Years ago, while doing my Ph.D research in respiratory medicine, I was fascinated by one of my friends chosen area of study. She was looking at the role of endothelial cells and nitric oxide in controlling blood vessels. At the time, it was particularly relevant to cardiovascular disease and most of the focus was in that area. However, at one of the University of London seminars where she was presenting, the conversation spilled into related areas such as where else the concepts could be applied. One of the students was doing related area in cancer research and was interested in how the learnings were relevant to his research. A fairly spirited debate ensued.
Fast forward a decade or two and I was amused to see a paper pop up last month in Science and Translational Medicine, although I only just got round to reading it in my huge pile of what I call ‘interestingness’.
We’ve covered angiogenesis extensively here on this blog, but not in the context of endothelial cells in the tumour microenvironment. Folkman’s seminal 1971 paper is well worth reading (or re-reading) on the topic:
“Tumor cells appear to stimulate endothelial-cell proliferation, and endothelial cells may have an indirect effect over the rate of tumor growth.”
In other words, tumour vessels were originally thought to control tumor growth through perfusion of metabolically active cancer cells. For those of you interested in a more recent review based on progress with angiogenic therapy, Kerbel (2008) published a thorough update on angiogenesis.
Meanwhile, the latest research from Franses et al., (2011) is crucial, because they realised that instead of the long held belief that endothelial cells providing support, they actually do something far more important i.e. secrete molecules that dynamically regulate cancer cell proliferation and invasiveness:
“Secretions from quiescent ECs muted the proliferative and invasive phenotype of lung and breast cancer cells in vitro and reduced cancer cell protumorigenic and proinflammatory signaling.”
The mechanism isn’t yet fully clear, but reducing signaling through intracellular pro-tumor and pro-inflammatory pathways was suspected.
From this study it looks as though endothelial cells (such as fibroblasts and immune cells) are therefore active participants in regulating the tumour microenvironment, and thereby potential targets for therapeutic intervention. Stromal-cancer crosstalk is rapidly becoming a hot topic and realising that the endothelial cells may be more important than originally thought may be a useful advance in our understanding of angiogenesis and how tumours proliferate.
So, to answer the question of whether stromal endothelial cells directly influence cancer progression, the answer would appear to be a surprising yes, which may have implications for future combination trials.
Franses, J., Baker, A., Chitalia, V., & Edelman, E. (2011). Stromal Endothelial Cells Directly Influence Cancer Progression Science Translational Medicine, 3 (66), 66-66 DOI: 10.1126/scitranslmed.3001542
Sherwood, L., Parris, E., & Folkman, J. (1971). Tumor Angiogenesis: Therapeutic Implications New England Journal of Medicine, 285 (21), 1182-1186 DOI: 10.1056/NEJM197111182852108
Kerbel, R. (2008). Tumor Angiogenesis New England Journal of Medicine, 358 (19), 2039-2049 DOI: 10.1056/NEJMra0706596