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Title: The clinical relevance of angiogenesis and lymphangiogenesis in haematological malignancies
Author: Al-Qouzi, Abdullah Ahmed
ISNI:       0000 0001 3407 8955
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2008
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Unlike solid tumours, the possible role of angiogenesis and lymphangiogenesis markers in human haematological malignancies has not been extensively examined. The first part of this study was undertaken to quantify a panel of angiogenic markers viz CDlO5, its two ligands TGF-Pl, TGF-p3, and receptor-ligand complexes (CDlO5/TGF-p1, CD105/TGF-P3) and a marker oflymphangiogenesis (VEGF-C) in plasma samples from 176 children with newly diagnosed leukaemia comprising common acute lymphoblastic leukaemia (cALL) (n=73), acute myeloid leukaemia (AML) (n=24), T cell acute lymphoblastic leukaemia (T cell ALL) (n=13) and with various other types ofleukaemia and lymphoma (n= 66). Plasma samples from normal age-matched 79 children were used as controls. CD105 is a transmembrane glycoprotein expressed on endothelial cells (EC) and is a part of TGF-P receptor. It is highly expressed in angiogenic EC and it is shed into the circulation either as single peptide or complexed with TGF-p1 or TGF-p3. Therefore, ELISAs were developed to quantify levels of these angiogenesis markers as well as VEGFC, a lymphangiogenic marker in samples from children with different types of leukaemia and lymphoma and the results were compared with normal controls. Analysis of data revealed that pre-treatment plasma levels of CD105, TGF-Pl, TGF-p3, the receptor-ligand complexes and VEGF-C were significantly elevated in children with all types of leukaemia and lymphoma compared to controls (p :s; 0.03, Mann-Whitney U test). In addition, levels of CDlO5, CDlO5/TGF-p3 significantly correlated with peripheral blood WBC counts in children with cALL (p = 0.008). However, none of the above parameters correlated with overall survival (OS). In the second part of this work, manual and computerised image analysis (lAC) techniques were used to quantify microvessel density (MVD), total microvessel area (tMVA), and individual microvessel area (iMVA) in bone marrow (BM) biopsies from adult patients diagnosed with AML (n=32; median age 56.5 years) and myelodysplastic syndrome (MDS) (n=13; median age 53 years). BM biopsies (n=lO) from age-matched individuals who had localised lymphoma without histological evidence of BM involvement were used as controls. Three BM biopsies Le. at diagnosis, during remission and at relapse from all patients were obtained, processed and the microvessels were stained immunohistochemically with anti-thrombomodulin antibody. Two independent observers quantified MVD manually and the inter- and intra-investigator counts were highly reproducible. MVD, tMVA, and iMVA in the same samples were also quantified utilizing lAC method. Statistical analysis of data revealed that MVD significantly increased in AML and MDS patients at all 3 stages of the disease compared to normal controls using manual and lAC (p :s; 0.002). tMVA was significantly higher in AML and MDS compared to control (p < 0.001). While iMVA was significantly higher in patients with MDS at all the 3 stages of the disease (p :s; 0.029), it was only significantly higher in AML patient at pre-treatment compared to controls (p =0.01). The last part of this thesis was a pilot study to identify genes significantly differentially expressed in samples from AML patients at dia~nosis in comparison with those after treatment from the same patients using Affymetrix GeneChip® HG-U133 Plus 2.0 arrays (Affymetrix® Inc.). All patients at presentation had high WBC count (> 100 X109 ) with more than 60% blast. A total of 89 (31 up-regulated and 58 down regulated) genes with 5 or higher fold change were identified
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available