KAIST identifies new treatment target to overcome limits of anti-cancer vascular therapy

South Korean researchers have identified a new therapeutic target that could help overcome the limitations of anti-angiogenic therapy — a cancer treatment approach that blocks the formation of new blood vessels supplying tumors with nutrients and oxygen.

KAIST announced Sunday that a joint research team led by Professor Jeong In-kyung of the Department of Biological Sciences, Professor Lee Ji-min of the Graduate School of Medical Science and Engineering, and Professor Ko Gyu-young of the Institute for Basic Science Center for Vascular Research had established that tumors drive angiogenesis — the process of generating new blood vessels — by reactivating a genetic program normally active only transiently during healthy vascular development.

Tumors stimulate the growth of new blood vessels nearby to obtain the oxygen and nutrients needed for growth and, ultimately, to spread to other tissues. Anti-angiogenic drugs have been developed to block this process, but their long-term effectiveness is often limited because tumor vascular cells can readily alter their properties in response to the surrounding environment.

Analyzing data from eight types of solid tumors, the research team confirmed that genes responsible for promoting new blood vessel growth and remodeling the cellular environment are commonly and actively expressed in tumor vascular cells, regardless of cancer type.

Using single-cell transcriptomics — which examines which genes are active in individual cells — alongside epigenomic analysis, which tracks gene regulation without changes to the underlying DNA sequence, the team also confirmed that these changes arise from a reprogramming of the gene regulatory network in tumor vascular cells.

To identify the cause, the team differentiated human embryonic stem cells — which can develop into a wide variety of cell types — into vascular endothelial cells, the cells lining the interior of blood vessels, thereby recreating the process by which normal blood vessels form.

By then analyzing which genes are active at each stage of normal vascular development, the team used single-cell epigenomic and three-dimensional genome analysis to show for the first time that the genetic program reactivated in tumor blood vessels closely resembles one that appears only briefly at the late progenitor stage — the point just before vascular cells fully mature.

Analysis of the tumor microenvironment — the cellular and tissue surroundings of a tumor — further revealed that integrin plays a key role in reactivating this genetic program. Integrin expression was elevated in the tumor blood vessels of colorectal cancer patients, and inhibiting it reduced both tumor vascularization and tumor growth in xenograft mouse models, in which human cancer tissue had been transplanted into laboratory mice.

"The significance of this research lies in showing that tumors do not invent a new method for building blood vessels, but instead reuse the program employed during normal vascular development," Professor Jeong said. "We plan to apply the model from this research to various diseases related to abnormal blood vessel formation."

The findings were published online in the journal Cancer Research on June 8.