Extracellular matrix and angiogenic factors in hematological diseases

Salvador, Daniela Filipa Nobre

http://hdl.handle.net/10400.1/3003

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Authors

Salvador, Daniela Filipa Nobre

Advisor(s)

Dias, Sérgio Jerónimo Rodrigues

Cachaço, Ana Sofia

Abstract(s)

Bone marrow (BM) malignancies are clonal disorders resulting from neoplastic transformation of hematopoietic stem/progenitor cells (HSPCs). Among them, acute myeloid leukemia (AML) is characterized by a rapid increase in immature blood cells numbers, due to apoptosis suppression; myelodysplastic syndromes (MDS) are characterized by peripheral cytopenia, related with increased apoptosis, and can develop to AML. Angiogenesis is an important event that mediates the progression from a chronic to a more acute and aggressive pathology, and its significance in hematological malignancies has just beginning to be explored. BM microenvironment, including soluble factors and extracellular matrix (ECM), in particular fibronectin (FN) that has been found increased in solid tumors, may be responsible for BM disease progression, but its precise role in this context has been poorly investigated. Thus, the aim of this thesis was to know if the BM microenvironment differs between MDS and AML and what role might such factor be playing in disease progression. Our results indicate that MDS BM has more soluble VEGF, a pro-angiogenic factor, and higher matrix metalloproteinases (MMPs) activity, which may be responsible for increased angiogenesis occurring in this disease. Notch pathway, known to be involved in solid tumors angiogenesis, does not regulate FN expression in MDS BM, which leads to new formed vessels instability. In AML, VEGF is kept majorly bounded to FN, and MMPs activity is lower than in MDS BM. In such conditions, VEGF bioavailability is more regulated, being angiogenesis less exuberant. In addition to this, Notch pathway regulates FN deposition around new vessels, contributing to the formation of a more functional and stable vasculature in AML. To our knowledge, nothing has been described about the regulation of VEGF bioavailability in BM diseases, as well as regarding the possible effect of Notch signaling in angiogenesis of hematological dysfunctions.