Special Project Angiogenesis
Accumulating evidences indicate that progressive tumor growth is dependent on angiogenesis. Most tumors in humans persist in situ for a long period of time (from months to years) in an avascular, quiescent status. In this phase the tumor may contain few million cells. When a subgroup of cells within the tumor switches to an angiogenic phenotype by changing the local equilibrium between positive and negative regulators of angiogenesis, tumor starts to grow rapidly and becomes clinically detectable.
Angiogenesis and Cancer
Tumor growth demonstrating progressive vessel regression correlating with expression patterns of Ang-2 and VEGF. A small tumor initially grows by coopting existing vessels (A). Ang-2 expression promotes vessel regression (B). Robust angiogenesis is apparent at the margin of the tumor where VEGF expression is upregulated (C). (from:http://www.rndsystems.com/cb/cbsu99/cbsu99a1.html)
All tissues and organs develop a specific and characteristic vascular architecture fulfilling their specific functional and nutritive requirements. The existence of a tumor type specific vascularity has been discussed controversially. 3D morphometric analysis of tumor casts suggests that individual tumor cell lines initiate individual microvascular networks.
Mathematical models have been developed to describe the tumor angiogenesis process. Fractal analysis of tumor vascular networks has indicated that the increase of the levels of diffusible angiogenesis growth factor(s) achieved by local release is a possible key determinant of the shape of the capillary networks. However, the same mathematical models have shown that also inhomogeneity of tumor extracellular microenvironment may play an important role.
The Deterministic Cellular Automata (DCA) technique has been developed by Dr. Anderson to describe tumor angiogenesis:
DCA of Tumour Induced Angiogenesis without Proliferation (left) or with Proliferation at t=10 (right):
A row of tumour cells are positioned at x=1 and the parent blood vessel with five initial sprouts is positioned at x=0. In the right panel, the endothelial cells that form the sprouts begin to proliferate at time 10. This induces a surge of migration, seen at approximately x=0.6 to 0.8, which leads to the capillary sprouts connecting with tumour and thus completing angiogenesis.
For more informations about this mathematical approach to tumor angiogenesis take a look at Dr. Anderson home page.
Interestingly, not only cancer cells but also inflammatory cells that infiltrate the tumor and the extracellular matrix can be a source of angiogenesis factors.
New blood vessels will provide nutrients to proliferating cancer cells, thus favouring tumor growth. On the other hand, new capillaries provide a port of entry for anti-neoplastic drugs, thus allowing the chemotherapeutic treatment of cancer patients. Unfortunately, leaky blood vessels cause an increase of interstitial pressure that limit drug diffusion within the tumor and favour tumor cell dissemination in the blood stream. Eventually, this will induce tumor spreading and the appearance of tumor metastases.
Clinical applications of research in tumor angiogenesis have taken three major directions:
Different positive and negative regulators of angiogenesis have been identified so far. They are produced by tumor cells as well as by infiltrating inflammatory cells. Most of them are stored in the extracellular matrix in a bioactive form. Also, receptors for angiogenesis factors have been demonstrated on the endothelial cell surface and the signal transduction mechanisms responsible for the induction of the angiogenic phenotype are currently being investigated.
- the identification of the positive and negative regulators of angiogenesis and the characterization of their mechanism of action;
- the identification of natural and synthetic inhibitors of angiogenesis;
- the quantitation of neovascularization in tumor biopsies for use in diagnosis and prognosis.
Quantitation of microvessel density in tumor specimens has been perfomed. The evaluation of blood vessel density in a tumor may help to predict the risk of metastases or recurrence. Recent observations have confirmed this hypothesis for different types of tumors, including breast cancer.