Tumor oxygenation and cancer therapy-then and now

Abstract

In 2012, cancer affected 14.1 million people worldwide and was responsible for 8.2 million deaths. The disease predominantly affects aged populations and is one of the leading causes of death in most western countries. In tumors, the aggressive growth of the neoplastic cell population and associated overexpression of pro-angiogenic factors lead to the development of disorganized blood vessel networks that are structurally and functionally different from normal vasculature. A disorganized labyrinth of vessels that are immature, tortuous and hyperpermeable typifies tumor vasculature. Functionally, the ability of the tumor vasculature to deliver nutrients and remove waste products is severely diminished. A critical consequence of the inadequate vascular networks in solid tumors is the development of regions of hypoxia [low oxygen tensions typically defined as oxygen tensions (pO₂ values) < 10 mm Hg]. Tumor cells existing in such hypoxic environments have long been known to be resistant to anticancer therapy, display an aggressive phenotype, and promote tumor progression and dissemination. This review discusses the physiological basis of hypoxia, methods of detection, and strategies to overcome the resulting therapy resistance.

Figure 1.

Fixed section of a human squamous cell carcinoma of the bronchus stained by hematoxylin and eosin. Modified with permission from Thomlinson and Gray.

Figure 2.

(a) Distribution of hypoxia, identified by the bioreductive nitroimidazole agent EF5 (green) and the endogenous hypoxia marker HIF-1 (red), in human cervical carcinoma (SiHa) xenograft with respect to blood vessel localization (CD31, blue). Image courtesy of D. Hedley. (b) Murine mammary carcinoma (4T1) after intravenous injection with Hoechst-33342 (40 mg kg^–1, blue) as a surrogate marker for perfusion, and stained with EF5 (red) and CD31 (green). Please see the online version of this publication for colour images.

Figure 3.

Patient with a FAZA PET positive oropharyngeal cancer. Reprinted with permission from Mortensen et al. FAZA is a PET tracer developed as a hypoxia identification method for preclinical and clinical application. FAZA, ¹⁸F-Fluoroazomycin arabinoside.

Figure 4.

Illustration of tumor cells growing as a cord around blood vessels from which they obtain oxygen and nutrients. The left side illustrates oxygen diffusion and utilization from the vessel resulting in the development of chronically hypoxic cells at the outer edge of the cord. The right side shows perfusion through the vessel that has been transiently compromised and results in the development of acute hypoxia; examples of the types of flow/oxygen changes reported during a 60-min period are illustrated in the four panels below. Reprinted with permission from Horsman et al.

Figure 5.

Effect of hypoxic modification in cancer patients treated with primary radiotherapy. Data are from 86 randomized trials including 10,108 patients with either bladder, cervical, head and neck, CNS, lung or other types of cancer such as esophagus and pancreas. Reprinted with permission from Overgaard.