Tumor Induced Angiogenesis

Tumor induced sprouting angiogenesis is the process of new capillary growth from an existing vasculature, induced by tumor cells that have the “angiogenic switch” turned on. Vascular endothelial growth factors(VEGF) released by tumor cells diffuse through the extracellular Matrix and stimulate endothelial cells lining existing vessels in the proximity of the tumor to form sprouts. As the newly formed sprout tips migrate through the ECM, defining the morphology of the dgradients determine their migration paths.

Simulation of blood vessel growth (red) in the presence of matrix-bound VEGF (blue)

A 3D Model of Sprouting Angiogenesis:
We have developed a novel model of sprouting angiogenesis that  quantifies several biological assumptions and their dynamic interactions. This enables the identification of critical factors in the process of angiogenesis and paving the way for future integration of experimental data.

Vascular Endothelial Growth Factors(VEGF): VEGF is implicated as a key regulator of pathological, tumor induced angiogenesis. We consider three distinct forms of VEGF:sVEGF (soluble VEGF) diffuses  and establishes a chemotactic gradient. bVEGF (matrix-bound VEGF) is bound to the Extra-Cellular Matrix (ECM). It bcomes soluble upon cleaving from the ECM byMMPs. cVEGF the cleaved form of bound the matrix bound VEGF.
Matrix Metalloproteinases(MMPs):primarily involved in the degradation of certain ECM proteins. MMPs are released by the endothelial sprout tip cells, and diffuse through the ECM. Upon contact with matrix-bound VEGF, they cleave the VEGF and transform it into a soluble form (cVEGF).
Fibronectin (FIB): released by endothelial sprout tip cells and binds to the ECM, establishing a haptotactic gradient for ECs.
Extracellular Matrix (ECM): fibrous collagen bundles providing guiding structures for migrating endothelial cells.
Migration Cues (MC) for the endothelial tip cells as combination of chemotaxis, haptotaxis and the structure of the ECM.
Endothelial Tip Cells (EC): guided by migration cues as they define the morphology of the capillary network.
Vessels: Vessels are represented by the endothelial cell density. The density is given by the track of the tip cells.

The implementation of this model allows for a large scale parametric study of blood vessel morphology as influenced the structure of the ECM, the distribution of matrix-bound VEGF and the intensity of cell-cell and cell-matrix adhesion.
  • Milde F., Bergdorf M., Koumoutsakos P., A Hybrid Model for 3D Simulations of Sprouting Angiogenesis,  Biophysical J., 95, 3146–3160, 2008 (Abstract) (pdf)
  • Milde F., Bergdorf M., Koumoutsakos P., A Hybrid Model of Sprouting Angiogenesis, Lecture Notes in Computer Science, 167-176, Springer Berlin, 2008 (Abstract) (pdf)