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1.
Cancer stem‐like cells (CSCs)/cancer‐initiating cells (CICs) are a small subpopulation of cancer cells that are responsible for the initiation, recurrence and metastasis of cancer. We previously demonstrated that, using the Hoechst 33342 dye‐based side population technique, CSCs/CICs in canine lung adenocarcinoma cell line exist. In this study, as CSCs/CICs are known to form spheres in anchorage‐independent environment in vitro, we evaluated the stemness of spheroid cells derived from canine lung adenocarcinoma and osteosarcoma cells by expression of stemness markers, and investigated radioresistance. Spheroid cells showed greater expression of stemness markers Oct‐4 and CD133 gene than those of adherent‐cultured cells. In nude mouse xenograft models, spheroid cells showed higher tumourigenic ability than adherent‐cultured cells. In addition, spheroid cells showed significantly resistant against radioactivity as compared with adherent‐cultured cells. These results suggest that spheroid cells could possess stemness and provide a CSCs/CICs research tool to investigate CSCs/CICs of canine tumour cells.  相似文献   

2.
ENMD‐2076 is an aurora kinase inhibitor that also has multi‐target tyrosine kinase inhibitor properties. In this study, the mRNA and the protein expression of aurora‐A and aurora‐B were evaluated in three canine mast cell tumour cell lines. Dose‐dependent cytotoxicity was seen in the cells treated, and it affected the cell cycle with cells in the G2/M phase being selectively killed. The cells were also evaluated for radiosensitivity with/without ENMD‐2076, and radiosensitization was seen after 3 Gy and 6 Gy exposures with ENMD‐2076 for 48 h. Protein expression of caspase‐3 was gradually increased, and the expression intensity was highest at 24 h post irradiation in cells without ENMD‐2076 treatment, which indicates that radiation exposure with ENMD‐2076‐induced cell death faster than radiation treatment alone. Our study results suggest the potential usefulness of treating canine mast cell tumours with aurora kinase inhibitors alone or in conjunction with radiation therapy.  相似文献   

3.
To determine the influence of the transplantation site of canine osteosarcoma (OS) cell lines on tumour growth and pulmonary metastasis, three OS cell lines were transplanted into nude mice via subcutaneous (SC), intratibial (IT) or intravenous (IV) injection. IT‐xenografts exhibited greater potential for developing primary masses and pulmonary metastasis than SC‐xenografts. In IT and IV xenografts, lung micrometastases along with phosphorylated ezrin–radixin–moesin (p‐ERM) overexpression were found in mice xenografted with HMPOS and OOS cells after 1 week and metastasis was found with decreased p‐ERM expression at later time points. The expression of ezrin and p‐ERM in the primary tumours of IT‐xenografted mice was higher than those in SC‐xenografted mice with HMPOS and OOS cells. The results suggest that the orthotopic transplantation site plays an important role in the spontaneous metastasis of canine OS and that ezrin phosphorylation may be involved in the early metastatic mechanism of canine OS cells.  相似文献   

4.
Adrenergic receptor (AR) expression has been demonstrated at several sites of primary and metastatic tumour growth and may influence proliferation, survival, metastasis and angiogenesis. AR antagonists like propranolol and carvedilol inhibit proliferation, induce apoptosis and synergize with chemotherapy agents in some cancers. Radiation resistance is mediated in many cells by upregulation of pro‐survival pathways, which may be influenced by ARs. Studies evaluating AR antagonists combined with radiation are limited. The purpose of this study was to determine the effect of propranolol and carvedilol on viability and radiosensitivity in sarcoma cell lines. The hypothesis was that propranolol and carvedilol would increase radiosensitivity in four primary bone sarcoma cell lines. Single agent propranolol or carvedilol inhibited cell viability in all cell lines in a concentration‐dependent manner. The mean inhibitory concentrations (IC50) for carvedilol were approximately 4‐fold lower than propranolol and may be clinically relevant in vivo. Immunoblot analysis confirmed AR expression in both human and canine sarcoma cell lines; however, there was no correlation between baseline AR protein expression and radiosensitivity. Short duration treatment with carvedilol and propranolol did not significantly affect clonogenic survival. Prolonged exposure to propranolol and carvedilol significantly decreased the surviving fraction of canine osteosarcoma cells after 3Gy radiation. Based on our results and possible in vivo activity in dogs, further studies investigating the effects of carvedilol on sarcoma are warranted.  相似文献   

5.
Non‐adherent, 3‐dimensional sphere formation is used as an in vitro surrogate to evaluate cellular potential for tumour initiation and self‐renewal. To determine if a shared molecular program underlies the capacity for sphere formation by cells originating from diverse tumour types, we characterized molecular and functional properties of 10 independent cell lines derived from 3 ontogenetically distinct dog cancers: hemangiosarcoma, osteosarcoma and glial brain tumours. Genome‐wide gene expression profiling identified tumour‐of‐origin‐dependent patterns of adjustment to sphere formation in a uniform culture condition. However, expression of the stem/progenitor markers CD34 and CD117, resistance to cytotoxic drugs and dye efflux (side population assays) showed no association with these gene expression profiles. Instead, primary sphere‐forming capacity was inversely correlated with the ability to reform secondary spheres, regardless of tumour ontogeny. Primary sphere formation seemed to be proportional to the number of pre‐existing cells with sphere‐forming capacity in the cell lines. Cell lines where secondary sphere formation was more proficient than primary sphere formation showed enrichment of genes involved in fatty acid synthesis and immunosuppressive cytokines. In contrast, cell lines where secondary sphere formation was approximately equivalent to or less proficient than primary sphere formation showed upregulation of CD40 and enrichment of genes involved in fatty acid oxidation. Our data suggest that in vitro sphere formation is associated with upregulation of gene clusters involved in metabolic and immunosuppressive functions, which might be necessary for self‐renewal and for tumour initiation and/or tumour propagation in vivo.  相似文献   

6.
Recent data suggest that mammary carcinogenesis may be driven by cancer stem cells (CSCs) derived from mutated adult stem cells, which have acquired aberrant cell self-renewal or by progenitor cells that have acquired the capacity for cell self-renewal. Spontaneous mammary cancers in cats and dogs are important models for the understanding of human breast cancer and may represent alternative species model systems that can significantly contribute to the study of human oncogenesis. With the goal of identifying markers for isolating human breast CSCs, we have generated a canine model system to isolate and characterize normal and CSCs from dog mammary gland. Insight into the hierarchical organization of canine tumours may contribute to the development of universal concepts in oncogenesis by CSCs. Cells with stem cell properties were isolated from normal and tumoural canine breast tissue and propagated as mammospheres and tumourspheres in long-term non-adherent culture conditions. We showed that cells obtained from spheres that display self-renewing properties, have multi-lineage differentiation potential, could generate complex branched tubular structures in vitro and form tumours in NOD/SCID mice. We analysed these cells for the expression of human stem and CSC markers and are currently investigating the tumour-initiating properties of these cells and the hierarchical organization of normal and neoplastic canine mammary tissue.  相似文献   

7.
The cancer stem cell (CSC) hypothesis proposes that tumour growth is maintained by a distinct subpopulation of ‘CSC’. This study applied flow cytometric methods, reported to detect CSC in both primary and cultured cancer cells of other species, to identify candidate canine subpopulations. Cell lines representing diverse canine malignancies, and cells derived from spontaneous canine tumours, were evaluated for expression of stem cell‐associated surface markers (CD34, CD44, CD117 and CD133) and functional properties [Hoecsht 33342 efflux, aldehyde dehydrogenase (ALDH) activity]. No discrete marker‐defined subsets were identified within established cell lines; cells derived directly from spontaneous tumours demonstrated more heterogeneity, although this diminished upon in vitro culture. Functional assays produced variable results, suggesting context‐dependency. Flow cytometric methods may be adopted to identify putative canine CSC. Whilst cell lines are valuable in assay development, primary cells may provide a more rewarding model for studying tumour heterogeneity in the context of CSC. However, it will be essential to fully characterize any candidate subpopulations to ensure that they meet CSC criteria.  相似文献   

8.
Diseases of companion animals are shifting from infectious diseases to neoplasms (cancer), and since radiation therapy is one of the effective choices available for cancer treatment, the application of radiotherapy in veterinary medicine is likely to increase. However tumor tissues have different radiosensitivities, and therefore it is important to determine the intrinsic radiosensitivity of tumors in individual patients in advance of radiotherapy. We have studied the relationship between the surviving cell fraction measured by a clonogenic assay and DNA double strand breaks detected by a comet assay under neutral conditions in three canine tumor cell lines, after gamma-ray and carbon ion irradiation. In all the cell lines, cell death assessed by the clonogenic assay was much higher following irradiation with carbon ions than with gamma-rays. The initial and residual (4 hr) DNA damage due to gamma-ray and carbon ion irradiation were higher in a radiosensitive cell line than in a radioresistant cell line. The surviving cell fraction at 2 Gy (SF2) showed a tendency for correlation with both the initial and residual DNA damage. In particular, the residual damage per Gy was significantly correlated with SF2, regardless of the type of radiation. This indicates that cellular radiosensitivity can be predicted by detection of radiation-induced residual DNA damage.  相似文献   

9.
The relationship between deoxyribonucleic acid (DNA) damage and the cell death induced by gamma-irradiation was examined in three kinds of cells, Chinese hamster ovary fibroblast CHO-K1, human melanoma HMV-II and mouse leukemia L5178Y. Cell survival was determined by a clonogenic assay. The induction and rejoining of DNA strand breaks induced by radiation were measured by the alkaline and neutral comet assays. L5178Y cells were the most radiosensitive, while CHO-K1 cells and HMV-II cells were radioresistant. There was an inverse relationship between the survival fraction at 2 Gy (SF2) and the yield of initial DNA strand breaks per unit dose under the alkaline condition for the comet assay, and also a relationship between SF2 and the residual DNA strand breaks (for 4 hr after irradiation) under the neutral condition for the comet assay, the latter being generally considered to be relative to cellular radiosensitivity. In the present analysis, it was considered that the alkaline condition for the comet assay was optimal for evaluating the initial DNA strand breaks, while the neutral condition was optimal for evaluating the residual DNA strand breaks. Since the comet assay is simpler and more rapid than other methods for detecting radiation-induced DNA damage, this assay appears to be a useful predictive assay for evaluating cellular clonogenic radiosensitivity of tumor cells.  相似文献   

10.
Cutaneous mast cell tumours (MCT) are the most common skin tumour in dogs, and to our knowledge, there are no previous studies regarding the global methylation of these tumours. DNA hypomethylation and hypermethylation have been described in several tumours and both mechanisms can lead to carcinogenesis. The purpose of this study was to evaluate the global DNA methylation in canine MCT. A total of 48 MCT samples were classified in grades 1, 2 and 3 or high‐grade or low‐grade. Monoclonal antibodies were used for the immunohistochemical detection of the 5‐methylcytosine. The immunostained nuclei were classified in strong, weak or negative pattern, and these were quantified in five distinct microscopic fields (40× objective) in each slide. The results showed that global DNA hypomethylation was predominant in grade 3, high‐grade, less differentiated MCT. These epigenetic changes in neoplastic mast cells warrant further detailed investigation aiming the establishment of tumour epigenetic therapies.  相似文献   

11.
Hepatic progenitor cells (HPCs) are bipotential stem cells residing in human and animal livers that are able to differentiate towards the hepatocytic or cholangiocytic lineages. HPCs are present in both hepatocellular (HCC) and cholangiocellular carcinoma (CC) in humans; and a small percentage of HCC can originate from cancer stem cells. However, its distribution in canine liver tumour has not been studied. Herein, we searched for stem/progenitor cells in 13 HCC and 7 CC archived samples by immunohistochemical analysis. We found that both liver tumours presented a higher amount of K19‐positive HPCs. Besides, 61.6% of HCC cases presented immature CD44‐positive hepatocytes. Nevertheless, only two cases presented CD133‐positive cells. As observed in humans, hepatic canine tumours presented activated HPCs, with important differentiation onto hepatocytes‐like cells and minimal role of cancer stem cells on HCC. These findings reiterate the applicability of canine model in the search for new therapies before application in humans.  相似文献   

12.
Technical advances make it possible to deliver radiation therapy for canine intracranial tumours in fewer fractions, under the assumption of equivalent tumour control. With the aim of estimating the late toxicity risk profile for various tumour sizes and locations, the present paper evaluates the normal tissue complication probability (NTCP) values for the intracranial organs at risk. By making isoeffect calculations, a new 10‐fraction radiation protocol was developed with the same tumour control probability (TCP) as a currently used 20‐fraction standard protocol, and complication risk profiles for brain, brainstem and optic chiasm were modelled using a representative population of 64 dogs with brain tumours. For >59% of cases, the new 10‐fraction protocol yielded an acceptable, low risk estimate of late toxicity (<10%). Our calculations suggest that it may be safe to treat small to intermediate‐sized tumours that are neither located near the optic chiasm nor at the brainstem with 10 daily fractions of 4.35 Gy.  相似文献   

13.
This study reports the main clinicopathological features of primary lung cancer (PLC) in 37 dogs, with special regard to the pathogenetic and prognostic role of epidermal growth factor receptor (EGFR) overexpression. For each case the following characteristics were evaluated: tumour‐node‐metastasis (TNM) stage, tumour histotype, histological grade, mitotic activity and immunohistochemical expression of EGFR. In samples with available normal lung tissue, the amount of background anthracosis was also measured by image analysis. In 27 tumours (73%) a variable number of cells (20–100%) stained positively for EGFR. The proportion of EGFR‐positive tumours was significantly higher in cases with background anthracosis, and the amount of anthracosis was correlated with the percentage of positive tumour cells. Additionally, a trend towards shortened survival for the high EGFR group was observed. These findings suggest an involvement of EGFR signalling pathway in canine PLC, a negative prognostic significance of protein overexpression and its potential implication in air pollution carcinogenesis.  相似文献   

14.
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15.
Regulatory T cells (Tregs) infiltrate into a variety of tumour tissues and associate with poor prognosis in humans. However, data on association of Treg infiltration with prognosis is limited in canine tumours. The purpose of this study was to examine the number of tumour‐infiltrating Tregs and its association with overall survival (OS) in dogs with malignant tumours. The following 168 canine tumours were included: 37 oral malignant melanomas (OMMs); 14 oral squamous cell carcinomas (OSCCs); 16 pulmonary adenocarcinomas (PAs); 37 mammary carcinomas (MCs); 36 mast cell tumours (MCTs) and 28 hepatocellular carcinomas (HCCs). Normal tissues were obtained from 8 healthy dogs as controls. The number of forkhead box P3 (Foxp3)‐positive Tregs in intratumoral and peritumoral areas was investigated by immunohistochemistry. OS was compared between high and low Treg groups. The number of intratumoral and peritumoral Foxp3‐positive Tregs was significantly higher in OMM, OSCC, PA and MC compared with each normal tissue. There were few Foxp3‐positive Tregs in MCT and HCC. With intratumoral Tregs, the OS in the high Treg group was significantly shorter than that in the low Treg group in OMM, OSCC and PA. With peritumoral Tregs, there was no significant difference for OS between the 2 groups in each tumour type. These results suggest that Tregs infiltrate into a variety of canine tumours and the abundance of Tregs are associated with poor prognosis in some solid tumour types.  相似文献   

16.
Increasing evidence suggests that diverse solid tumours arise from a small population of cells known as cancer stem cells or tumour-initiating cells. Cancer stem cells in several solid tumours are enriched for aldehyde dehydrogenase (ALDH) activity. High levels of ALDH activity (ALDH(high)) were detected in four cell lines derived from canine mammary carcinomas. ALDH(high) cells were enriched in a CD44(+)CD24(-) population having self-renewal capacity. Xenotransplantation into immunodeficient mice demonstrated that 1×10(4) ALDH(high) cells were sufficient for tumour formation in all injected mice, whereas 1×10(4) ALDH(low) cells failed to initiate any tumours. ALDH(high)-derived tumours contained both ALDH(+) and ALDH(-) cells, indicating that these cells had cancer stem cell-like properties.  相似文献   

17.
Electrochemotherapy combined with peritumoral interleukin‐12 (IL‐12) gene electrotransfer was used for treatment of mast cell tumours in 18 client‐owned dogs. Local tumour control, recurrence rate, as well as safety of combined therapy were evaluated. One month after the therapy, no side effects were recorded and good local tumour control was observed with high complete responses rate which even increased during the observation period to 72%. IL‐12 gene electrotransfer resulted in 78% of patients with detectable serum IFN‐γ and/or IL‐12 levels. In the treated tumours vascular changes as well as minimal T‐lymphocytes infiltration was observed. After 1 week, the plasmid DNA was not detected intra‐ or peritumorally and no horizontal gene transfer was observed. In summary, our study demonstrates high antitumour efficacy of electrochemotherapy combined with IL‐12 electrotransfer, which also prevented recurrences or distant metastases, as well as its safety and feasibility in treatment of canine mast cell tumours.  相似文献   

18.
The aim of this study was to identify mutations in the hypervariable region of mitochondrial DNA in canine mammary tumours and to determine their association with the process of neoplastic transformation. A total of 93 biological samples, including blood as well as normal and neoplastic tissue samples from 31 dogs with diagnosed malignant canine mammary tumours were analysed. DNA extraction, amplification and sequencing of the D‐loop as well as bioinformatic and statistical analyses were performed. In the mitochondrial D‐loop sequence, 26 polymorphic loci and 5 mutations were identified. For the first time, D‐loop length heteroplasmy was detected in dogs with mammary tumours. The malignancy grade exerted no effect on the presence of nucleotide changes. A statistically significant association between the presence of mutations and polymorphisms and the size of dogs was demonstrated. The 100% frequency of length heteroplasmy may imply that this is a hotspot mutation of canine mammary tumour.  相似文献   

19.
This prospective study describes the feasibility and toxicity of 192Iridium high‐dose‐rate (HDR) brachytherapy as an alternative strategy for the treatment of canine intranasal tumours. Fifteen dogs with malignant intranasal tumours were treated twice weekly using a hypofractionated protocol with eight fractions, 5 Gy per fraction, resulting in a total dose of 40 Gy. Acute and chronic adverse side‐effects appeared to be rare. Only 7% of the acute side‐effects and 5% of the chronic were classified as severe (grade 3). Eight dogs showed clinical complete remission, and five dogs had partial remission, with a resolution of tumour‐related symptoms. Magnetic resonance imaging showed a reduced tumour mass in 12 cases. Median survival time was 17 months (range 4–48 months), with four dogs (three without disease) still alive. Median time to recurrence of these dogs was 14 months. In nine dogs, progression or recurrence of the tumour was the cause of death. This study suggests that HDR brachytherapy is feasible and well tolerated.  相似文献   

20.
The study of the immune response in several types of tumours has been rapidly increasing in recent years with the dual aim of understanding the interactions between neoplastic and immune cells and their importance in cancer pathogenesis and progression, as well as identifying targets for cancer immunotherapy. Despite being considered one of the most immunogenic tumour types, melanoma can progress in the presence of abundant lymphocytic infiltration, therefore suggesting that the immune response is not able to efficiently control tumour growth. The purpose of this study was to investigate whether the density, distribution and grade of tumour‐infiltrating lymphocytes (TILs) in 97 canine melanocytic tumours is associated with histologic indicators of malignancy and can be considered a prognostic factor in the dog. As a further step in the characterization of the immune response in melanocytic tumours, an immunohistochemical investigation was performed to evaluate the two main populations of TILs, T‐lymphocytes (CD3+) and B‐lymphocytes (CD20+). The results of our study show that TILs are present in a large proportion of canine melanocytic tumours, especially in oral melanomas, and that the infiltrate is usually mild. The quantity of CD20+ TILs was significantly associated with some histologic prognostic factors, such as the mitotic count, the cellular pleomorphism and the percentage of pigmented cells. Remarkably, a high infiltration of CD20+ TILs was associated with tumour‐related death, presence of metastasis/recurrence, shorter overall and disease‐free survival, increased hazard of death and of developing recurrence/metastasis, hence representing a potential new negative prognostic factor in canine melanocytic tumours.  相似文献   

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