New Organ-on-a-chip Technology to Study Angiogenesis and Develop Anti-cancer Drugs

Organ-on-a-chip technology allows to visualize formation of new blood vessels and study the effect of drugs on angiogenesis.

A new organ-on-a-chip technology developed by research teams at the Institute of Industrial Science (IIS), the University of Tokyo, CNRS and INSERM help study the formation of blood vessel and the drugs that target this. The technology recreates a human blood vessel and shows how new capillaries grow from the parent vessel in response to biochemical signaling cues. The chip can further be used to develop drugs targeting angiogenesis as a therapeutic to treat cancer and blood-vessel-related diseases. The study is published in EBioMedicine.

Angiogenesis

Angiogenesis
Angiogenesis is the process of formation of new blood vessels from pre-existing blood vessels. It occurs both in health as well as disease.

‘The ability to study angiogenesis in a vessel-on-a-chip model allows to develop and test efficacy of drugs that target angiogenesis in cancer and other blood-vessel-related diseases.’

Angiogenesis describes a specific process of blood vessel formation from pre-existing blood vessels. Dr. Yukiko Matsunaga, lecturer at the IIS, the University of Tokyo, has been working in the SMMIL-E project, a joint French-Japanese project against cancer (involving the CNRS, COL, Universite de Lille, the University of Tokyo), by using tissue engineering and organ-on-a-chip technology to study various biological phenomena including angiogenesis. Her new technology provides a simple setting to study angiogenesis other effects such as the dynamics of blood vessel permeability.

Vascular endothelial growth factors (VEGF) are the primary proteins responsible for angiogenesis. They signal to the parental vessel to initiate sprouting and the direction toward which the new capillaries must grow.

"The biochemistry of sprouting angiogenesis is well understood. VEGF leads endothelial cells to express DLL4, which activates NOTCH signaling. What is lacking is a good system to study drugs that are effective on angiogenesis," said Matsunaga.

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New FDA approved drug, plerixafor, which is a CRCX4 inhibitor, reduces resistance to anti-angiogenesis treatment by blocking VEGF-signaling pathway.

Indeed, while necessary for organ survival, angiogenesis also sustains diseases like cancer. Several anti-cancer drugs such as sorafenib and sunitinib are effective in large part because of their anti-angiogenic effects.

In the new system, which was designed by Dr. Joris Pauty, a scientist in the Matsunaga laboratory, a single human blood vessel is fabricated into a collagen gel scaffold on a chip, indicating the initiation of new blood vessels. Subsequent experiments performed with the support of a member of the SMMIL-E project, Dr. Fabrice Soncin (INSERM, France) confirmed that VEGF activated NOTCH signaling through DLL4 just as in the human body. Adding either sorafenib or sunitinib inhibited the sprouting, but only sorafenib made the vessels highly permeable, which is a non-physiological condition. That both drugs prevented new vessel growth but with different effects on blood vessel permeability may explain why the two work differently in cancer treatment.

How Anti-Angiogenesis Treatment Would Help Eliminate a Tumor
Deciphering and targeting mechanisms involved in resistance to anti-angiogenic therapy is critical to realizing the potential of the promising cancer therapy.

Since many diseases like cancer and diabetic retinopathy induce new vessels for their progression, Matsunaga noted that the chips could be used for even more advanced studies for drug effects on angiogenesis and cancer or diabetes.

"We can also use cancer cells into the chip to test their combined effects with the drugs on angiogenesis."

Angiogenesis Drugs may Help Treat Several Metastatic Cancers
Blood vessel growth, or angiogenesis, is critical for cancer to grow and spread throughout the body.

Source-Eurekalert