Essential Role of Angiogenic Factors and Bone Marrow-Derived Endothelial/Hematopoietic Cells in the Growth of Solid Tumors

Abstract

The current thesis examines the role of vascular endothelial growth factor receptor-1 (VEGFR-1) autocrine and paracrine loops in different subsets of cells, namely, breast tumor, endothelial and bone marrow (BM)-derived cells, and their role on tumor growth regulation. These studies highlight the functional relevance of the biological pathways mediated by this receptor and the importance of therapies against VEGFRs as antitumor and antiangiogenesis targets. These findings open new perspectives for the study and development of novel and more effective strategies to fight tumor growth and invasion, and lay the foundation for further development of clinical trials. It is well established that angiogenesis is essential for tumor development. Although the process is controlled by several molecules, the vascular endothelial growth factor (VEGF), by signaling through its receptors, VEGFR-1 and VEGFR-2, seems to be the main mediator. Whereas VEGFR-2 biological functions on tumor endothelium are clearly defined, VEGFR-1 roles are mostly unknown. Moreover, besides being initially described as endothelial specific, VEGFR-1 has also been reported in other types of cells of nonendothelial origin, such as subsets of breast tumor cells and hematopoietic stem and progenitor cells. These observations led us to hypothesize the following: (1) If breast tumor cells express VEGFR-1 and produce VEGF, VEGF/VEGFR-1 autocrine loops could occur and promote breast tumor growth in an endothelial cell-independent fashion. (2) Tumorproduced VEGF could also activate, in a paracrine fashion, VEGFR-1 on tumorassociated endothelium promoting angiogenesis, a feature still unclarified. (3) Tumor cells, by releasing VEGF, may be able to induce in a paracrine way the mobilization of populations of VEGFR-1, expressing BM-derived hematopoietic cells that, in addition to VEGFR-2+ endothelial progenitor cells (EPCs) recruitment to tumor sites, might influence malignant cell growth and neovascularization. The in vitro and in vivo functional expression of VEGFR-1 in human breast cancer cells, and the relevance of the specific impairment of this receptor as a therapeutic target, using monoclonal antibodies (mAbs) as strategy, was first evaluated. VEGFR-1 was functionally expressed on subsets of primary human invasive ductal breast carcinoma tissues and breast cancer cell lines, directly promoting their in vitro proliferation by the