Scientists at Massachusetts General Hospital (MGH) say the use of current hypertension drugs could improve the outcome of cancer chemotherapy by opening up collapsed blood vessels in solid tumors.
In an online article (“Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels”) in the current issue of Nature Communications, the researchers describe how an angiotensin inhibitor improved the delivery of chemotherapy drugs and oxygen throughout tumors by increasing blood flow in mouse models of breast and pancreatic cancer. A clinical trial based on the findings of this study is now underway.
In their article, the investigators note that cancer, stromal cells, and the interstitial matrix of the tumor all act to compress tumor blood vessels, thus restricting vascular perfusion. They added that hyaluronan acts as the key matrix molecule leading to vessel compression.
“We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-b1, CCN2, and ET-1, downstream of angiotensin-II-receptor-1 inhibition,” wrote the investigators. “Consequently, losartan reduces solid stress in tumors resulting in increased vascular perfusion.”
“Angiotensin inhibitors are safe blood pressure medications that have been used for over a decade in patients and could be repurposed for cancer treatment,” explains Rakesh K. Jain, Ph.D., director of the Steele Laboratory for Tumor Biology at MGH and senior author of the study. “Unlike anti-angiogenesis drugs, which improve tumor blood flow by repairing the abnormal structure of tumor blood vessels, angiotensin inhibitors open up those vessels by releasing physical forces that are applied to tumor blood vessels when the gel-like matrix surrounding them expands with tumor growth.”
Dr. Jain and his colleagues found that losartan improves the distribution within tumors of relatively large molecules (nanomedicines) by inhibiting the formation of collagen, a primary constituent of the extracellular matrix. The current study looked at whether losartan and other drugs that block the action of angiotensin could release the elevated forces within tumors that compress and collapse internal blood vessels. These stresses are exerted when cancer-associated fibroblasts (CAFs) proliferate and produce increased levels of both collagen and hyaluronan.
The team's experiments in several mouse models showed that both collagen and hyaluronan are involved in the compression of blood vessels within tumors and that losartan inhibited production of both molecules by CAFs through reducing the activation and overall density of these cells. Compared with ACE inhibitors, which block angiotensin signaling in a different way, losartan and drugs of its class, known as angiotensin receptor blockers, appeared better at reducing compression within tumors. In models of breast and pancreatic cancer, treatment with losartan alone had little effect on tumor growth, but combining losartan with standard chemotherapy drugs delayed the growth of tumors and extended survival.
“Increasing tumor blood flow in the absence of anticancer drugs might actually accelerate tumor growth, but we believe that combining increased blood flow with chemotherapy, radiation therapy, or immunotherapy will have beneficial results,” said Dr. Jain. “Based on these findings in animal models, our colleagues at the MGH Cancer Center have initiated a clinical trial to test whether losartan can improve treatment outcomes in pancreatic cancer.”