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Tumors often target dendritic cells (DCs) to evade host immune surveillance. DC injury is reported in many rodent and human tumors but seldom in tumors of other mammals. Canine transmissible venereal tumor (CTVT), a unique and spontaneous cancer transmitted by means of viable tumor cells. CTVT causes manifold damage to monocyte-derived DCs. This ca...
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... In the regression phase, there is a high concentration of interleukin-6 and interferonγ, antagonizing the effects of transforming growth factorβ and restoring NK activity (Hsiao et al., 2004;Liu et al., 2008), characterizing the regression phase (Chiang et al., 2013). ...
Cancer is a group of complex diseases resulting from the accumulation of genetic and epigenetic changes affecting control and activity of several genes, especially those involved in cell differentiation and growth processes, leading to an abnormal proliferation. When the disease reaches an advanced stage, cancer can lead to metastasis in other organs. Interestingly, recent studies have shown that some types of cancer spread not only through the body, but also can be transmitted among individuals. Therefore, these cancers are known as transmissible tumors. Among the three types of transmissible tumors that occur in nature, the canine transmissible venereal tumor (CTVT) is known as the oldest cancer in the world, since it was originated from a single individual 11 000 years ago. The disease has a worldwide distribution, and its occurrence has been documented since 1810. The CTVT presents three types of cytomorphological classification: lymphocytoid type, mixed type, and plasmacytoid type, the latter being chemoresistant due to overexpression of the ABCB1 gene, and consequently increase of the P‐glycoprotein. More knowledge about the epidemiology and evolution of CTVT may help to elucidate the pathway and form of the global spread of the disease.
... The rapid growth of lesions is related to mechanisms of evasion of immunological recognition through regulation of expression of MHC class I and II molecules, reducing the action of dendritic cells and Tcytotoxic response. This phase tends to last between three to six months in adult and immunocompetent dogs (2,3,5,8,9) . TVCT tends to be more aggressive in older dogs, puppies, and immunosuppressed dogs, with progressive or disseminated disease. ...
The canine transmissible venereal tumor (TVTC) is a neoplasm transmitted mainly through copulation and with a high incidence in stray dogs in Brazil. In the process of tumor evolution of TVTC, the progression, stationary and regression phases are recognized. The host immunity is related to the disease’s biological behavior, however, spontaneous regression observation in cases of naturally occurring TVTC is uncommon. A canine patient was attended, after beeing rescued from the street, due to an ulcerated mass in the external genitália and tick infestation. Cytopathological examination, which diagnosed TVTC, and laboratory tests that showed mild anemia and severe thrombocytopenia were performed. In view of the impossibility of carrying out other exams, it was made the presumptive diagnosis of canine monocytic ehrlichiosis (CME), and treatment was instituted. During follow-up it was observed quick improvement in clinical signs and laboratory changes, as well as a reduction in tumor mass. A new cytopathological evaluation was carried out, and was verified increase in mature lymphocytes and plasmocytes in the midst of the tumor cells, finding compatible with the stationary phase of the disease. From that moment on, it was decided to perform only clinical and cytopathological follow-up. In the following evaluations, continuous clinical remission and cytopathological findings compatible with those described in the regression phase were observed, until its complete remission. It is considered that the improvement in the general health of the patient after the treatment of CME is related to the spontaneous regression of TVTC, and that simultaneous performance of serial clinical and cytopathological exams may be feasible and useful for monitoring the stages of evolution of TVTC.
... O rápido crescimento das lesões está relacionado aos mecanismos de evasão ao reconhecimento imunológico, através da regulação da expressão de moléculas MHC classes I e II, reduzindo a ação de células dendríticas e da resposta Tcitotóxica. Essa fase tende a durar entre três e seis meses em cães adultos e imunocompetentes (2,3,5,8,9) . Em cães idosos, filhotes e aqueles imunossuprimidos, o comportamento biológico do TVCT tende a ser mais agressivo, com a manifestação de quadros progressivos ou disseminados da doença, podendo ocorrer focos metastáticos regionais ou à distância, e não evoluir para as próximas fases observadas em cães com boa resposta imunológica (3,7,10,11) . ...
O tumor venéreo transmissível canino (TVTC) é uma neoplasia transmitida principalmente através da cópula, com elevada incidência em cães errantes no Brasil. No processo de evolução tumoral do TVTC, são reconhecidas as fases de progressão, estacionária e de regressão. O estado imunológico do hospedeiro está relacionado ao comportamento biológico da doença, contudo, a observação de regressão espontânea em casos de TVTC de ocorrência natural é incomum. Foi atendida uma paciente canina, resgatada da rua, por apresentar massa ulcerada na genitália externa e infestação por carrapatos. Foram realizados exame citopatológico, que diagnosticou TVTC, e exames laboratoriais que evidenciaram anemia discreta e grave trombocitopenia. Com isso e diante da impossibilidade de realizar outros exames, foi também estabelecido o diagnóstico presuntivo de erlichiose monocítica canina (EMC) e instituído tratamento para a hemoparasitose. Durante o acompanhamento, foi observada rápida melhora dos sinais clínicos e das alterações laboratoriais, bem como a redução espontânea da massa tumoral. Em sequência, foi realizada nova avaliação citopatológica do TVTC e verificado o aumento quantitativo de linfócitos maduros e plasmócitos, em meio as células tumorais, achado compatível com a fase estacionária da doença. A partir desse momento, optou-se por realizar apenas acompanhamento clínico e avaliação citopatológica da neoplasia. Foram observados contínua remissão clínica e achados microscópicos compatíveis com a fase de regressão do tumor, até sua remissão completa. Pondera-se que a melhora na saúde geral da paciente após o tratamento da EMC esteja relacionada à regressão espontânea do TVTC, e que realização simultânea de exames clínico e citopatológico seriados pode ser viável e útil ao acompanhamento das fases de evolução do TVTC.
Palavras-chave: cães; células redondas; citopatologia; ehrlichiose; neoplasia.
... Thus, this study intended to determine the possible details or mechanisms between host immunity and CTVT, a tumour that can be grown in any immunocompetent dog. CTVTs usually spontaneously regress (the SR phase) after progressive growth (the P phase), during which the tumours secrete a high concentration of TGF-β, which suppresses the expression of MHC class I and II molecules in tumours [8]. These inhibitory immune activities describe the rapid tumour growth that occurs during the P phase. ...
Background
Canine transmissible venereal tumours (CTVTs) can cross the major histocompatibility complex barrier to spread among dogs. In addition to the transmissibility within canids, CTVTs are also known as a suitable model for investigating the tumour–host immunity interaction because dogs live with humans and experience the same environmental risk factors for tumourigenesis. Moreover, outbred dogs are more appropriate than inbred mice models for simulating the diversity of human cancer development. This study built a new model of CTVTs, known as MCTVTs, to further probe the shaping effects of immune stress on tumour development. For xenotransplantation, CTVTs were first injected and developed in immunodeficient mice (NOD.CB17-Prkdcscid/NcrCrl), defined as XCTVTs. The XCTVTs harvested from NOD/SCID mice were then inoculated and grown in beagles and named mouse xenotransplantation of CTVTs (MCTVTs).
Results
After the inoculation of CTVTs and MCTVTs into immune-competent beagle dogs separately, MCTVTs grew faster and metastasized more frequently than CTVTs did. Gene expression profiles in CTVTs and MCTVTs were analysed by cDNA microarray to reveal that MCTVTs expressed many tumour-promoting genes involved in chronic inflammation, chemotaxis, extracellular space modification, NF-kappa B pathways, and focal adhesion. Furthermore, several well-known tumour-associated biomarkers which could predict tumour progression were overexpressed in MCTVTs.
Conclusions
This study demonstrated that defective host immunity can result in gene instability and enable transcriptome reprogramming within tumour cells. Fast tumour growth in beagle dogs and overexpression of tumour-associated biomarkers were found in a CTVT strain previously established in immunodeficient mice. In addition, dysregulated interaction of chronic inflammation, chemotaxis, and extracellular space modification were revealed to imply the possibly exacerbating mechanisms in the microenvironments of these tumours. In summary, this study offers a potential method to facilitate tumour progression and provide a niche for discovering tumour-associated biomarkers in cancer research.
... CTVT appears to have a complex interaction with the immune system of the host, which has evolved over the long life of the tumour. According to current models of the interaction of CTVT with host immune cells, tumour cells lack MHC molecules and release transforming growth factor-p (TGF-9), which suppresses T cells and Natural Killer (NK) cells during the growth phase (Hsiao et al., 2004;Liu et al., 2008;Tez and Kanca, 2018). Although, Tumour infiltrating lymphocytes (TlLs) produce high levels of lnterferon (lFN)-γ which promotes MHC expression, lFN-y activity is inhibited by TGF-P. ...
... The levels of (lFN)-γ and MHC expression increase, leading to cytotoxicity by T cells and NK cells (Tez and Kanca, 2018). The immunologic interactions between host and CTVT involving TGF-, IL-6, IFN-ƴ, MHC expression and DC activities makes CTVT, a reasonable model for the study of the immunologic interaction between host and cancers (Hsiao et al., 2004;Liu et al., 2008). Although CTVT samples have been subjected to immune-histochemical analysis for several tumour markers, including keratin, vimentin, desmin, CD3, αsmooth muscle actin, immunoglobulins G and IgM, λlight chains, κ-light chains, lysozyme, ACM1, and A-1antitrypsin, its origin and immune-phenotype remain vague (Mukaratirwa and Gruys, 2003;Zayas et al., 2019). ...
Canine transmissible venereal tumour (CTVT) is a contagious tumour of dogs, transmitted via coitus or coital behaviour which in some cases spreads by metastasis but primarily, CTVT appears as reddish soft nodules or papilla, protruding from the surface of the penis, prepuce, vagina and vulva but sometimes appears in locations outside the genitals. There was early evidence of CTVT more than 10,000 years ago and this disease has been reported in at least 90 countries across the continents of the world, especially in third world countries, where there are high numbers of stray dogs. CTVT natural infection occurs only in dogs but this disease can be experimentally inoculated into other species of the family, Canidae. Macroscopic lesions are mainly cauliflower-like, papillary or multilobulated which most times immunologically regress but occasionally may progress to malignancy. Due to the uniqueness of this tumour in its transmission, broad geographical, sex and breed distribution and because CTVT is the world's oldest known neoplasm, this disease has attracted great global research interest. Diagnostic techniques including clinical examination, histopathology, cytology, immunohistochemistry, cytogenetic, computer tomographic imaging and molecular diagnostic methods such as Polymerase chain reaction (PCR) have been invaluable in the diagnosis of CTVT. Therefore, this review casts a searchlight on the aetiology, structure, epidemiology, disease status, transmission, pathogenesis, molecular biology, macroscopic and microscopic pathology, immunology, diagnosis, prevention, treatment and control of this unique tumour.
... It is usually transmitted to genital organs during sexual intercourse but can affect the skin via the direct implantation of tumor cells during contact between skin and tumor masses. Transplantation occurs when intact host tumor cells lose the expression of MHC class I and II molecules, enable-ng transposition of the tissue to a healthy animal by contact between skin and damaged mucosa [21]. Tumor could only be transferred between healthy animals that shared the same MHC or into immunocompromised recipients, as the tumor cells induce an immune response in healthy recipients. ...
Tumor is an excessive and uncoordinated proliferation of cells with no useful function. It is a common cause of death in dog. Canine transmissible venereal tumor (CTVT) is a tumor of the dogs and other canines that mainly affect the external genitalia and is transmitted from animal to animal through sexual contacts, but may also be passed on as the dog bites, sniffs or licks the tumor affected areas. It is the only known naturally occurring tumor that can be transplanted as an allograft across major histocompatibility (MHC) barriers within the same species, and even to other members of the canine family, such as foxes, coyotes and wolves. The tumor is usually seen in young, sexually active dogs from an environment with high concentration of free-roaming dogs with uncontrolled reproduction. The progression of this tumor is unique in that, it follows a predictable growth pattern. Clinical signs of this disease include friable nodule in the genitalia, accompanied by hemorrhagic discharge. Definitive diagnosis is reached by cytological and histopathological findings. It is many times, self-limiting. As a form of treatment chemotherapy, surgery, radiotherapy and immunotherapy may be used. Cancer chemotherapy is the best option.
... However, unlike the low diversity of MHC I in the Tasmanian devils, CTVS cells show downregulation of MHC I and a complete absence of MHC II, thus evading host immune recognition, permitting successful transmission and progression [73]. CTVS also causes severe damage to monocyte-derived dendritic cells, which has been proposed as another of its mechanisms for evading host immunity [74]. ...
Humans are not the only species to spontaneously develop metastatic cancer as cases of metastasis have been reported in a wide range of animals, including dinosaurs. Mouse models have been an invaluable tool in experimental and clinical metastasis research, with the use of genetically-engineered mouse models that spontaneously develop metastasis or ectopic/orthotopic transplantation of tumour cells to wildtype or immunodeficient mice being responsible for many key advances in our understanding of metastasis. However, are there other species that can also be relevant models? Similarities to humans in terms of environmental exposures, life-span, genetics, histopathology and available therapeutics are all factors that can be considered when looking at species other than the laboratory mouse. This review will explore the occurrence of metastasis in multiple species from a variety of domestic, captive and free-living veterinary cases to assist in identifying potential alternative experimental and clinical research models relevant to humans.
... Elle est sécrétée par les lymphocytes infiltrant la tumeur et possède un effet antagoniste au TGF-β permettant ainsi de rétablir l'activité des NK, des cellules dendritiques et d'induire l'expression des CMH. Ces éléments permettent le passage de la phase de progression à la phase de régression de la TVTC comme cela a été décrit(Hsiao et al., 2004 ;Liu et al., 2008). Il est ainsi apparu que l'IL-6 était la substance mise en évidence par Hsiao en 2002 et qu'elle constituait l'élément essentiel de la transition entre les deux phases de la tumeur. ...
... Les mastocytes seraient également davantage représentés lors de la deuxième phase avec un rôle dans l'angiogenèse(Mukaratirwa et al., 2006). Lors de la progression de la tumeur, il y a une diminution de 40 % des monocytes (desquels dérivent les cellules dendritiques) avec les conséquences sur l'immunité qui s'en suivent(Liu et al., 2008). Il a été mis en évidence quel'augmentation de production d'IL-6 était en lien avec activation des gènes TIMD-4, GPNMB et PLTP durant la phase de régression de cette tumeur. ...
À ce jour trois tumeurs naturellement transmissibles circulant d’un individu à un autre, ont été décrites. Il s’agit de la tumeur vénérienne transmissible canine (ou sarcome de Sticker), de la tumeur faciale transmissible du diable de Tasmanie et de la néoplasie disséminée des bivalves (ou leucémie des mollusques). La tumeur vénérienne transmissible canine est la plus ancienne lignée cellulaire connue. Elle circule au sein de l’espèce canine (Canis lupus familiaris) depuis plusieurs milliers d’années et dans le monde entier. La transmission intervient majoritairement lors de l’accouplement. Cette tumeur, d’origine histiocytaire supposée, affecte donc en premier lieu les organes génitaux des deux sexes. La tumeur faciale transmissible du diable de Tasmanie a, quant à elle, une origine plus récente (une vingtaine d’années environ) et affecte les diables de Tasmanie (Sarcophilus harrisii) sur l’île du même nom. Cette tumeur, supposée dérivée des cellules de Schwann, est transmise par morsure au niveau de la face. La néoplasie disséminée des bivalves aurait, elle, émergé il y a une quarantaine d’années sur la côte ouest de l’océan Atlantique, dans l’espèce Mya arenaria (Mye commune). Cette tumeur d’origine hémocytaire supposée a récemment été décrite dans d’autres espèces de bivalves. Les individus s’infecteraient en filtrant de l’eau de mer contaminée par des cellules tumorales. Dans ces trois exemples, divers mécanismes d’échappement des tumeurs aux défenses immunitaires de l’hôte permettent la colonisation de nouveaux hôtes. Dans le cadre de la tumeur vénérienne transmissible, des signaux paracrines et autocrines permettent le passage d’une phase de progression de la tumeur à une phase de régression jusqu’à une possible guérison,en modulant l’expression du complexe majeure d’histocompatibilité (CMH). L’épigénétique joue un rôle prépondérant dans la tumeur faciale transmissible du diable de Tasmanie en limitant l’expression du CMH par les cellules tumorales, permettant la progression de la tumeur au sein d’un nouvel individu jusqu’à sa mort. Concernant les néoplasies disséminées des bivalves, un système de reconnaissance immunitaire de type CMH semble impliqué dans la progression de la maladie et dans l’infection de nouveaux individus, avec parfois des transmissions interspécifiques. Les micro- et macro-environnements tumoraux jouent donc un rôle prépondérant dans le développement de ces tumeurs transmissibles qui constituent des modèles originaux d’étude du cancer. Ce travail de synthèse présente ces trois tumeurs et discute de leurs similitudes et différences.
... The treatment has almost no toxicity, but the immune responses were transient and the clinical outcome is not particularly successful. This may be partly due to degradation of DCs after injection, or inhibition of DC function by certain tumors [5,6], and various suppressor cells in the tumor environment [7]. Three improvements are required to enhance DC-based cancer immunotherapy. ...
Although dendritic cell (DC)-based immunotherapy shows little toxicity, improvements should be necessary to obtain satisfactory clinical outcome. Using interferon-gamma injection along with DCs, we previously obtained significant clinical responses against small or early stage malignant tumors in dogs. However, improvement was necessary to be effective to largely developed or metastatic tumors. To obtain effective methods applicable to those tumors, we herein used a DC-targeting Toll-like receptor ligand, h11c, and examined the therapeutic effects in murine subcutaneous and visceral tumor models and also in the clinical treatment of canine cancers. In murine experiments, most and significant inhibition of tumor growth and extended survival was observed in the group treated with the combination of h11c-activated DCs in combination with interferon-gamma and a cyclooxygenase2 inhibitor. Both monocytic and granulocytic myeloid-derived suppressor cells were significantly reduced by the combined treatment. Following the successful results in mice, the combined treatment was examined against canine cancers, which spontaneously generated like as those in human. The combined treatment elicited significant clinical responses against a nonepithelial malignant tumor and a malignant fibrous histiocytoma. The treatment was also successful against a bone-metastasis of squamous cell carcinoma. In the successful cases, the marked increase of tumor-responding T cells and decrease of myeloid-derived suppressor cells and regulatory T cells was observed in their peripheral blood. Although the combined treatment permitted the growth of lung cancer of renal carcinoma-metastasis, the marked elevated and long-term maintaining of the tumor-responding T cells was observed in the patient dog. Overall, the combined treatment gave rise to emphatic amelioration in DC-based cancer therapy.
... CTVT can be transplanted allogenically within a healthy dog population by transferring viable cells (Yang and Jones 1973). Tumor cells can be transplanted when intact host tumor cells lose their expression of major histocompatibility complex (MHC) class I and II molecules, which enables transplant of the tumor cells to a healthy animal by direct (mating) or mucosal (licking of external genital organs) contact (Murgia et al. 2006, Liu et al. 2008. ...
Matrix metalloproteases (MMPs) are endogenous proteases that are responsible for degradation of extracellular matrix (ECM) proteins and cell surface antigens. The breakdown of ECM participates in the local invasion and distant metastases of malignant tumors. Canine transmissible venereal tumor (CTVT) is a naturally occurring contagious round cell neoplasm of dogs that affects mainly the external genitalia of both sexes. CTVT generally is a locally invasive tumor, but distant metastases also are common in puppies and immunocompromised dogs. We investigated the immune expressions and activities of MMP-2 and MMP-9 in CTVT. The presence of these enzymes in tumor cells and tissue homogenates was demonstrated by immunohistochemistry and western blotting. We used gelatin substrate zymography to evaluate the activities of MMP-2 and MMP-9 enzymes in tumor homogenates. We found that tumor cells expressed both MMP-2 and MMP-9. Electrophoretic bands corresponding to MMP-9 and MMP-2 were identified in immunoblots and clear bands that corresponded to the active forms of MMP-2 and MMP-9 also were detected in gelatin zymograms. Our study is the first detailed documentation of MMPs in CTVT.
