Prognostic value of serum vascular endothelial growth factor (VEGF) and plasma activity of matrix metalloproteinase (MMP) 2 and 9 in lymphoma-affected dogs
Introduction
Neoangiogenesis is a tightly controlled phenomenon regulated by complex interactions of many different molecules. In recent years, evidence has accumulated which shows that abnormal angiogenesis, besides its well-known role in solid tumor growth and metastasis, is also critically involved in hematologic malignancies such as multiple myeloma (MM), leukemia, myelodisplastic syndromes (MDS) and non-Hodgkin's lymphoma (NHL) [1], [2]. Many authors have measured the circulating levels of angiogenic factors in patients affected by lymphoproliferative disorders with the aim of establishing their possible association with prognosis and outcome. Among pro-angiogenic molecules, VEGF and MMP 2 and 9 (gelatinases A and B) play a pivotal role in tumor-associated angiogenesis. VEGF circulating levels are increased in acute myeloid leukaemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukaemia (CML), MDS, MM, NHL and Hodgkin disease (HD) [1], [2], [3]. Recently, either circulating VEGF and MMP 9 levels or the expression of MMP 9 has been further correlated with a poor prognosis, response to therapy, overall survival and/or event-free period in NHL-affected patients [4], [5], [6].
Human non-Hodgkin's lymphomas present overlapping features with canine lymphomas allowing the formulation of a comparative classification system [7], [8] and the consideration of canine NHL as spontaneous models for its human counterpart [9].
In the present study, serum VEGF concentration and plasma MMPs activity in lymphoma-affected dogs were evaluated in order to investigate their relevance as prognostic markers and to clarify the possible role of spontaneous canine lymphoma as an animal model in experimenting with antiangiogenic drugs.
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Patients and samples
We retrospectively evaluated two cohorts of samples, 48 sera and 23 platelet poor citrated plasma (PPCP), in order to test VEGF concentrations and matrix metalloproteinase activity, respectively, at admission and before chemotherapy in 51 NHL affected dogs having stored samples available and which had been diagnosed at the University of Bologna Veterinary Teaching Hospital between January 2001 and August 2004. Twenty dogs were shared in both cohorts. As controls, an additional group of 16
Results
Forty-eight sera obtained from lymphoma-affected dogs at admission, and 16 samples of healthy blood donor dogs were assayed for VEGF concentrations. Lymphoma-affected dogs showed significantly (p < 0.001) higher values when compared to healthy dogs (Table 2). VEGF concentration levels were not statistically correlated with platelets counts (Spearman R = −0.22, p = 0.110). Twenty-three PPCP of lymphoma-affected dogs at admission and 16 healthy control dogs were assayed for MMP 2 and 9 activities (Fig.
Discussion
It has previously been reported by others that the preanalytical steps of blood collections and the type of specimen both influence the validity of circulating angiogenesis markers. Many of the pitfalls are addressed in detail elsewhere [14], [15], [16]. In brief, serum VEGF measurement is influenced mainly by the VEGF storage and release functions of platelets [17]. This fact has raised concerns about which is the most appropriate sample to better represent the real increase of serum
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