In human cancer cell and mouse studies, researchers have found that a set of proteins work in tandem to build supply lines that deliver oxygen and nutrients to tumors, enabling them to survive and grow. The protein twosome, PADI4 and HIF-1, ramp up their activity under low-oxygen conditions that are typically found in a fast-growing tumor, allowing it to build new blood vessels that feed the cancer’s growth.
The researchers say the discovery provides new avenues for developing anti-cancer therapies that interfere with blood vessel development. A report describing the study was published in Science Advances.
Within the cell, DNA is negatively charged, which allows it to interact with positively charged proteins called histones. The DNA is wound like a spool of thread around the histones when it is not being used.
Specifically, the senior author says, PADI4 incites a reaction that causes the histones to lose their positive charge, allowing the DNA to unwind.
To explore the partnership between HIF-1 and PADI4, the researchers studied human breast and liver cancer cells grown in the laboratory. The researchers first interfered with the cells’ ability to produce PADI4, and then exposed the cells to low oxygen conditions for 24 hours. By analyzing gene activity within these cells, the researchers found that 87% of the 1,300 genes turned on by HIF-1 in response to hypoxia were not turned on in cells lacking PADI4 protein.
The researchers then injected the cancer cells into the breast tissue of mice and tracked tumor growth. Tumors without PADI4 were five times smaller and developed five times fewer blood vessels compared with tumors formed from cells with normal levels of PADI4. This showed that in a living organism, elimination of PADI4 impaired the tumor’s ability to grow.
The findings in mice, say the researchers, allow them to tie together studies from human cancers where higher HIF-1 activity in patients’ primary tumor biopsies correlates with higher rates of mortality.
“The more we know about the cellular ecosystem of cancer, the better shot we have at controlling it,” says the senior author.
Mechanism of hypoxia dependent tumor vascularization
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