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.

Capillary growth from an existing vasculature

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.

A novel model of sprouting angiogenesis

Vascular Endothelial Growth Factors (VEGF): VEGF is implicated as a key regulator of pathological, tumor induced angiogenesis. We consider three distinct forms of VEGF:

  1. sVEGF: Soluble VEGF diffuses and establishes a chemotactic gradient.
  2. bVEGF: Matrix-bound VEGF is bound to the Extra-Cellular Matrix (ECM). It becomes soluble upon cleaving from the ECM by MMPs.
  3. cVEGF: The cleaved form of 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 and transform it into a soluble form (cVEGF).

Fibronectin (FIB): Released by endothelial sprout tip cells and binds ti 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.

People: Florian Milde, Michael Bergdorf

Funding: ETH Zurich

Publications

2008

  • F. Milde, M. Bergdorf, and P. Koumoutsakos, “A hybrid model for three-dimensional simulations of sprouting angiogenesis,” Biophys. J., vol. 95, iss. 7, p. 3146–3160, 2008.

BibTeX

@article{milde2008b,
author = {Florian Milde and Michael Bergdorf and Petros Koumoutsakos},
doi = {10.1529/biophysj.107.124511},
journal = {{Biophys. J.}},
month = {oct},
number = {7},
pages = {3146--3160},
publisher = {Elsevier {BV}},
title = {A Hybrid Model for Three-Dimensional Simulations of Sprouting Angiogenesis},
url = {https://cse-lab.seas.harvard.edu/files/cse-lab/files/milde2008b.pdf},
volume = {95},
year = {2008}
}

Abstract

Recent advances in cancer research have identified critical angiogenic signaling pathways and the influence of the extracellular matrix on endothelial cell migration. These findings provide us with insight into the process of angiogenesis that can facilitate the development of effective computational models of sprouting angiogenesis. In this work, we present the first three- dimensional model of sprouting angiogenesis that considers explicitly the effect of the extracellular matrix and of the soluble as well as matrix-bound growth factors on capillary growth. The computational model relies on a hybrid particle-mesh representation of the blood vessels and it introduces an implicit representation of the vasculature that can accommodate detailed descriptions of nutrient transport. Extensive parametric studies reveal the role of the extracellular matrix structure and the distribution of the different vascular endothelial growth factors isoforms on the dynamics and the morphology of the generated vascular networks.
  • F. Milde, M. Bergdorf, and P. Koumoutsakos, “A hybrid model of sprouting angiogenesis,” in Computational science – ICCS 2008, Springer, 2008, p. 167–176.

BibTeX

@incollection{milde2008a,
author = {Florian Milde and Michael Bergdorf and Petros Koumoutsakos},
booktitle = {Computational Science – {ICCS} 2008},
doi = {10.1007/978-3-540-69387-1_19},
pages = {167--176},
publisher = {Springer},
series = {Lecture Notes in Computer Science},
title = {A Hybrid Model of Sprouting Angiogenesis},
url = {https://cse-lab.seas.harvard.edu/files/cse-lab/files/milde2008a.pdf},
year = {2008}
}

Abstract

We present a computational model of tumor induced sprouting angiogenesis that involves a novel coupling of particle-continuum descriptions. The present 3D model of sprouting angiogenesis accounts for the effect of the extracellular matrix on capillary growth and considers both soluble and matrix-bound growth factors. The results of the simulations emphasize the role of the extracellular matrix and the different VEGF isoforms on branching behavior and the morphology of generated vascular networks.