Angiogenic and vasculogenic phenotyping allows distinguishing lymphoma from leukemic 'stages' of chronic lymphocytic leukemia

• Author(s): Teixeira, Cristiana Alexandra Ferreira Monteiro
• Date: 2009
• Persistent ID: http://hdl.handle.net/10451/1431
• Origin: Repositório da Universidade de Lisboa
• Subject(s): Biologia celular; Leucemia; Linfocitose; Teses de mestrado
• Document Type: Master thesis
• Language: English
• Advisor(s): Dias, Sérgio Jerónimo Rodrigues; Rodrigues, Maria Gabriela
• Contributor(s): Repositório da Universidade de Lisboa

Description

Tese de mestrado, Biologia (Biologia Humana e Ambiente), 2009, Universidade de Lisboa, Faculdade de Ciências

During tumor angiogenesis bone marrow (BM)-derived endothelial progenitor cells (EPC) are recruited to circulation and contribute to the neo-vasculature of growing tumors. Although the pathophysiologic role of angiogenesis in solid tumors has been extensively studied, its involvement in hematological malignancies has only recently been recognized. Increased angiogenesis has been documented in patients with Chronic Lymphocytic Leukemia (CLL). The World Health Organization classification of hematopoietic neoplasias recognizes some lymphomas and corresponding lymphoid leukemias as different phases (solid and circulating, respectively) of the same disease: CLL as a leukemic, lymphocytic lymphoma, only distinguishable from small lymphocytic lymphoma (SLL) by its leukemic presentation and lower aggressiveness. It arises mainly from a slow accumulation of mature-looking malignant B lymphocyte population resistant to apoptosis, in the peripheral blood (PB), BM and/or lymph nodes (LN). Given the clinical importance of distinguishing leukemic from lymphoma forms of CLL, we characterized the angiogenic and vasculogenic profile of CLL patients to test the hypothesis that there might be differences in angiogenesis-related parameters in circulation (circulating endothelial progenitor cells (CEPC) and vascular endothelial growth factor (VEGF) and incorporated into the affected BM and LN tissues between the two phases of the disease. Our data shows that patients with SLL under treatment have higher number of circulating EPC and higher levels of circulating VEGF. Importantly, we show that CEPC are functional in CLL and SLL patients, as seen in vitro in endothelial differentiation assays. We also observed increased microvessel density, decreased tumor cell apoptosis and higher CD38 expression by the tumor cells in BM biopsies from SLL patients which could be related with increased aggressiveness and bad prognosis of the disease at this phase. The miRNAs expression profile showed that there are different miRNAs patterns associated with SLL and CLL phases. Our study demonstrates for the first time significant differences in angiogenic and vasculogenic factors in circulation and in the affected tissues between leukemia and lymphoma phases, as suggested by a significant higher number of CEPC in SLL patients vs. CLL patients; this result together with increased MVD observed in BM of SLL patients could be related with a more aggressive phenotype.

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