A team from Heidelberg University is studying the mechanisms of metastasis with the goal to develop more gentle supportive adjuvant therapies for tumour patients without detectable metastases following surgery of the primary tumour. Towards this end, the scientists focused on novel findings that suggest a much more active tumour-promoting role for endothelial cells, the cells lining the inner wall of blood vessels. The opensource study is published in the journal Cancer Cell.
Cancer patients without overt metastases appear to be tumour-free upon surgical removal of the primary tumour. Yet, metastatic spread of tumour cells may already have occurred at the time of surgery. Many tumour patients are consequently treated with chemotherapy after surgery to fight metastasis. This may be necessary in patients with detectable metastases, but what kind of more gentle treatment options can be offered in patients without overt metastasis? It’s a major dilemma for many tumour patients after surgery, should they opt for a high-dose chemotherapy with all its devastating side effects? Or should they just wait-and-see and possibly live with a higher risk of metastatic disease?.
Tumour cells engage nearby blood vessels to grow new capillaries that nourish the tumour and thereby facilitate its growth. This process, called angiogenesis, is well understood and has already led to clinical application 10 years ago. Albeit still limited in efficacy, angiogenesis-inhibiting drugs have become part of standard tumour therapy supporting the efficacy of established chemotherapies.
The classical concepts of angiogenesis consider the endothelial cells within tumours as a rather passive cell population that merely reacts in response to growth factors released by the tumour cells. Yet, more recent discoveries suggest a much more active role of endothelial cells during tumour growth than has been anticipated so far.
The researchers in the current study consequently pursued preclinical tumour therapy experiments, which were aimed at not just blocking angiogenesis, but to also suppress the production of tumour-promoting growth factors in endothelial cells. They focused towards this end on the vascular growth factor Angiopoietin-2, which is produced by endothelial cells and does not just control angiogenesis, but acts as a key responsiveness factor for endothelial cells.
The researchers grafted breast or lung tumours in mice, allowed the tumours to grow to small size and removed these tumours surgically, essentially mimicking the situation in a human tumour patient in which the tumour is surgically removed as soon as possible after diagnosis. The mice appeared after surgery to be apparently ‘tumour-free’; yet, metastatic cells had already seeded from the small tumours. The mice were upon surgery consequently treated with various forms of chemotherapy as well as with a blocking antibody targeting Angiopoietin-2.
Surprisingly, while neither form of chemotherapy had any effect on the growth of these seeded metastases, Angiopoietin-2 antibody treated mice had significantly less metastases in the lungs and in the bone and survived longer than untreated control mice. This therapeutic effect was enhanced by combining the Angiopoietin-2 antibody with a so-called metronomic chemotherapy. In this kind of therapy, chemotherapeutic drugs are given continuously at much lower dose as in the classical high-dose chemotherapy. Mice treated with such combination therapy survived significantly longer than mice just treated with the Angiopoietin-2 antibody.
Based on these therapeutic effects, the scientists initiated experiments aimed at unraveling the underlying molecular mechanisms of the novel combination therapy. These analyses showed that Angiopoietin-2 is not just affecting angiogenesis, but controls at the same time the production of tumour promoting growth factors in endothelial cells. These endothelial-derived factors stimulate the recruitment of tumor-promoting macrophages into the tumour. The blockade of Angiopoietin-2 reduced the recruitment of these macrophages.
The second branch of the combination therapy, the low-dose metronomic chemotherapy, was similarly found to exert its therapeutic effect through a novel, hitherto unrecognized mechanism. The metronomic chemotherapy turned out to not primarily target the tumour cells, but to act on the recruitment of yet another tumour-promoting cell population from the bone marrow.
The team state that this novel combination therapy simultaneously targets multiple pathways contributing to metastasis. In the current study the team inhibited the growth of new blood vessels in metastases. They also blocked the recruitment of macrophages, which elicit an inflammatory response and thereby contribute to shaping the conductive soil on which metastases can grow.
The team caution that human studies are yet to be started. Yet, the fundamental insights into the mechanisms of metastasis will pave the way for the rationale translation of these preclinical discoveries into clinical application.