ENDOCAM · TARGETING ENDOTHELIAL CELL AND CANCER AMOEBOID MOVEMENT TO OVERCOME RESISTANCE TO ANTI-VEGF AND ANTI-PROTEASE THERAPIES
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-12-01 → 2021-09-01
- EU contribution
- €244,269
- Participants
- 2
- Scheme
- MSCA-IF-GF
Lines connect the coordinator with its partners.
Results in brief
TARGETING ENDOTHELIAL CELL AND CANCER AMOEBOID MOVEMENT TO OVERCOME RESISTANCE TO ANTI-VEGF AND ANTI-PROTEASE THERAPIES
Cancer cells, like healthy cells, need oxygen and nutrients to survive and grow. The angiogenic factors are signals sent by cancer cells to encourage new blood vessels to grow into tumor to bring in nutrients and oxygen. Therefore, based on cumulative experimental and clinical evidences, tumor angiogenesis is a well-established therapeutic target. Growth factors secreted by the tumor create chemotactic gradients to recruit endothelial cells (EC) and pericytes from pre-existent vascular beds and endothelial progenitor cells (EPC) from the bone marrow. With the support of the cooperative tumor microenvironment, cancer continues to have the opportunity to survive, to accumulate mutations and metastasize. Understanding the tumor as an organ requires an understanding of angiogenesis. It was known that ECs could form new blood vessels only using the mesenchymal type of motility characterized by the activity of membrane-associated proteases that open a new path allowing the invasion of endothelial cells through the extracellular matrix. The experiments conducted for this research project demonstrated that endothelial cells can move and differentiate into vascular structures in vitro and in vivo also in the absence of proteases activity, performing a new type of neovascularization: the “amoeboid angiogenesis”.
Data: CORDIS, © European Union
Project objective
Unlike mesenchymal migration, the amoeboid motility doesn’t require proteases and is an opportunistic movement of cancer cells which allows cells to glide through, rather than degrade, ECM barriers, using movements based on adaptations of the cell body. Preliminary experiments we conducted using a mixture of physiologic inhibitors of serine-proteases, metallo-proteases and cysteine-proteases, thus mimicking a physiological environment, showed no differences in vessel formation for both Endothelial Progenitor Cells (EPCs) and mature Endothelial Cells (ECs) under mesenchymal or amoeboid conditions. Thus, we hypothesized the existence of an “amoeboid angiogenesis”. We also hypothesized that the failure of cancer treatment using synthetic metalloproteinase inhibitors (MPIs) could be ascribed to the ability of cancer and ECs to skip the attack of the MPI therapy by allowing cancer invasion and blood vessel formation using the “amoeboid” strategy. Even the VEGFA targeting partially disregarded the expectations because of the resistance onset followed by the progression of the disease. Our preliminary experiments showed also an “indifference” of ECs and EPCs to VEGF stimulation under amoeboid conditions. Therefore, the aim of this project is to identify the multiple mechanisms shared by cancer cells and ECs/EPCs in the regulation of amoeboid movement, to identify common therapeutic strategies impairing vascular growth and cancer cell invasion at the same time, overcoming resistance to anti-VEGF and anti-protease therapy. The molecules identified (ephrin, protease receptors, etc.) will be used as candidates for targeted therapy through the delivery of cargo liposomes containing inhibitors of the connection of such molecules with the cortical actin cytoskeleton, in pre-clinical experiments with the perspective of a possible application to humans. We expect that this approach will give a progress in the treatment of tumors thus improving outcomes for cancer patients.
Original text from CORDIS.
Participants
- UNIVERSITA DEGLI STUDI DI FIRENZE · FlorenceCoordinatorItaly
- THE REGENTS OF THE UNIVERSITY OF CALIFORNIA · OaklandUnited States
Links
Data: CORDIS, © European Union