Pathophysiological Basis for the Formation of the Tumor Microenvironment

Abstract

Poor microenvironmental conditions are a characteristic feature of solid tumors. Such conditions occur because the tumor vascular supply, which develops from the normal host vasculature by the process of angiogenesis, is generally inadequate in meeting the oxygen and nutrient demands of the growing tumor mass. Regions of low oxygenation (hypoxia) is believed to be the most critical deficiency, since it has been well documented to play a significant role in influencing the response to conventional radiation and chemotherapy treatments, as well as influencing malignant progression in terms of aggressive growth and recurrence of the primary tumor and its metastatic spread. As a result, significant emphasis has been placed on finding clinically applicable approaches to identify those tumors that contain hypoxia and realistic methods to target this hypoxia. However, most studies consider hypoxia as a single entity, yet we now know that it is multifactorial. Furthermore, hypoxia is often associated with other microenvironmental parameters, such as elevated interstitial fluid pressure, glycolysis, low pH, and reduced bioenergetic status, and these can also influence the effects of hypoxia. Here, we review the various aspects of hypoxia, but also discuss the role of the other microenvironmental parameters associated with hypoxia.

Keywords: chemotherapy; hypoxia; malignant progression; radiotherapy; tumor microenvironment.

Figure 1

Vascular casting images showing differences in microcirculation between normal tissues (top three panels) and malignant tumors (lower three panels). Specific details of the corrosion casting technique used to produce these images can be found in Konerding et al. (14). Images shown were obtained courtesy of Prof. Konerding, Dept. Functional and Clinical Anatomy, University Medical Center, Mainz, Germany and are from Vaupel (10). Bottom text lists the major structural and functional abnormalities of tumor vessels when compared to normal tissues; composite information based on work by Kimura et al. (12), Reinhold and van der Berg-Blok (15), Vaupel et al. (10, 16), and Baronzio et al. (17).

Figure 2

Schematic illustration of the relationship between the tumor vasculature and microenvironment. The left side shows tumor cells growing in a corded structure around a functional vessel from which the cells receive their oxygen and nutrient supply, but as these substances diffuse out from the vessel they are utilized by the cells so that gradients are established. On the right side is a flow chart showing the relationship between the hostile microenvironment of tumors and the factors that give rise to its development. Figure is modified from Ref. (1, 27).