Previously, most tumors were thought to originate as avascular masses that subsequently induce vascularization.1,2 A number of tumor types have now been shown to initiate growth by coopting existing blood vessels. Vascular endothelial growth factor (VEGF) and Angiopoietin-2 (Ang-2) appear to play crucial roles in the balance between vascular regression and growth of this subset of tumors.2
There is evidence that not all tumors follow the classically accepted stages associated with tumor growth. Holash et al.3 identified three types of tumors that develop by coopting existing vessels. As the tumor grows, internal vasculature starts to regress. As vascular regression progresses, the interior of the tumor becomes avascular and the cells undergo apoptosis and necrosis. The tumor is then rescued by robust angiogenesis at its margin (see Figure 1).
|Figure 1. 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).
The expression patterns of VEGF (pro-angiogenic factor) and Ang-2 (angiogenic antagonist) mark these stages. Ang-2, released by endothelial cells of the interior tumor vessels, cause the vessels to destabilize and regress as well as disassociate from surrounding tumor cells. Induction of Ang-2 was proposed to be a survival signal to thwart the tumor's growth process. However, VEGF upregulation coincident with Ang-2 expression induces angiogenesis at the margins of the tumor, allowing the tumor to thrive. Late expression of tumor-derived VEGF may serve to repress the signal for vessel regression by Ang-2, which is consistent with the observation that VEGF is necessary for promoting tumor vessel survival.
- Folkman, J. (1971) N. Engl. J. Med. 285:1182.
- Hanahan, D. and J. Folkman (1996) Cell 86:353.
- Holash, J. et al. (1999) Science 284:1994.
- Benjamin, L. et al. (1999) J. Clin. Invest. 103:159.