2022/02/14
Keio University School of Medicine
A joint research group—including Professor Yoshiaki Kubota of the Department of Anatomy, the Department of Surgery (General and Gastroenterological), the Division of Cardiology, the Department of Biochemistry, and the Institute for Advanced Medical Research at the Keio University School of Medicine, along with Hamamatsu University School of Medicine and the University of Oxford, UK—has identified FLRT2, previously known as a neural guidance factor, as a structural maintenance factor used exclusively in blood vessels within tumors. The group revealed that FLRT2 expression levels are inversely correlated with the prognosis of human colorectal cancer and that cancer metastasis is suppressed in mice lacking FLRT2 in their blood vessels.
The growth of blood vessels into tumors is considered a cause of cancer progression and metastasis. For this reason, drugs that stop blood vessel growth (such as VEGF inhibitors) are widely used in clinical practice. However, in some cases, their effect on suppressing cancer metastasis is insufficient, and the search has been on for new molecular targets to more effectively inhibit cancer metastasis.
In this study, the group found that FLRT2 is highly expressed in the blood vessels of human colorectal cancer, especially in advanced cancer, and that its expression level is inversely correlated with prognosis. Next, when cancer cells were transplanted into the skin of mice with a blood vessel-specific deletion of the FLRT2 gene, they found that leaky blood vessels (which serve as entry and exit points for cancer metastasis) were significantly reduced, and metastasis to the lungs and liver was substantially decreased. Furthermore, it was also found that this change in blood vessels (a decrease in leaky vessels) allowed blood flow to be delivered deep into the tumor, significantly enhancing the effect of the anti-PD-1 antibody, an immune checkpoint inhibitor.
These research findings elucidate a unique mechanism by which blood vessels promote cancer cell metastasis. From a practical standpoint, this is expected to lead to the development of groundbreaking molecular targeted drugs that can efficiently suppress cancer metastasis, which has been insufficiently addressed by conventional drugs that stop blood vessel growth. Furthermore, it is also expected to be applied in combination therapies as a "ground-prepping" approach to maximize the effectiveness of immune checkpoint inhibitors.
These research findings were published in the online edition of "The Journal of Clinical Investigation" on February 1, 2022 (U.S. Eastern Time).
For the full press release, please see below.