Bone Marrow-derived Cells in Angiogenesis and Cancer
Year: 2014
Type: dissertation
Abstract: Tumor is more than a mass of transformed cells. Tumor cells are embedded in the supporting tumor stroma, that is composed of cellular and non-cellular components. The cellular components include vascular cells, bone marrow-derived cells (BMDCs), and fibroblasts. In concert, tumor cells and stromal cells secrete proteases, cytokines, chemokines, and growth factors that modulate the tumor behavior. The mechanisms how stromal cells contribute to the tumor growth and tumor angiogenesis are still incompletely understood. This thesis aimed to study the role of BMDCs in angiogenesis and cancer. First, the role of BMDCs as a source of vascular endothelium was examined. The second study addressed the effects of an EGFR inhibitor, gefitinib, on the vascular cells and BMDCs in an EGFR-deficient B16 mouse melanoma tumor model. In the third study, chemokine-like prokineticins, that may have both angiogenic and immunomodulatory properties, were examined in a virus-associated human skin cancer type, Merkel cell carcinoma (MCC). BMDCs did not incorporate into the vascular endothelium in any of the experimental models, suggesting that the pre-existing vasculature is the main source of endothelium during angiogenesis. The potential of the BMDCs to differentiate into vascular endothelium may require specific molecular microenvironments, which needs further analysis. Treatment of B16 tumors with the EGFR inhibitor gefitinib reduced the pericyte number and coverage in the small CD31+ capillaries and the numbers of perivascular BMDCs suggesting that gefitinib treatment might have vascular and stromal effects in some tumors. The identity of the perivascular BMDCs that responded to treatment is not currently known, but the intimate perivascular location of the affected cells proposes that these cells might contribute to tumor angiogenesis via paracrine mechanisms. In MCC, higher than median tumor prokineticin-2 (PROK2) mRNA content was strongly associated with the presence of Merkel cell polyomavirus (MCPyV) DNA, viral large T antigen expression, higher than median number of tumor infiltrating CD68+ and CD163+ macrophages, and with favorable survival. The presence of prokineticin-1 (PROK1) mRNA in the tumor was associated with absence of MCPyV DNA and tended to be associated with poor survival. Neither PROK1 nor PROK2 mRNA content was associated with the tumor microvascular density. Taken together, these findings support the immunomodulatory role of prokineticins and suggest that prokineticins are involved in mediating the immune response in MCC, but their role in tumor angiogenesis in MCC requires further evaluation.
Source: Työväentutkimus Vuosikirja
Author: Susanna Lauttia
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W815187169