The seed falls on fertile soil. This is the image — which may seem cynical to those concerned — that cancer researchers use to describe the proliferation of a tumour. According to the "seed and soil" model, cancerous cells spread from a primary tumour to other places all over the body but only build metastases in suitable organs. But what makes an organ suitable? One answer, which demonstrates clearly the perfidious nature of this illness, is that the tumour prepares the organ for invasion. This conclusion can be drawn from a new study by ETH Professor of Pharmacogenomics Michael Detmar (1) and his team. Their findings were published in the latest Journal of Experimental Medicine, and an image from the study also graces the issue’s cover (2).

Increased levels of VEGF-A mean more tumours

Detmar and his team obtained new insights while examining the role of the protein VEGF-A. They carried out their work using two groups of mice. The first group was transgenic and engineered to produce more VEGF-A than the second, control, group. A first finding was that the transgenic animals developed both more benign, as well as more malignant tumours. The mutation rate of benign to malignant tumours, however, was comparable in both groups of mice. This indicates that VEGF-A simply acts as an accelerator.

Both strains of mice manifested an increased growth of vascular tissue in their tumours compared to sections of the skin where no tumours ensued even though these locations had been subjected to carcinogenic chemicals. Surprisingly, the VEGF-A mice developed an increased number of larger lymph node vessels around the tumour. These vessels also contained the receptor for VEGF-A.

Lymph node formation prior to metastases

Naturally, this did not explain the spread of the tumour. Further examination showed that in the transgenic mice more tumour cells spread to the sentinel lymph node located nearest to the tumour. The VEGF-A mice also developed metastases twice as often in other lymph nodes. Two other findings emerged. First, the transgenic mice exhibited an increased growth of lymphatic vessels in lymph nodes that were free of cancer. Secondly, these mice continued to develop lymphatic vessels even after metastases had developed in the nodes.

Revealing images: in lymph nodes free of metastases (D) transgenic mice show more vascular tissue (red) than the control group (C). These mice developed more blood vessels (green) and more vascular tissue in the lymph nodes with metastases (F) (control group (E)). (white lines = 100 micrometers). Picture: Michael Detmar. large

"Our findings give the ’seed and soil‘ model a new twist," says Michael Detmar. For the first time, their research shows that tumours actually induce the growth of vascular tissue in the lymph node. This complements earlier findings published by the group in 2001 in Nature Medicine (3). At that time Detmar showed that the formation of metastases in a sentinel lymph node is promoted by the growth of lymphatic vascular tissue in the tumour. Asked how nearly the situation of the transgenic mice mirrors a clinical situation, Detmar says, "The concentration of VEGF-A in the vascular tissue of tumours in these mice is similar to that in many human tumours“. In addition, experience and studies up to now point to a correlation between the level of VEGF-A and the aggressiveness of a tumour.

Progress for diagnosis, and perhaps also for treatment

But is growth in lymphatic tissue a prerequisite for metastase building in all tumours? Detmar thinks that it is not equally important for all tumour types. In a publication just released in Modern Pathology, he also demonstrates for the first time that the extent of vascular lymphatic tissue growth in human melanoma is a precise indicator of the occurrence of metastases in the sentinel lymph node (4).

As it seems a solid prognosis now exists as to the risks of a skin cancer spreading, the question arises of early medicinal intervention. In their publication the researchers mention that Bevacizumab, which blocks VEGF-A, , may hinder the formation of metastases. To date it has only been prescribed for intestinal and kidney cancer after metastasisation has already commenced.

Detmar himself is not researching early intervention by a direct attack on VEGF-A. His own work is currently directed towards inhibiting the VEGF-A receptor; in this way he hopes to influence already-existing lymph node metastases.