Jason Mendler, MD, PhD
In 1971, Dr. Judah Folkman wrote in the New England Journal of Medicine that all cancerous tumors were angiogenesis-dependent. Though most experts in the field initially disregarded his hypothesis, it eventually became clear that tumors do in fact require new blood vessel formation for nourishment and sustenance. Studying the mechanisms underlying this process and developing novel therapeutic approaches have been active areas of research for many years. Dr. Elzbieta Pluskota and colleagues from the Cleveland Clinic have continued this work as described in their plenary talk yesterday.
The gene central to their work, kindlin-2, is a widely expressed, cytoskeletal protein and integrin activator that had previously been shown by their group to be important for the adhesion and migratory properties of endothelial cells. Integrins are a large family of cell surface proteins involved in cell adhesion, migration, and angiogenesis. This knowledge led to their hypothesis that kindlin-2 might also be important for tumor angiogenesis. To test this hypothesis, the group utilized a mouse model in which the gene dosage of kindlin-2 was cut in half (full loss of kindlin-2 is lethal for mice). They found that prostatic tumors implanted into these mice had shorter and thinner blood vessels and reduced vascular area. The blood vessels that did form were immature and leaky. This blunted angiogenic response led to significantly smaller, more necrotic tumors (the tumors grown in kindlin-2-deficient animals had a 2-fold larger necrotic core and were 2.5-fold smaller than those grown in wild-type mice). They also found that endothelial cells from kindlin-2-deficient mice had reduced activation of β-3 integrin, providing a possible mechanistic explanation for perturbed tumor angiogenesis. The results of these studies identify kindlin-2 as a key mediator of tumor angiogenesis and suggest that targeting of this molecule might be a viable therapeutic strategy. When asked to provide a take-home message from her lecture, Dr. Pluskota replied, “Angiogenesis is kindled by kindlin-2, a novel integrin activator.”
Her talk raised not only the idea of targeting kindlin-2 to inhibit angiogenesis in cancer patients, but also whether deficiency of this protein plays a role in human disease. Whereas deficiency of the other members of the kindlin family, kindlin-1 and kindlin-3, have been implicated in human disease, there is still no clear role for kindlin-2. Based on the increased vascular permeability seen in the mice heterozygous for this gene, it was speculated by Dr. Evan Sadler, president-elect of ASH, that deficiency of this gene might contribute to disorders of vascular permeability in humans, such as angioedema.
When she is not busy investigating the inner workings of endothelial cells, Dr. Pluskota can probably be found reading fantasy books. In particular, she is a fan of J.R.R. Tolkien and thinks that “there is a hobbit in all of us, and we are all capable of doing great things even if we do not know that yet.” Hopefully, with the acclaim that her work has received at this year’s ASH meeting, Dr. Pluskota now knows that she has the capability and kindling for great things.
Dr. Mendler indicated no relevant conflicts of interest.