A review of the development of tumor vasculature and its effects on the tumor microenvironment

Abstract

Background: The imbalance of angiogenic regulators in tumors drives tumor angiogenesis and causes the vasculature to develop much differently in tumors than in normal tissue. There are several cancer therapy techniques currently being used and developed that target the tumor vasculature for the treatment of solid tumors. This article reviews the aspects of the tumor vasculature that are relevant to most cancer therapies but particularly to vascular targeting techniques.

Materials and methods: We conducted a review of identified experiments in which tumors were transplanted into animals to study the development of the tumor vasculature with tumor growth. Quantitative vasculature morphology data for spontaneous human head and neck cancers are reviewed. Parameters assessed include the highest microvascular density (h-MVD) and the relative vascular volume (RVV). The effects of the vasculature on the tumor microenvironment are discussed, including the distributions of hypoxia and proliferation.

Results: Data for the h-MVD and RVV in head and neck cancers are highly varied, partly due to methodological differences. However, it is clear that the cancers are typically more vascularized than the corresponding normal tissue. The commonly observed chronic hypoxia and acute hypoxia in these tumors are due to high intratumor heterogeneity in MVD and lower than normal blood oxygenation levels through the abnormally developed tumor vasculature. Hypoxic regions are associated with decreased cell proliferation.

Conclusion: The morphology of the vasculature strongly influences the tumor microenvironment, with important implications for tumor response to medical intervention such as radiotherapy. Quantitative vasculature morphology data herein may be used to inform computational models that simulate the spatial tumor vasculature. Such models may play an important role in exploring and optimizing vascular targeting cancer therapies.

Keywords: cancer; head and neck; hypoxia; radiotherapy response; vasculature morphology.

Figure 1

Organized vasculature in normal tissue contrasted with chaotic vasculature in tumors. Note: Adapted with permission from Macmillan Publishers Ltd.: Nature Medicine, Jain RK, Molecular regulation of vessel maturation, 2003;9(6):685–693, copyright (2003).

Figure 2

Fluorescence microscopic image of a tumor section after staining for hypoxia (green) and vessels (red). Notes: A typical corded structure is recognizable. There are well-oxygenated areas directly adjacent to vessels, further out there is hypoxia and at even greater distances there is necrosis (white arrow). Adapted with permission from Macmillan Publishers Ltd on behalf of Cancer Research UK: British Journal of Cancer, Wijffels KIEM, Kaanders JHAM, Rijken PFJW, et al, Vascular architecture and hypoxic profiles in human head and neck squamous cell carcinomas, 2000;83(5):674–683, copyright 2000.