



Sickle cell disease is a lethal disorder in which misshapen red blood cells can clog blood vessels and cut of blood flow to organs. However, new research shows that this normally harmful characteristic may also be used for a beneficial purpose—to cut off blood flow to cancerous tumors. Researchers from Duke Medicine and Jenomic developed a process of exploiting sickle-shaped red blood cells to selectively target oxygen-deprived cancer tumors in mice and block the blood vessels that surround them.

“Sickle cells appear to be a potent way to attack hypoxic (oxygen-starved) solid tumors, which are notable for their resistance to existing cancer chemotherapy agents and radiation,” says senior author Mark W. Dewhirst, DVM, Ph.D., a radiation oncologist and director of Duke’s Tumor Microcirculation Laboratory. “This is an exciting finding that suggests a potential new approach to fighting tumors that are currently associated with aggressive disease.”

Sickle cells are typically associated with a potentially life-threatening disease in which red blood cells are deformed in the shape of a crescent moon or sickle. Unlike healthy red blood cells that flow smoothly through vessels, the sickle cells get stuck, causing blockages that are painful and damaging to tissue.

A collaborative effort between Duke researchers and scientists from Jenomic began in 2006 to explore whether sickle cells could similarly build clots in the vast networks of blood vessels that feed oxygen-starved cancer tumors, which can grow increasingly lethal as their oxygen needs escalate.

In an NIH-funded study of mice with breast cancer, the researchers gave the animals an infusion of fluorescently dyed sickle cells and viewed them under window chambers that provide real-time observation of processes inside the body. Within five minutes, the deformed cells began to adhere to the blood vessels surrounding the hypoxic tumors. Over 30 minutes, the cells had formed clots and began blocking the small blood vessels that fed the tumor. The team says the sickle cells ultimately formed microaggregates that obstructed up to 88% of tumor microvessels.

Dr. Dewhirst says the sickle cells stick like Velcro to the hypoxic tumor because it produces an abundance of adhesion molecules as part of its distress from oxygen deprivation. Normal cells don’t produce the adhesion molecules, so there’s nothing for the sickle cells to snag onto.

“Unlike normal red blood cells, we found that sickle cells show a highly unique natural attraction to oxygen-deprived tumors where they stick, cluster, and plug tumor blood vessels. Once clustered within the tumor, the sickle cells deposit a toxic iron residue as they die, causing tumor cell death,” says David S. Terman, M.D., head of molecular genetics at Jenomic.

To boost that caustic effect, the researchers added zinc compounds (zinc protoporphyrin alone or in combination with doxorubicin) to the sickle cells, which caused even greater oxidative stress in the tumor and surrounding blood vessels. This resulted in a dramatic delay in tumor growth, quadrupling the amount of time the tumors were inactive compared to tumors exposed to regular blood cells. Mice showed no acute toxicity to the sickle cell treatment, the researchers report. They also note the importance of the induced injury to both tumor microvessels and tumor cells, in contrast to existing treatments directed only to the hypoxic tumor cell.

Drs. Dewhirst and Terman say the research team would continue to conduct studies in animals before moving to human trials. The study appears online in the January 9, 2013, edition of the PLOS ONE, in a paper titled “Sickle Erythrocytes Target Cytotoxics to Hypoxic Tumor Microvessels and Potentiate a Tumoricidal Response”.



























