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1.
The expression of 5 markers associated with angiogenesis was studied in canine squamous cell carcinomas (SCCs) (n = 19) and canine trichoepitheliomas (TCPs) (n = 24). SCCs were assigned histologic grades, and tissue sections from both tumor types were immunohistochemially stained for the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), as well as intratumoral microvessel density (iMVD), tumor proliferation index (PI), and tumor apoptotic index (AI), using antibodies against VEGF, VEGFR-2, von Willebrand's factor, Ki-67 antigen, and the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate end-labeling method (TUNEL), respectively. VEGF and VEGFR-2 were detected in 17/19 (89.4%) and 19/19 (100%) SCCs and in 17/24 (70.8%) and 20/24 (83.3%) TCPs, respectively. In SCCs, there was substantial correlation between histologic grade and PI (r = 0.51); and moderate correlation between VEGF and histologic grade (r = 0.43), VEGFR-2 and histologic grade (r = 0.47), VEGF and PI (r = 0.47), and VEGFR-2 and PI (r = 0.47) (Spearman rank correlation coefficient). In TCPs, there was substantial correlation between VEGF and PI (r = 0.51) and a moderate correlation between VEGFR-2 and iMVD (r = 0.36). The median iMVD of SCCs (15.5) was significantly higher than the median iMVD of TCPs (9.05) (P value < .05). It was concluded that VEGF and VEGFR-2 may promote tumor cell proliferation in TCPs and SCCs. An autocrine pathway for VEGF probably operates in canine SCCs and TCPs, as VEGF and VEGFR-2 expression was found in most tumors and was associated with evidence for tumor cell proliferation.  相似文献   

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3.
Vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE-2) appear to play a critical role in tumour neovascularization. In this study, we have investigated the expression of VEGF and PGE-2 in 53 canine cutaneous mast cell tumours (MCTs). Immunohistochemistry of tissue sections revealed that VEGF and PGE-2 were expressed in all mast cell tumours studied. When the expression patterns of VEGF and PGE-2 were compared with tumour grade according to Patnaik criteria, the only significant correlation observed was between PGE-2 staining intensity and tumour pathological grade, with grade II and III tumours having higher PGE-2 staining, both in intensity and percentage of cells stained, than grade I tumours ( P < 0.05).  相似文献   

4.
Canine mammary gland tumours (CMTs) are the most common malignancies in female dogs. The receptor tyrosine kinase EGFR (erbb1), a receptor for epidermal growth factor (EGF) and related factors, mediates multiple oncogenic functions in human epithelial neoplasms. While previous studies have demonstrated EGFR expression in canine tumours, its function has not been studied in canine cancer. The purpose of this study was to determine the in vitro effects of EGF and vandetanib (ZD6474), a small molecule inhibitor of VEGFR-2, EGFR and RET tyrosine kinases, on proliferation, invasion, survival and chemosensitivity in CMT cells. In low serum, EGF enhanced proliferation and chemotaxis, attenuated apoptosis, and stimulated vascular endothelial growth factor (VEGF) production. Vandetanib dose-dependently inhibited EGFR phosphorylation as well as PI3K/Akt activation, and inhibited all EGF-induced phenotypic effects. In conclusion, EGF stimulates multiple features promoting the malignant phenotype in CMT. Thus, CMT may be an important translational model for the investigation of novel EGFR-directed therapies.  相似文献   

5.
OBJECTIVE: To quantitatively evaluate expression of vascular endothelial growth factor (VEGF) in intracranial tumors in dogs and determine whether relationships exist between circulating and intratumoral VEGF concentrations and tumor type and grade. ANIMALS: 27 dogs with primary intracranial neoplasms and 4 unaffected control dogs. PROCEDURES: Plasma and brain tumor samples were obtained from each dog, and plasma and intratumoral concentrations of VEGF were measured by use of an ELISA. RESULTS: Dogs with meningiomas (n = 11) were significantly older than dogs with oligodendrogliomas (7) or astrocytomas (9). Measurable VEGF was detected in all tumors, and a significant negative correlation between age and intratumoral VEGF concentration was detected. Age-adjusted comparisons identified significant differences in intratumoral VEGF concentrations among all tumor types; the highest VEGF concentrations were associated with astrocytomas. Within each tumor type, increasing tumor grade was significantly associated with increasing VEGF expression. Plasma VEGF concentrations were detectable in 9 of 27 dogs; the proportion of dogs with astrocytomas and a detectable circulating VEGF concentration (7/9 dogs) was significantly higher than the proportion of dogs with meningiomas (1/11 dogs) or oligodendrogliomas (1/7 dogs) with a detectable circulating VEGF concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Overexpression of VEGF appears common in canine astrocytomas, oligodendrogliomas, and meningiomas. In the neoplasms examined, intratumoral VEGF concentrations correlated well with tumor malignancy. The VEGF expression patterns paralleled those of analogous human tumors, providing evidence that dogs are a suitable species in which to study angiogenesis and intracranial neoplasia for human application.  相似文献   

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7.
Vascular Endothelial Growth Factor (VEGF) and its receptor KDR are involved in the regulation of angiogenesis and are up-regulated in a number of tumours in humans and in particular, breast cancer. We therefore evaluated the prognostic potential of the angiogenetic process in feline and canine mammary carcinomas by the immunohistochemical assessment of VEGF expression and micro vessel density (MVD) quantification and examined the interplay between VEGF and KDR. These variables were related to some relevant clinicopathological parameters and to overall survival (OS). VEGF and KDR expression were evaluated in epithelial, stromal and endothelial compartments in order to identify autocrine and/or paracrine loops. In dogs an increased VEGF expression did not show any statistical correlation with the clinicopathological parameters examined and was not correlated to a poorer prognosis. MVD was found to be significantly correlated to the histologic type (P=0.04), tumour grading (P=0.02), and to the OS (P=0.01). In cats VEGF expression was significantly correlated to tumor grading (P=0.01) and OS (P=0.03), while no significant associations were found between MVD and the other parameters. VEGF and KDR were found to be detected on the epithelial, and/or endothelial and/or stromal cells of the carcinomas in both species, suggesting indications for some possible autocrine and paracrine loops. Our results encourage further studies on the possible prognostic role of VEGF and MVD in canine and feline mammary tumours and on the role of growth factors and their receptors in promoting tumour proliferation and an "angiogenetic shift". The VEGF/KDR system may play a role in malignant transformation and tumor progression.  相似文献   

8.
Samples from feline invasive mammary carcinomas (FMCs) were used to determine the prognostic significance of the immunohistochemical expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD). Forty-eight queens bearing FMCs were included in a 2-year follow-up study. Mammary tumors were classified according to the World Health Organization system and graded on the basis of histologic criteria. Tumor sections were immunostained using anti-VEGF and anti-von Willebrand factor (vWf) antibodies. VEGF expression was quantified on the basis of the percentage of positive cells. MVD of vWf-positive microvessels was determined by both mean microvessel counts and highest microvessel counts. Normal mammary gland tissues showed an inconspicuous VEGF staining. In FMCs the proportion of VEGF-positive cells was significantly higher in papillary and solid carcinomas than in tubular and papillary cystic tumors. An increased number of cells expressing VEGF was also observed in poorly differentiated FMCS. Sixteen (33.3%) of the queens bearing invasive carcinomas were still alive at the end of the 2-year follow-up period, and 32 (66.7%) had died. The VEGF expression was significantly correlated with the clinical outcome, but no correlation was observed with the invasion of lymphatic vessels. A correlation between the higher percentage of VEGF-positive cells and the unfavorable prognosis was demonstrated by the estimation of curves for overall survival (P = 0.03). Univariate analysis showed that MVD did not correlate with the overall survival. The results of our study demonstrated that VEGF expression, although not associated with increased angiogenesis, is a prognostic indicator in feline mammary tumors. In contrast, there is no support for a role of neovascularization as an indicator of survivability.  相似文献   

9.
In order to establish base-line data on angiogenic factors in development of mesenchymal tumors, expressions of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in implanted MT-8 and MT-9 tumors, both derived from a transplantable malignant fibrous histiocytoma (MFH) in the F344 rat, were investigated by immunohistochemistry and Western blotting method. MT-8 and MT-9 tumors were developed in syngeneic rats by implant of a tumor tissue fragment. MT-8 tumors were examined on post-implantation (PI) days 3, 6, 9 and 17, and MT-9 tumors were on PI days 9, 14, 17 and 23. The growth of MT-8 tumors was faster than that of MT-9 tumors. Histologically, MT-8 tumors were features of undifferentiated sarcomas, whereas MT-9 tumors exhibited a typical storiform growth pattern of MFH. Immunohistochemically, all cells constituting MT-8 and MT-9 tumors reacted with antibodies to VEGF and bFGF, indicating production of these factors by mesenchymal neoplastic cells. However, there were no marked differences in these immunoreactions between tumors examined. Thus, the bands obtained in the Western blotting methods were densitometrically scanned. The expression levels of VEGF and bFGF gradually increased PI day 3 to 9 in MT-8 tumors and PI day 9 to 17 in MT-9 tumors. On last examination day, the levels of bFGF in both tumors and of VEGF in MT-9 tumors decreased, but the VEGF expression level in MT-8 tumors was still increased. These findings indicated that VEGF and bFGF may contribute cooperatively to angiogenesis in an early growth of mesenchymal tumor development.  相似文献   

10.
Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis and a potential autocrine growth factor for neoplastic cells in various malignancies. In the present study, we have investigated expression of VEGF and VEGF receptors in canine mastocytomas and the canine mastocytoma cell line C2. As assessed by immunostaining of tissue sections and cytospin slides, primary neoplastic mast cells (MC) and C2 cells were found to express the VEGF protein. In Northern blot and RT-PCR experiments, C2 cells expressed VEGF mRNA in a constitutive manner. VEGF mRNA expression in C2 cells was counteracted by LY294002 and rapamycin, suggesting involvement of the PI3-kinase/mTOR pathway. Moreover, C2 cells were found to express VEGF receptor-1 (Flt-1) and VEGF receptor-2 (KDR). However, recombinant VEGF failed to promote (3)H-thymidine uptake in C2 cells, and a neutralizing anti-VEGF antibody (bevacizumab) failed to downregulate spontaneous proliferation in these cells. In addition, rapamycin decreased the expression of VEGF in C2 cells at the mRNA and protein level without suppressing their proliferation. Together, canine mastocytoma cells express VEGF as well as VEGF receptors. However, despite co-expression of VEGF and its receptors, VEGF is not utilized as an autocrine growth regulator by canine mastocytoma cells.  相似文献   

11.
Vascular endothelial growth factor (VEGF) is an angiogenic factor which targets vascular endothelial cells. In this study, cDNA encoding a feline VEGF (fVEGF) isoform was cloned from a feline lymphoid tumor cell line and sequenced. The fVEGF cDNA contained an open reading frame of 567 nucleotides coding for a polypeptide of 163 amino acids with a putative signal peptide of 26 amino acids. The predicted fVEGF amino acid sequence shared 98.4, 94.2 and 94.2% homology with the sequences of canine, bovine and human VEGF, respectively. Though predicted fVEGF polypeptide was two amino acid residues shorter than human VEGF165, a potential glycosylation site and regions critical for receptor binding were conserved in all the species examined. Transient expression of fVEGF in mammalian cells resulted in secretion of VEGF which could be detected by antibodies against human VEGF165. Furthermore, wide expression of fVEGF mRNA was observed in various feline tissues using RT-PCR methods.  相似文献   

12.
Expression of vascular endothelial growth factor in canine mammary tumors   总被引：2，自引：0，他引：2  
Vascular endothelial growth factor (VEGF) is a dimeric protein that stimulates angiogenesis in vitro and in vivo by inducing endothelial cell proliferation and migration. In this immunohistochemical study, VEGF-immunolabeled cells were counted in a series of 10 benign and 40 malignant canine mammary tumors. The morphologic pattern of VEGF positivity (intensity of immunolabeling and VEGF granule size and distribution) was also evaluated. A low number of cells weakly positive for VEGF with few and small granules polarized to the luminal pole was detected in benign neoplasms. In contrast, in malignancies a high number of VEGF-positive cells had strong immunolabeling, often with large granules found diffusely in the cytoplasm. This level of immunolabeling was more pronounced in the less differentiated, more malignant phenotypes (grade 3). Macrophages, which can synthesize VEGF, were strongly positive. Stromal and myoepithelial cells were negative. VEGF data were correlated statistically with intratumoral microvessel density (number of newly formed microvessels) and both measures were greater in less differentiated malignant neoplasms, demonstrating that angiogenesis and malignancy increase together. VEGF appears to be a powerful angiogenic factor in canine mammary tumors.  相似文献   

13.
Vascular endothelial growth factor (VEGF) is a dimeric glycosylated polypeptide growth factor with potent angiogenic, mitogenic, and vascular permeability-enhancing properties specific for endothelial cells. In humans, VEGF seems to play a major role in tumor growth, and plasma concentrations correlate with tumor burden, response to therapy, and disease progression. This study compared plasma VEGF concentrations in healthy client-owned dogs (n = 17) to dogs with hemangiosarcoma (HSA; n 16). Dogs with HSA were significantly more likely to have detectable concentrations of plasma VEGF (13/17) compared to healthy dogs (1/17; P < .001). The median plasma VEGF concentration for dogs with HSA was 17.2 pg/mL (range, < 1.0-66.7 pg/mL). Plasma VEGF concentrations in dogs with HSA did not correlate with stage of disease or tumor burden, but 1 dog had undetectable VEGF during chemotherapy that subsequently increased with disease progression.  相似文献   

14.
Serum, plasma and tissue expression of vascular endothelial growth factor (VEGF) was measured in 20 dogs previously diagnosed histologically with oral melanoma. The concentrations of VEGF in serum and plasma were significantly higher in dogs with melanoma than in a control population (P ≤ 0.002). Concentrations of VEGF in the serum and plasma of dogs with melanoma were highly correlated (r = 0.867). Ninety‐five per cent of melanoma tissues expressed VEGF. Two staining patterns were detected: diffuse and granular cytoplasmic staining. High blood concentrations of VEGF were correlated to a shorter survival time in dogs receiving definitive therapy (P = 0.002). Survival times were significantly longer in dogs receiving definitive therapy versus palliative therapy (median 496 versus 97 days, P = 0.007). Blood concentrations of VEGF were associated with stage (P < 0.05). Dogs with oral melanoma have increased serum, plasma and tissue concentrations of VEGF. Increased expression of VEGF may be a reasonable target for future therapy of canine oral melanoma.  相似文献   

15.
The role of VEGF and its receptors has extensively been studied in tumours. In contrast, the presence and function of VEGF in normal tissues like the lymph node has not been given much attention until now. To study the expression of VEGF, VEGFR-1, VEGFR-2 and VEGFR-3 in the heterogenous cell population of the canine lymph node, laser capture microdissection was used to isolate pure cell fractions of macrophages, lymphocytes, endothelial cells, and capsule cells of the canine lymph node. To clarify if macrophages take up VEGF from the environment or express VEGF, VEGFR-1, VEGFR-2 or VEGFR-3 themselves, the mRNA expression was studied by real-time RT-PCR. After RNA isolation and subsequent analysis with the Agilent 2100 Bioanalyzer only RNA samples with appropriate RNA integrity were used for real-time PCR. For the accurate relative quantification of mRNA expression levels several reference genes were evaluated. It was shown that the reference genes HPRT1 and B2M serve as reliable reference genes for gene expression studies in the canine lymph node. Expression data analysis revealed no significant difference in VEGF expression levels between endothelial cells and the other investigated cells. VEGFR-1 expression was significantly lower in lymphocytes. Also macrophages showed a highly significant lower expression of VEGFR-1 compared to endothelial cells. In addition, the VEGFR-2 expression in lymphocytes and macrophages was significantly lower in comparison to endothelial cells. We were not able to detect VEGFR-3 mRNA in the lymphocyte cell population, in macrophages and cells of the lymph node capsule VEGFR-3 was expressed at very low levels. It was shown that laser capture microdissection in combination with quantitative real-time PCR is a valuable tool for studying the expression patterns of specific cells in their microenvironment. Our results support the hypothesis that VEGF and its receptors have other biological roles besides stimulating angiogenesis in the normal lymph node. These biological functions need to be clarified in further studies.  相似文献   

16.
Vascular endothelial growth factor (VEGF) is a key angiogenic growth factor, playing putative roles in both tumour growth and metastasis. The purpose of this study was to correlate pretreatment serum concentrations of VEGF in dogs with osteosarcoma (OSA) with disease‐free interval (DFI) and overall survival (OS). Additionally, the effect of serum from dogs with OSA on ex vivo canine endothelial cell (EC) growth was determined. Pretreatment platelet‐corrected serum VEGF levels correlated significantly with DFI. No other examined variable predicted outcome. The ability of sera from dogs with OSA to stimulate canine EC proliferation did not correlate with VEGF concentration or outcome. These data support a role for VEGF in the development or progression of metastatic disease in dogs with OSA. The VEGF concentration in tested sera was not a major determinant of ex vivo canine EC proliferation in this study.  相似文献   

17.
Angiogenesis, which is essential for malignancies to progress, depends on various signalling proteins including vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors 1 and 2 (VEGFR-1 and VEGFR-2). Microvessel density (MVD) is frequently used to evaluate angiogenesis. This study assessed the relationship between expression of VEGF, VEGFR-1 and VEGFR-2, MVD and the survival time in dogs with lymphoma. VEGF, VEGFR-1 and VEGFR-2 expression was evaluated immunohistochemically and microvessel profiles were counted in 34 lymphoma samples. Seventy-nine percent of the samples showed high VEGF expression and 62% were highly positive for VEGFR-1; VEGFR-2 immunoreactivity was mostly negative. Dogs treated with chemotherapy had a median survival time of 266days, but no significant relationships were found between overall survival time, MVD and expression of VEGF, VEGFR-1 or VEGFR-2. In this study, VEGF its receptors and the MVD were no prognostic factors in dogs with lymphoma.  相似文献   

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19.
Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are proteins implicated in tumor-associated microvascular angiogenesis. Expressions of VEGF and bFGF in various stages of chemical-induced rat bladder carcinogenesis were immunohistochemically investigated. Thirty-two male 6-week-old Wistar rats were given drinking water containing 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 20 weeks. VEGF and bFGF were not detected in the normal bladder epithelium. In simple hyperplasia, intensive expression of VEGF was observed in a few epithelial cells, and the expression of epithelial VEGF became more pronounced in papillary or nodular (PN) hyperplasia and papilloma. In carcinoma, heterogeneous expression of VEGF was observed in focal tumor cells, intensely expressed in the invading tumor cells. Ultrastructurally, carcinoma cells showed VEGF immunoreactivity in the cytoplasmic matrix and some rough endoplasmic reticulum, and VEGF-positive and -negative carcinoma cells were also clearly defined. High levels of VEGF mRNA were observed in the carcinoma. However, bFGF was not detected in the epithelium throughout the carcinogenesis. Increased microvessel counts appeared at simple hyperplasia and became more pronounced in PN hyperplasia, papilloma, and carcinoma (F-test; P < 0.05). In the carcinoma, the microvessel counts of the VEGF-expressing tumor areas were significantly higher than that of the non-VEGF-expressing tumor areas (U-test; P < 0.05). The present study suggests that upregulation of epithelial VEGF may begin at a quite early stage in BBN-induced rat bladder carcinogenesis, but bFGF may not be involved.  相似文献   

20.
Integrins are the major receptors within the extracellular matrix (ECM) that mediate several functions connected with cell life and metabolism, such as cell adhesion, migration, cytoskeletal organization, proliferation, survival, and differentiation. A vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors. It has been suggested that the expression of this gene may play crucial physiological roles in reproductive organs. All investigated endometrial tissues were isolated on day 10-12 after mating. Control bitches, used in this study, were in metestrus, which was determined according to the vaginal cytology and progesterone level in blood. Early pregnancy was verified by flushing the uterine horns with PBS. Total RNA was isolated from the bitches endometrium by means of the Chomczyński and Sacchi method, treated by DNase I, and reverse-transcribed into cDNA. A quantitative analysis of integrins alpha2b, beta2 and beta3, VEGF 164, 182 and 188 cDNA was performed by RT-PCR. In results we have shown an increased expression of all investigated genes (integrins alpha2b, beta2 and beta3, VEGF 164, 182, and 188) in pregnant bitches uterus as compared to non-pregnant females (P < 0.001). Our results indicated that the expression of genes encoding integrins and vascular endothelial growth factors is different in relation to the time of the embryo implantation and it is increased in the first period of this process. This may be associated with the induction of specific mechanisms responsible for receptivity of uterus following the embryo attachment. In addition, all of investigated genes are up-regulated in a pregnancy-specific manner and the increased expression of these genes may regulate the uterus function during the implantation of canine embryos.  相似文献   

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