 is a master regulator of MHC-I in humans and mice but its role in transmissible cancers remains unknown. In this study, we explored the regulation and role of MHC-I in these unique genetically mis-matched tumors. METHODS: We used transcriptome and flow cytometric analyses to determine how MHC-I shapes allogeneic and anti-tumor responses. Cell lines that overexpress NLRC5 to drive antigen presentation, and B2M-knockout cell lines incapable of presenting antigen on MHC-I were used to probe the role of MHC-I in rare cases of tumor regressions. RESULTS: Transcriptomic results suggest that NLRC5 plays a major role in MHC-I regulation in devils. NLRC5 was shown to drive the expression of many components of the antigen presentation pathway but did not upregulate PDL1. Serum from devils with tumor regressions showed strong binding to IFNG-treated and NLRC5 cell lines; antibody binding to IFNG-treated and NRLC5 transgenic tumor cells was diminished or absent following B2M knockout. CONCLUSION: MHC-I could be identified as a target for anti-tumor and allogeneic immunity. Consequently, NLRC5 could be a promising target for immunotherapy and vaccines to protect devils from transmissible cancers and inform development of transplant and cancer therapies for humans.
Asunto(s)
Presentación de Antígeno/inmunología , Biomarcadores de Tumor/metabolismo , Neoplasias Faciales/inmunología , Regulación Neoplásica de la Expresión Génica , Antígenos de Histocompatibilidad Clase I/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Animales , Biomarcadores de Tumor/genética , Neoplasias Faciales/genética , Neoplasias Faciales/metabolismo , Neoplasias Faciales/patología , Antígenos de Histocompatibilidad Clase I/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Marsupiales , Transcriptoma , Células Tumorales CultivadasRESUMEN
Immune evasion is critical to the growth and survival of cancer cells. This is especially pertinent to transmissible cancers, which evade immune detection across genetically diverse hosts. The Tasmanian devil (Sarcophilus harrisii) is threatened by the emergence of Devil Facial Tumour Disease (DFTD), comprising two transmissible cancers (DFT1 and DFT2). The development of effective prophylactic vaccines and therapies against DFTD has been restricted by an incomplete understanding of how allogeneic DFT1 and DFT2 cells maintain immune evasion upon activation of tumour-specific immune responses. In this study, we used RNA sequencing to examine tumours from three experimental DFT1 cases. Two devils received a vaccine prior to inoculation with live DFT1 cells, providing an opportunity to explore changes to DFT1 cancers under immune pressure. Analysis of DFT1 in the non-immunised devil revealed a 'myelinating Schwann cell' phenotype, reflecting both natural DFT1 cancers and the DFT1 cell line used for the experimental challenge. Comparatively, immunised devils exhibited a 'dedifferentiated mesenchymal' DFT1 phenotype. A third 'immune-enriched' phenotype, characterised by increased PDL1 and CTLA-4 expression, was detected in a DFT1 tumour that arose after immunotherapy. In response to immune pressure, mesenchymal plasticity and upregulation of immune checkpoint molecules are used by human cancers to evade immune responses. Similar mechanisms are associated with immune evasion by DFTD cancers, providing novel insights that will inform modification of DFTD vaccines. As DFT1 and DFT2 are clonal cancers transmitted across genetically distinct hosts, the Tasmanian devil provides a 'natural' disease model for more broadly exploring these immune evasion mechanisms in cancer.
Asunto(s)
Neoplasias Faciales , Marsupiales , Vacunas , Animales , Neoplasias Faciales/terapia , Humanos , Inmunoterapia , VacunaciónRESUMEN
OBJECTIVE: To estimate the incidence of failed induction of labor and the associated patient risk factors. METHODS: We performed a case-control study from a cohort of nulliparous women who delivered between 39 and 41 weeks of gestation after an induction of labor in one of seven hospitals. Cases of failed induction were defined using the Obstetric Care Consensus criteria (ie, cesarean delivery performed in early labor [less than 6 cm dilatation] after at least 12 hours of oxytocin administration from membrane rupture). For each case of failed induction, the next four women who did not meet the criteria for failed induction of labor were selected for the control group, matched by hospital. We identified characteristics associated with failed induction of labor using a multivariable conditional logistic regression that was constructed with backward stepwise method for variable selection. RESULTS: Across the hospitals, 4,123 of 10,175 nulliparous women were induced (40.5%), of whom 82 had a failed induction of labor (2.0%). A total of 328 women were selected for the matched control group. Baseline characteristics were similar between the groups. Compared with women in the control group, women with a failed induction were more likely to have a delivery body mass index (BMI) of 40 or higher (28.0 vs 8.2%, P<.001), shorter height (mean 63.9 vs 64.8 inches, P=.01), and closed cervix on admission (41.5 vs 24.1%, P=.002). Factors significantly associated with induction failure in the multivariable model included: 1) delivery BMI (adjusted odds ratio [aOR] 7.93, 95% CI 3.48-18.09, for BMI 40 or higher relative to BMI lower than 30, 2) height in inches (aOR 0.89, 95% CI 0.80-0.98), and 3) number of centimeters dilated on admission 2 or more (aOR 0.30, 95% CI 0.14-0.65). CONCLUSION: Failed induction of labor occurs infrequently. Risk factors include shorter height, BMI 40 or higher, and cervical dilatation of less than 2 cm on admission. Even so, most women with these risk factors will not experience failed labor induction.
Asunto(s)
Trabajo de Parto Inducido/estadística & datos numéricos , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Embarazo , Factores de Riesgo , Insuficiencia del TratamientoRESUMEN
Devil Facial Tumour Disease (DFTD) is an emerging infectious disease that provides an excellent example of how diagnostic techniques improve as disease-specific knowledge is generated. DFTD manifests as tumour masses on the faces of Tasmanian devils, first noticed in 1996. As DFTD became more prevalent among devils, karyotyping of the lesions and their devil hosts demonstrated that DFTD was a transmissible cancer. The subsequent routine diagnosis relied on microscopy and histology to characterise the facial lesions as cancer cells. Combined with immunohistochemistry, these techniques characterised the devil facial tumours as sarcomas of neuroectodermal origin. More sophisticated molecular methods identified the origin of DFTD as a Schwann cell, leading to the Schwann cell-specific protein periaxin to discriminate DFTD from other facial lesions. After the discovery of a second facial cancer (DFT2), cytogenetics and the absence of periaxin expression confirmed the independence of the new cancer from DFT1 (the original DFTD). Molecular studies of the two DFTDs led to the development of a PCR assay to differentially diagnose the cancers. Proteomics and transcriptomic studies identified different cell phenotypes among the two DFTD cell lines. Phenotypic differences were also reflected in proteomics studies of extracellular vesicles (EVs), which yielded an early diagnostic marker that could detect DFTD in its latent stage from serum samples. A mesenchymal marker was also identified that could serve as a serum-based differential diagnostic. The emergence of two transmissible cancers in one species has provided an ideal opportunity to better understand transmissible cancers, demonstrating how fundamental research can be translated into applicable and routine diagnostic techniques.
RESUMEN
Immune checkpoint immunotherapy is a pillar of human oncology treatment with potential for non-human species. The first checkpoint immunotherapy approved for human cancers targeted the CTLA4 protein. CTLA4 can inhibit T cell activation by capturing and internalizing CD80 and CD86 from antigen presenting cells, a process called trans-endocytosis. Similarly, CD28 can capture CD80 and CD86 via trogocytosis and retain the captured ligands on the surface of the CD28-expressing cells. The wild Tasmanian devil (Sarcophilus harrisii) population has declined by 77% due to transmissible cancers that evade immune defenses despite genetic mismatches between the host and tumors. We used a live cell-based assay to demonstrate that devil CTLA4 and CD28 can capture CD80 and CD86. Mutation of evolutionarily conserved motifs in CTLA4 altered functional interactions with CD80 and CD86 in accordance with patterns observed in other species. These results suggest that checkpoint immunotherapies can be translated to evolutionarily divergent species.
Asunto(s)
Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Antígenos CD28/metabolismo , Antígeno CTLA-4/metabolismo , Marsupiales/inmunología , Secuencias de Aminoácidos/genética , Animales , Antígenos CD28/antagonistas & inhibidores , Células CHO , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/genética , Células Cultivadas , Clonación Molecular , Cricetulus , Especies en Peligro de Extinción , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Microscopía Intravital , Marsupiales/metabolismo , Mutación , TrogocitosisRESUMEN
Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 coinfection are high. DFT1 gradually accumulates copy number variants (CNVs), and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability, and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche.
Asunto(s)
Neoplasias Faciales/veterinaria , Marsupiales/genética , Enfermedades de los Animales/epidemiología , Enfermedades de los Animales/genética , Enfermedades de los Animales/transmisión , Animales , Variaciones en el Número de Copia de ADN , Evolución Molecular , Neoplasias Faciales/epidemiología , Neoplasias Faciales/genética , Femenino , Inestabilidad Genómica , Masculino , Filogenia , Tasmania/epidemiología , Acortamiento del Telómero/genética , Células Tumorales CultivadasRESUMEN
Around 40% of humans and Tasmanian devils (Sarcophilus harrisii) develop cancer in their lifetime, compared to less than 10% for most species. In addition, devils are affected by two of the three known transmissible cancers in mammals. Immune checkpoint immunotherapy has transformed human medicine, but a lack of species-specific reagents has limited checkpoint immunology in most species. We developed a cut-and-paste reagent development system and used the fluorescent fusion protein system to show that immune checkpoint interactions are conserved across 160,000,000 years of evolution, CD200 is highly expressed on transmissible tumor cells, and coexpression of CD200R1 can block CD200 surface expression. The system's versatility across species was demonstrated by fusing a fluorescent reporter to a camelid-derived nanobody that binds human programmed death ligand 1. The evolutionarily conserved pathways suggest that naturally occurring cancers in devils and other species can be used to advance our understanding of cancer and immunological tolerance.
Asunto(s)
Neoplasias Faciales , Marsupiales , Animales , Neoplasias Faciales/metabolismo , Neoplasias Faciales/patología , Evasión Inmune , InmunoterapiaRESUMEN
OBJECTIVE: Educating medical students about buprenorphine may lessen barriers to providing treatment for opioid use disorder (OUD) by addressing stigma, removing the need to complete training while practicing, and normalizing it as a pharmacological option. We conducted a needs assessment to measure student interest in buprenorphine waiver training and pilot tested an online course with an in-person discussion for feasibility and acceptability. METHODS: All 2019 graduating students were surveyed to assess interest in completing buprenorphine waiver training and understand in which format they preferred to receive the training. Interested students received information about a free online buprenorphine waiver course and an optional in-person case discussion with a faculty member. Baseline and follow-up surveys were used to assess the intervention. RESULTS: Out of 228 students contacted, 173 (75.9%) responded to at least 1 survey. Of the 228, 62 (27.2%) responded to the initial survey asking students about receiving buprenorphine waiver training. The 166 non-responding students were sent a second survey, and 111 (66.9%) students responded. Of those 111, 29 (26.1%) indicated they forgot to respond to the first survey, and 24 (21.6%) did not see the survey. Of the 62 interested students, 41 students (66.1%) wanted a combination of online and in-person training. Of the 62, 30 (48.4%) interested students completed the online course and 10 (16.1%) attended the case discussion. While not significantly different, a higher proportion of students (88.9%) indicated being likely to prescribe buprenorphine after attending the case discussion than after completing the online course only (69.2%). CONCLUSIONS: This assessment suggested that most of the medical students are willing to complete a buprenorphine waiver course. Feedback indicated an in-person component could increase future prescribing more than an online-only curriculum, and additional advertising could result in higher participation.
RESUMEN
Devil facial tumor disease (DFTD) encompasses two independent transmissible cancers that have killed the majority of Tasmanian devils. The cancer cells are derived from Schwann cells and are spread between devils during biting, a common behavior during the mating season. The Centers for Disease Control and Prevention (CDC) defines a parasite as "An organism that lives on or in a host organism and gets its food from, or at, the expense of its host." Most cancers, including DFTD, live within a host organism and derive resources from its host, and consequently have parasitic-like features. Devil facial tumor disease is a transmissible cancer and, therefore, DFTD shares one additional feature common to most parasites. Through direct contact between devils, DFTD has spread throughout the devil population. However, unlike many parasites, the DFTD cancer cells have a simple lifecycle and do not have either independent, vector-borne, or quiescent phases. To facilitate a description of devil facial tumor disease, this review uses life cycles of parasites as an analogy.
RESUMEN
The Tasmanian devil (Sarcophilus harrisii) is the only mammalian species known to be affected by multiple transmissible cancers. Devil facial tumours 1 and 2 (DFT1 and DFT2) are independent neoplastic cell lineages that produce large, disfiguring cancers known as devil facial tumour disease (DFTD). The long-term persistence of wild Tasmanian devils is threatened due to the ability of DFTD cells to propagate as contagious allografts and the high mortality rate of DFTD. Recent studies have demonstrated that both DFT1 and DFT2 cancers originated from founder cells of the Schwann cell lineage, an uncommon origin of malignant cancer in humans. This unprecedented finding has revealed a potential predisposition of Tasmanian devils to transmissible cancers of the Schwann cell lineage. In this review, we compare the molecular nature of human Schwann cells and nerve sheath tumours with DFT1 and DFT2 to gain insights into the emergence of transmissible cancers in the Tasmanian devil. We discuss a potential mechanism, whereby Schwann cell plasticity and frequent wounding in Tasmanian devils combine with an inherent cancer predisposition and low genetic diversity to give rise to transmissible Schwann cell cancers in devils on rare occasions.
Asunto(s)
Neoplasias Faciales/veterinaria , Marsupiales , Animales , Neoplasias Faciales/genética , Neoplasias Faciales/patología , Humanos , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/veterinaria , Células de Schwann/fisiologíaRESUMEN
Devil facial tumour disease (DFTD) comprises two genetically distinct transmissible cancers (DFT1 and DFT2) endangering the survival of the Tasmanian devil (Sarcophilus harrisii) in the wild. DFT1 first arose from a cell of the Schwann cell lineage; however, the tissue-of-origin of the recently discovered DFT2 cancer is unknown. In this study, we compared the transcriptome and proteome of DFT2 tumours to DFT1 and normal Tasmanian devil tissues to determine the tissue-of-origin of the DFT2 cancer. Our findings demonstrate that DFT2 expresses a range of Schwann cell markers and exhibits expression patterns consistent with a similar origin to the DFT1 cancer. Furthermore, DFT2 cells express genes associated with the repair response to peripheral nerve damage. These findings suggest that devils may be predisposed to transmissible cancers of Schwann cell origin. The combined effect of factors such as frequent nerve damage from biting, Schwann cell plasticity and low genetic diversity may allow these cancers to develop on rare occasions. The emergence of two independent transmissible cancers from the same tissue in the Tasmanian devil presents an unprecedented opportunity to gain insight into cancer development, evolution and immune evasion in mammalian species.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Faciales/veterinaria , Marsupiales/fisiología , Proteoma/análisis , Células de Schwann/patología , Transcriptoma , Animales , Biomarcadores de Tumor/genética , Neoplasias Faciales/genética , Neoplasias Faciales/metabolismo , Neoplasias Faciales/patología , Humanos , Células de Schwann/metabolismoRESUMEN
Emerging infectious diseases are rising globally and understanding host-pathogen interactions during the initial stages of disease emergence is essential for assessing potential evolutionary dynamics and designing novel management strategies. Tasmanian devils (Sarcophilus harrisii) are endangered due to a transmissible cancer-devil facial tumour disease (DFTD)-that since its emergence in the 1990s, has affected most populations throughout Tasmania. Recent studies suggest that devils are adapting to the DFTD epidemic and that disease-induced extinction is unlikely. However, in 2014, a second and independently evolved transmissible cancer-devil facial tumour 2 (DFT2)-was discovered at the d'Entrecasteaux peninsula, in south-east Tasmania, suggesting that the species is prone to transmissible cancers. To date, there is little information about the distribution, epidemiology and effects of DFT2 and its interaction with DFTD. Here, we use data from monitoring surveys and roadkills found within and adjacent to the d'Entrecasteaux peninsula to determine the distribution of both cancers and to compare their epidemiological patterns. Since 2012, a total of 51 DFTD tumours have been confirmed among 26 individuals inside the peninsula and its surroundings, while 40 DFT2 tumours have been confirmed among 23 individuals, and two individuals co-infected with both tumours. All devils with DFT2 were found within the d'Entrecasteaux peninsula, suggesting that this new transmissible cancer is geographically confined to this area. We found significant differences in tumour bodily location in DFTD and DFT2, with non-facial tumours more commonly found in DFT2. There was a significant sex bias in DFT2, with most cases reported in males, suggesting that since DFT2 originated from a male host, females might be less susceptible to this cancer. We discuss the implications of our results for understanding the epidemiological and evolutionary interactions of these two contemporary transmissible cancers and evaluating the effectiveness of potential management strategies.