Warburg revisited: imaging tumour blood flow and metabolism

Abstract

In the 1930s, Otto Warburg reported that anaerobic metabolism of glucose is a fundamental property of all tumours, even in the presence of an adequate oxygen supply. He also demonstrated a relationship between the degree of anaerobic metabolism and tumour growth rate. Today, this phenomenon forms the basis of tumour imaging with fluorodeoxyglucose positron emission tomography (FDG-PET). More recently, Folkman has demonstrated that malignant growth and survival are also dependent on tumour vascularity which is increasingly evaluated in vivo using techniques such as contrast enhanced computed tomography or magnetic resonance imaging (MRI). Although it is reasonable to hypothesise that the metabolic requirements of tumours are mirrored by alterations in tumour haemodynamics, the relationship between tumour blood flow and metabolism is in fact complex. A well-developed tumour vascular supply is required to ensure a sufficient delivery of glucose and oxygen to support the metabolism essential for tumour growth. However, an inadequate vascularisation of tumour will result in hypoxia, a factor that is known to stimulate anaerobic metabolism of glucose. Thus, the balance between tumour blood flow and metabolism will be an important indicator of the biological status of a tumour and hence the tumour's likely progression and response to treatment. This article reviews the molecular biology of tumour vascularisation and metabolism, relating these processes to currently available imaging techniques while summarising the imaging studies that have compared tumour blood flow and metabolism. The potential for vascular metabolic imaging to assess tumour aggression and sub-classify treatment response is highlighted.

Figure 1

Conventional CT (A) and images of tumour blood flow (B) and glucose metabolism (C) acquired using perfusion CT and FDG-PET, respectively, from a patient with non-small cell lung cancer.

Figure 2

Conventional contrast-enhanced CT (A), perfusion CT (B) and FDG-PET (C) images of a large hepatic metastasis from colorectal cancer demonstrating regional areas of mismatch between vascularity and metabolism. The orange polygon outlines an area of tumour necrosis with markedly reduced vascularity and metabolism. Regions of reduced vascularity but increased FDG uptake can be seen adjacent to the necrotic zone and in the left lobe of the liver (arrow).

Figure 3

Changes in tumour size (left), perfusion (centre) and metabolism (right) of a colorectal liver metastases following chemotherapy. There has been a partial morphological response with a predominantly vascular functional response. This combination may indicate adaptation of the tumour to the development of hypoxia during therapy. This response pattern could potentially indicate a need to adapt therapy in order to achieve a full response.