Introduction to symposium on vascular biology, metabolism and cancer


  • L. Claesson-Welsh

    Corresponding author
    1. Uppsala University, Dept. Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden
    • Correspondence: Lena Claesson-Welsh, Dept. Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv. 20, 751 85 Uppsala, Sweden.

      (fax: 46-18 66 89 31; e-mail:

    Search for more papers by this author

A Life Science symposium in vascular biology, metabolism and cancer was held at Uppsala University on 16–17 February 2012, and was supported by the Journal of Internal Medicine. A series of reviews from this symposium, published in the current issue of the Journal, highlight the recent developments in therapeutic targeting of the vasculature in cancer, the influence of vessel metabolism and immune regulatory cells on disease progression.

Blood vessels form in growing tissues regardless of whether this occurs in physiological processes or in pathological conditions such as cancer. The concept that growth of tissues can be controlled by limiting vascular neoangiogenesis stimulated tumour biology research and led to the development of promising drugs targeting the tumour vasculature. Typically, such drugs are either small molecular weight inhibitors targeting tyrosine kinase activity or antibodies that neutralize growth factors and their receptors. The expectation of clinical success of such drugs has been high, not least from the pharmaceutical industry, which has invested considerable resources in the development of these agents. Drugs targeting tumour blood vessels were also initially regarded as particularly promising, as the endothelial cells in the tumour were expected to be ‘normal’ and therefore sensitive to treatment without the ability to develop resistance. It is now clear that this is not the case; tumour vessels adapt to their environment and can lose their sensitivity to a specific growth factor and yet form new vessels in response to stimulation by other factors produced by the tumour. In fact, tumour endothelial cells may be entirely insensitive to the principal stimulator of endothelial cells, vascular endothelial growth factor (VEGF; see symposium review by Claesson-Welsh and Welsh [1]).

Vascular endothelial growth factor was first identified as a potent permeability factor and, subsequently, as a growth factor essential for vascular development in embryogenesis. The fact that VEGF production is stimulated by hypoxia is consistent with the finding that tumours often contain increased amounts of VEGF. The results from many studies have highlighted the role of VEGF in angiogenesis and various pathological conditions such as retinopathy, chronic inflammation and cancer. Drugs targeting VEGF have been successful in the treatment of patients with retinopathy. In certain cancer types, efficient responses with VEGF inhibitors have been observed only in limited cohorts of patients. It has been difficult to establish predictive biomarkers for responsiveness to anti-VEGF therapy. Moreover, there is now clear evidence that VEGF-targeted therapy may promote increased invasiveness and metastatic spread of cancers (see symposium review by Moserle and Casanovas [2]). Mechanistically, both c-MET and epidermal growth factor receptors have been implicated in the increased malignancy that may develop during VEGF therapy ([2]).

Although aggressive suppression of VEGF function may promote tumour malignancy as described above, partial suppression promotes vascular normalization. Normalized vessels show improved functionality with a continuously open lumen, reduced apoptosis of endothelial cells and better perivascular support (see symposium review by Serini et al. [3]). The fact that normalization of tumour vessels impairs tumour growth is to some extent counterintuitive. The improved vessel functionality allows better flow and supply of nutrients and oxygen to the tumour and should therefore enhance tumour growth. However, although vascular normalization in tumour models leads to improvements with less necrosis and apoptosis of the tumour tissue, tumour growth and spread are not enhanced. This may be due to the improved vessel integrity that simply provides a tighter barrier, which impairs the efficiency of tumour cell exit. It may also be that the increased oxygenation in the tumour environment slows down tumour invasiveness. Clearly, tumour metabolism represents a promising field of study (Fig. 1; see symposium review by Feron [4]).

Figure 1.

Anaerobic metabolism dominates in the aggressive tumour with abnormal vessels (left), where invasiveness and metastatic spread may be enhanced by anti-VEGF therapy. Therapy that promotes vessel normalization and antitumour immunity reduces tumour expansion and metastasis (right). For details, see symposium reviews [1-5].

Another mechanism potentially explaining the lack of correlation between tumor growth and vessel normalization is anti-tumor immunity. Antitumour immunity is regulated by inflammatory cells in the tumour. Vessel normalization appears to be accompanied by a shift in the inflammatory cell characteristics, towards production of factors that stimulate both invasion and activity of a range of immune cells (natural killer, dendritic and cytotoxic T cells) that target tumour cells. The resulting, favourable scenario in which tumour expansion is controlled by antitumour immunity, accompanied by decreased metastatic spread, has been demonstrated in preclinical trials and is now being transferred to the clinic. In particular, engineered T cell-based therapy is a promising possibility for clinical application (see symposium review by Essand and Loskog [5]).

Over the last two decades, we have seen a dramatic increase in understanding of the role of the tumour vasculature and implementation of this knowledge in clinical medicine. We have also experienced setbacks, as promising preclinical therapies have failed in the clinic. In hindsight, some of these failures could have been predicted. Thus, efforts must continue to improve all available treatment options for the benefit of patients with cancer.

Conflict of interest statement

No conflict of interest was declared.