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J. K. McCleese M. D. Bear S. K. Kulp C. Mazcko C. Khanna C. A. London 《Veterinary and comparative oncology》2013,11(2):124-139
The receptor tyrosine kinase (RTK) Met is known to be over‐expressed in canine osteosarcoma (OSA). In human cancers, the RTKs Met, epidermal growth factor receptor (EGFR) and Ron are frequently co‐expressed and engage in heterodimerization, altering signal transduction and promoting resistance to targeted therapeutics. We found that EGFR and Ron are expressed in canine OSA cell lines and primary tissues, EGFR and Ron are frequently phosphorylated in OSA tumour samples, and Met is co‐associated with EGFR and Ron in canine OSA cell lines. Transforming growth factor alpha (TGFα) and hepatocyte growth factor (HGF) stimulation induced amplification of ERK1/2 and STAT3 phosphorylation in OSA cells and Met was phosphorylated following TGFα stimulation providing evidence for receptor cross‐talk. Lastly, treatment of OSA cells with combined gefitinib and crizotinib inhibited cell proliferation in an additive manner. Together, these data support the notion that Met, EGFR and Ron interact in OSA cells and as such, may represent viable targets for therapeutic intervention. 相似文献
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Raquel Snchez‐Cspedes Paolo Accornero Silvia Miretti Eugenio Martignani Francesca Gattino Lorella Maniscalco Cecilia Gola Selina Iussich Marina Martano Emanuela Morello Paolo Buracco Luca Aresu Raffaella De Maria 《Veterinary and comparative oncology》2020,18(1):117-127
Canine osteosarcoma (OSA) is the most common primary malignant bone tumour in dogs, and it has a high metastatic rate and poor prognosis. Toceranib phosphate (TOC; Palladia, Zoetis) is a veterinary tyrosine kinase inhibitor that selectively inhibits VEGFR‐2, PDGFRs and c‐Kit, but its efficacy is not yet fully understood in the treatment of canine OSA. Here, we evaluated the functional effects of TOC on six OSA cell lines by transwell, wound healing and colony formation assays. Subsequently, two cell lines (Wall and Penny) were selected and were inoculated in mice by intrafemoral injection to develop an orthotopic xenograft model of canine OSA. For each cell line, 30 mice were xenografted; half of them were used as controls, and the other half were treated with TOC at 40 mg/kg body weight for 20 days. TOC inhibited cell growth of all cell lines, but reduced invasion and migration was only observed in Penny and Wall cell lines. In mice engrafted with Penny cells and subjected to TOC treatment, decreased tumour growth was observed, and PDGFRs and c‐Kit mRNA were downregulated. Immunohistochemical analyses demonstrated a significant reduction of Ki67 staining in treated mice when compared to controls. The results obtained here demonstrate that TOC is able to slightly inhibit cell growth in vitro, while its effect is evident only in a Penny cell xenograft model, in which TOC significantly reduced tumour size and the Ki67 index without modifying apoptosis markers. 相似文献
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Introduction: Aberrant expression of the proto‐oncogene c‐Met has been noted in a variety of human cancers. In dogs, inappropriate Met expression has been identified in canine osteosarcoma (OSA) tumor samples. To better define the potential role of Met dysregulation in canine cancer, we cloned canine Met, HGF, and HGF activator and evaluated their expression patterns in a variety of canine tumor cell lines.
Methods: Canine Met, HGF, and HGF activator were cloned from normal canine liver and canine OSA cell lines using primers based on regions of homology between mouse and human sequences as well as 5' and 3' RACE.
Results: Inappropriate expression of Met was found in canine cell lines derived from OSAs, mast cell tumors, histiocytic sarcomas, hemangiosarcoma, and melanomas. Both HGF and HGF activator were found to be expressed in several of these tumor cell lines, providing evidence of a possible autocrine loop of Met stimulation. Incubation of canine tumor cell lines with rhHGF resulted in Met autophosphorylation and activation of the downstream signaling elements Gab1, Akt and Erk1/2. Scattering of tumor cells in response to HGF occurred under conditions of cell stress, such as serum starvation. Lastly, the Met inhibitor PHA‐665752 blocked HGF induced phosphorylation of canine Met and Gab1.
Conclusions: These studies provide evidence that similar to the case in human tumors, aberrant Met expression may play an important role in the biology of canine cancer. As such, inhibition of Met function may represent a potentially useful novel therapeutic approach. 相似文献
Methods: Canine Met, HGF, and HGF activator were cloned from normal canine liver and canine OSA cell lines using primers based on regions of homology between mouse and human sequences as well as 5' and 3' RACE.
Results: Inappropriate expression of Met was found in canine cell lines derived from OSAs, mast cell tumors, histiocytic sarcomas, hemangiosarcoma, and melanomas. Both HGF and HGF activator were found to be expressed in several of these tumor cell lines, providing evidence of a possible autocrine loop of Met stimulation. Incubation of canine tumor cell lines with rhHGF resulted in Met autophosphorylation and activation of the downstream signaling elements Gab1, Akt and Erk1/2. Scattering of tumor cells in response to HGF occurred under conditions of cell stress, such as serum starvation. Lastly, the Met inhibitor PHA‐665752 blocked HGF induced phosphorylation of canine Met and Gab1.
Conclusions: These studies provide evidence that similar to the case in human tumors, aberrant Met expression may play an important role in the biology of canine cancer. As such, inhibition of Met function may represent a potentially useful novel therapeutic approach. 相似文献
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Analysis of genomic mutation and immunohistochemistry of platelet‐derived growth factor receptors in canine vascular tumours 
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下载免费PDF全文 S. Abou Asa T. Mori K. Maruo A. Khater A. El‐sawak E. Abd el‐Aziz T. Yanai H. Sakai 《Veterinary and comparative oncology》2015,13(3):237-245
We examined whether mutation of the platelet‐derived growth factor receptor protein tyrosine kinase (PDGFR)‐α and PDGFR‐β genes contributes to their overexpression in canine vascular tumours. Genomic sequences of trans‐ or juxtamembrane regions of PDGFR‐α and PDGFR‐β were analysed with immunohistochemical staining and polymerase chain reaction‐direct sequencing using DNA from paraffin‐embedded neoplastic tissues of 27 hemangiosarcomas (HSAs) and 20 hemangiomas (HAs). Immunohistochemically, 75% of the HA cases were positive for PDGFR‐α and almost most of the HA cases were negative for PDGFR‐β. Of the HSA cases, 55.6% were negative for PDGFR‐α and 63% were strongly positive for PDGFR‐β. Among the HA cases, 1 missense mutation was detected in PDGFR‐α exon 18 and 1 in PDGFR‐β exon 17. Two HSA cases had missense mutations in exon 14 and 1 in exon 17 of PDGFR‐β. Thus, genomic mutation of trans‐ or juxtamembrane regions of PDGFRs was not the main mechanism driving the activation of receptors in HSA and HA. 相似文献
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Takeuchi Y Fujino Y Watanabe M Nakagawa T Ohno K Sasaki N Sugano S Tsujimoto H 《The Journal of veterinary medical science / the Japanese Society of Veterinary Science》2011,73(10):1295-1302
Options of systemic treatment for canine MCT have been still limited and most canine cases with MCTs eventually undergo relapses even after achievement of a remission. Thus additional therapies are required to establish for the tumor. To identify the novel candidate therapeutic targets for canine MCT, the mRNA expression and phosphorylation statuses of several receptor or non-receptor kinases as well as the inhibitory effect of 95 specific inhibitors on the growth were assessed in three canine MCT cell lines (HRMC, VIMC1 and CMMC1). Among the 14 targets, the mRNAs of 11, 7 and 7 kinases were amplified in HRMC, VIMC1 and CMMC1, respectively. The mRNAs of VEGFR3, PDGFRα, SRC, YES, LCK and FYN were detected in all cell lines. The phosphorylation of 12, 8 and 7 kinases was observed by using specific antibody arrays in HRMC, VIMC1 and CMMC1, respectively. DTK, EPHB6, AMPKα1, CREB, STAT5a and STAT5b were phosphorylated in all cell lines. The 10, 9 and 17 inhibitors exhibited the biological activity against the growth of HRMC, VIMC1 and CMMC1, respectively. Only three inhibitors such as SB218078 (for Chk1), PDGF RTK inhibitor IV (for PDGFR) and radicicol (for Hsp90) suppressed the growth of all three cell lines. The present study indicated that several kinases, such as Chk1, PDGFR and Hsp90, could be used as therapeutic targets in the treatment for canine MCT. Further studies and clinical trials are warranted to apply the inhibitors for the treatment of the tumor. 相似文献
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Lawrence J Saba C Gogal R Lamberth O Vandenplas ML Hurley DJ Dubreuil P Hermine O Dobbin K Turek M 《Veterinary and comparative oncology》2012,10(2):143-154
Dysregulation of platelet-derived growth factor receptor (PDGFR) may play a role in feline injection-site sarcoma (ISS) cell growth and viability. Masitinib, a tyrosine kinase inhibitor approved for treatment of canine mast cell tumours, is highly selective for the PDGFR signalling pathway and may offer a new therapeutic approach for this disease. The in vitro effects of masitinib on growth, apoptosis and PDGFR signalling in two novel ISS cell lines were investigated. PDGFR expression was confirmed by Western blot in cell lines derived from a primary ISS tumour (JB) and a corresponding, histologically confirmed ISS lung metastasis (JBLM). Masitinib inhibited cell growth and PDGFR phosphorylation in both cell lines. Higher drug concentrations were required to inhibit growth than to modulate ligand-induced autophosphorylation of PDGFR. These in vitro data suggest that masitinib displays activity against both primary and metastatic ISS cell line and may aid in the clinical management of ISS. 相似文献
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Osteosarcoma (OSA) is the most common bone tumour in humans and companion animals, and has a poor long‐term prognosis. The identification of new markers and targeted therapies may help increase long‐term survival of these patients. Previous studies have demonstrated that interleukin‐11 receptor alpha (IL‐11Rα) is expressed in human and murine OSA but not in normal bone. The current study demonstrated via western analysis, immunoflourescence and immunohistochemistry that IL‐11Rα was expressed in primary canine OSA tissues as well as in a number of canine OSA cell lines, but not in normal canine bone. Cytotoxin‐conjugated antibodies targeting IL‐11Rα‐mediated canine OSA cytotoxicity. Thus, canine OSA may be a valuable model for the evaluation of IL‐11Rα directed therapies. 相似文献
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A. T. Liao J. McCleese S. Kamerling J. Christensen C. A. London 《Veterinary and comparative oncology》2007,5(3):177-196
The receptor tyrosine kinase Met is dysregulated in several human cancers including osteosarcoma (OSA) in which overexpression is a negative prognostic indicator and enforced Met expression in normal osteoblasts leads to genomic instability and malignant transformation. Met is also known to be inappropriately expressed in canine OSA tumour samples and cell lines. The purpose of this study was to evaluate the potential utility of an orally bioavailable small molecule Met inhibitor, PF2362376, against canine OSA cell lines as a prelude to future clinical work. PF2362376 inhibited phosphorylation of Met, Gab‐1, Erk and Akt, but not of Src or STAT3. Furthermore, PF2362376 inhibited proliferation of canine OSA cell lines and induced cell death at biologically achievable concentrations. Last, activities associated with Met signalling including migration, invasion, branching morphogenesis and colony formation in soft agar were blocked by PF2362376. These studies support the notion that Met is a relevant target for therapeutic intervention in OSA. 相似文献
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PDGFRs expression in dogs affected by malignant oral melanomas: correlation with prognosis 下载免费PDF全文
下载免费PDF全文 S. Iussich L. Maniscalco A. Di Sciuva B. Iotti E. Morello M. Martano F. Gattino P. Buracco R. De Maria 《Veterinary and comparative oncology》2017,15(2):462-469
Canine malignant melanoma (CMM) is the most common canine oral tumour, and up to 70–75% of dogs in stage II–III die within 1 year after surgery. The purpose of this study was to evaluate the expression of platelet‐derived growth factors receptors (PDGFR)‐α and ‐β in stage II and III CMMs and to correlate it with prognosis. PDGFRs expression was evaluated by immunohistochemistry on 48 cases of formalin‐fixed CMM samples and correlated with clinical–pathological findings and outcome after surgery. PDGFRs co‐expression was observed in 37.5% of cases. Positivity for PDGFR‐α and ‐β receptor was present in 54.2 and 47.9% of cases, respectively. Ki67 values >19.5% were ascertained in 66.7% of cases. Statistical analysis showed that PDGFRs co‐expression and Ki67 values > 19.5% were both associated with worse prognosis. PDGFRs expression suggests a role in the pathogenesis and progression of CMM, and α and β co‐expression appears to be associated to worse prognosis. 相似文献
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K. Kow S. M. Bailey E. S. Williams S. Withrow S. E. Lana 《Veterinary and comparative oncology》2006,4(3):184-187
Appendicular osteosarcoma (OSA) is the most common primary bone tumour in dogs, and the prognosis with standard of care therapy of amputation and adjunctive chemotherapy is generally poor, with median survival times of 1 year. The ability of neoplastic cells to maintain their telomere length, by either telomerase activity or alternate methods, is an important step in tumour development and malignancy. The purpose of this study was to determine the presence of telomerase activity in canine OSA. To evaluate the frequency of alternative lengthening of telomeres in canine OSA, we have used the telomeric repeat amplification protocol in five canine cell lines and in six samples taken from clinical patients at the time of amputation. Our results reveal the presence of telomerase activity in 100% of canine OSA cell lines and 83% of clinical samples evaluated. This is in contrast to human OSA where 25–40% expression levels of telomerase are reported. Importantly, our results not only suggest that canine OSA may serve as a good model for aggressive telomerase‐positive forms of human OSA but also that antitelomerase therapy strategies for treatment of canine OSA may be more successful than in the treatment of majority of human patients with OSA. 相似文献
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Osteosarcoma (OSA) is the most common primary bone tumour in dogs. The appendicular locations are most frequently involved and large to giant breed dogs are commonly affected, with a median age of 7–8 years. OSA is a locally invasive neoplasm with a high rate of metastasis, mostly to the lungs. Due to similarities in biology and treatment of OSA in dogs and humans, canine OSA represents a valid and important tumour model. Differences between canine and human OSAs include the age of occurrence (OSA is most commonly an adolescent disease in humans), localisation (the stifle is the most common site of localisation in humans) and limited use of neoadjuvant chemotherapy in canine OSA. 相似文献
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Zhang M Sheng X Zhang H Wang Q Xu M Weng Q Watanabe G Taya K 《The Journal of reproduction and development》2012,58(3):353-359
The platelet-derived growth factor (PDGF) system is expressed and can exert its biological role in the male reproductive system including the maintenance of morphological structure and function of the epididymis. The aim of this study was to clarify the relationship between the PDGF system and seasonal changes in morphology of the wild ground squirrel epididymis during the breeding and nonbreeding seasons. Hematoxylin-eosin (HE) staining was used to observe the epididymal morphology and histology. Immunohistochemistry and Western blotting were performed to detect the immunoreactivities of PDGF-A and B and PDGFR-α. Significant seasonal changes in epididymal morphology were observed in the breeding and nonbreeding seasons. The proportions of the three compartments (interstitial tissue, epithelium and lumen of the duct) revealed distinct variances. Strong immunostaining of PDGF-A was present in the myoid cell and on the sperm in the breeding season, whereas there was a faint signal in the myoid cell in the nonbreeding season. PDGFR-α was expressed in all cell types of the epithelium throughout the whole seasonal cycle, and immunostaining of PDGFR-α in the breeding season was significantly stronger compared with that of the nonbreeding season. PDGF-B was not detected in the epididymis of wild ground squirrels. These results suggested that seasonal morphological changes in epididymis were correlated with immunoreactivities of PDGF-A and its receptor PDGFR-α and that PDGF-A and PDGFR-α might function as paracrine, autocrine or apocrine factors in wild ground squirrels. 相似文献
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Stein TJ Holmes KE Muthuswamy A Thompson V Huelsmeyer MK 《Veterinary and comparative oncology》2011,9(1):65-73
Osteosarcoma (OSA) is the most frequently occurring malignant primary bone tumour in dogs and children and arises from cells of the osteoblast lineage. Inappropriate Wnt signalling activity has been implicated in human OSA. Altered expression of β-catenin, an integral member of the Wnt signalling pathway, has been associated with numerous human cancers, including OSA. In this study, 30 of the 37 primary canine OSA tissues and 2 of the 3 metastatic OSAs were positive for β-catenin expression as determined by immunohistochemistry, whereas 2 normal bones stained negative for β-catenin. No mutations were identified in exon 3 of β-catenin in the three OSA cases in which DNA sequencing was performed. Finally, there was no relationship between β-catenin expression and overall survival time or disease-free interval. Our results indicate β-catenin is frequently expressed within the cytoplasm of neoplastic cells in canine OSA but contains no detectable mutations in exon 3, similar to human OSA. 相似文献
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Donnelly BP Nixon AJ Haupt JL Dahlgren LA 《American journal of veterinary research》2006,67(7):1218-1225
OBJECTIVE: To characterize the nucleotide sequence of equine platelet-derived growth factor (PDGF)-A and -B and analyze temporal expression of these genes in equine tendon after induced tendinitis injury. Animals-18 mature horses. PROCEDURES: Genes for equine PDGF-A and -B were reverse transcribed and sequenced from synovial tissue mRNA obtained from a 3-year-old horse. Collagenase-induced lesions were created in the tensile region of the superficial digital flexor tendon in 14 horses; 3 horses served as uninjured control animals. Tendons were harvested and total RNA was isolated from experimental horses 1, 2, 4, 8, and 24 weeks after collagenase injection. Temporal gene expression for PDGF-A and -B was determined by use of quantitative PCR analysis. RESULTS: Equine PDGF-A shared 83.8% sequence and 87.5% peptide homology with human PDGF-A, with a discrepancy of 70 bp from the human sequence. Equine PDGF-B was similar in length to the human gene, sharing 90.3% and 91.7% nucleotide and peptide identity, respectively. Expression of PDGF-A mRNA in collagenase-induced tendinitis lesions was unchanged, compared with expression for normal control tendon, and remained steady throughout the 24-week study. Expression of PDGF-B mRNA decreased over time, and the expression at 24 weeks was significantly reduced, compared with expression in normal and acutely injured tendon. CONCLUSIONS AND CLINICAL RELEVANCE: Injured tendon mounts a minimal constitutive PDGF-A or -B mRNA response. Serial exogenous treatment with either PDGF isoform within the first 2 to 4 weeks after tendon injury may bolster the meager PDGF paracrine-autocrine intrinsic response to injury. 相似文献