| Abstract |
Background: Angiogenesis denotes the formation of new blood vessels from preexisting
ones. It is an adaptive mechanism of the human body and is controlled by a fine
balance between pro- and anti-angiogenic factors. In solid tumours, the balance is lost in
favour of proangiogenic signals promoting the growth and dissemination of the tumour.
Hodgkin and Non Hodgkin lymphomas are lymphoid malignancies with unique
biological and immunological features. The degree of dependence of lymphomas on
angiogenesis is currently unknown.
Aim: The aim of the current study was to examine the role of angiogenesis in Hodgkin
and B cell Non Hodgkin lymphomas. In order to achieve this, the histological and
peripheral expression of a series of active molecules and their receptors as well as the
microvessel density was measured in affected lymphomas. The relation of angiogenesis
to the peripheral expression of representative inflammatory and immunomodulatory
cytokines was also determined.
Materials & Methods: In the prospective part of this study, serum was collected from 60
newly diagnosed Hodgkin patients and used to determine the concentration of: VEGF
(vascular endothelial growth factor), receptor VEGF R2, HGF (hepatocyte growth
factor), bFGF (basic fibroblast growth factor), angiogenin, angiopoietin-2, MMP-2
(metalloproteinase-2), IL-8, TNFα, IL-6, IL-10 και IL-12 by the ELISA method. Serum
was also collected from 49 newly diagnosed patients with Non Hodgkin Lymphoma for
the measurement of VEGF, angiogenin, IL-8, IL-6, IL-2 and IL-16. The aforementioned
molecules were determined in a subgroup of patients at the end of standard treatment and
in a group of normal controls.
In the retrospective part of this study, the histological expression of microvessel density
(using an anti-CD31 antibody), VEGF, PDGFRα (platelet derived growth factor receptor
α), HIF-1α (hypoxia inducible factor 1α), Ki-67 and p53 was assessed in 65 Hodgkin
lymph nodes by immunohistochemistry.
Results: In Hodgkin lymphomas there is increased peripheral expression of the
angiogenic molecules HGF, VEGF and IL-8 in comparison to healthy controls, which
decreases after effective treatment. Increased levels of HGF and IL-8 are associated with
advanced stages of disease. Prognostic value is attributed to HGF as serum levels below
2306 pg/ml are associated with a higher probability of complete response to treatment.
The inflammatory response comprises an increase in the levels of TNFα and IL-6. IL-6
levels show a positive association with HGF and VEGF levels. The immunological
response is characterized by a predominance of IL-10 (indicative of a Th2 response) and
depressed levels of IL-12.
Immunohistochemical expression of VEGF and p53 in the reactive cells of Hodgkin
lymphoma was found at the initial stages of the disease. Neoplastic cells show strong
staining of PDGFRα in the majority of cases and weak staining of HIF-1α in half of the
cases examined. Microvessel density is not increased in Hodgkin in comparison to
normal lymph nodes but increases in parallel to the Ki-67 positivity of reactive cells.
B Non Hodgkin lymphomas have increased peripheral levels of VEGF and IL-8, whereas
angiogenin is within the normal range. The inflammatory response is characterized by an
increase in IL-6, whereas the increase in IL-2 is indicative of a Th1-type immunological
reaction.
Conclusions: 1. Increased histological expression of key angiogenic factors is observed
in Hodgkin tissues. 2. There is also an increase in the levels of angiogenic factors in the
serum of Hodgkin and Non Hodgkin patients. 3. The release of angiogenic factors in the
periphery relates to the release of inflammatory cytokines supporting a role of
inflammation as a positive feedback in angiogenic signalling. 4. The difference in
prevailing angiogenic signals between the two lymphomas may be associated with the
specific immunological reaction. This is supported by the difference in cytokine profile
seen between Hodgkin (dominant Th2) and Non Hodgkin (dominant Th1 reaction)
lymphoma. 5. The microvessel density in Hodgkin lymph nodes is not increased in
comparison to normal lymph nodes implying alternative roles (rather than vessel
formation) for overexpressed angiogenic molecules. Such roles may be the positive
control of lymphangiogenesis, inflammation and immunosuppression. 6. The relation of
microvessel density to Ki-67 in reactive cells implies that increased blood supply is
important mainly for the reactive dividing compartment rather than the malignant
Hodgkin clone itself. 7. The dominant angiogenic pathways in Hodgkin lymphoma are
HGF and PDGF, which may prove useful for the selection of specific anti angiogenic
treatment in the future.
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