A compound that mimics the main protein in high-density lipoprotein cholesterol — HDL, or “good” cholesterol — significantly reduced the number of tumors in the lungs of mice, a team of UCLA researchers reports. The findings help explain the connection between HDL cholesterol and reduced cancer risk and suggest that a similar compound may be an effective therapy in humans.
Previous research, both in lab animals and humans, had suggested that higher HDL cholesterol levels were linked to reduced cancer risk. The team’s earlier work had found that small peptide “mimetics,” or mimics, of an HDL protein reduced tumor growth in mice, but it was not totally clear which immune and genetic mechanisms were responsible for the connection. The new study, says Srinivasa Reddy, PhD, professor in the Departments of Medicine and Molecular & Medical Pharmacology, set out to determine if and how the compound, called Tg6F, might alter the immune system both in the intestine and in a distant organ, in this case, the lung.
Representative pictures of lungs with tumors from mice fed normal diet (Chow) or normal diet that was supplemented with transgenic tomato extract containing Tg6F peptide (Chow+Tg6F). Image: Courtesy of Dr. Arnab Chattopadhyay
The team used a mouse model of lung cancer, injecting cancer cells into the tail veins of mice, explains Arnab Chattopadhyay, PhD, assistant project scientist in the UCLA Department of Medicine. The cancerous cells migrate to the lungs, where they grow into tumors. One group of mice was given Tg6F orally, starting the day after they were injected with cancer cells, along with their regular mouse food; another group of mice received an inactive version of the compound. After four weeks of treatment, the number of tumor nodules was significantly lower in the lungs of Tg6F-fed mice — on average 75 percent lower than controls, Dr. Chattopadhyay says.
The team also looked at how the compound was exerting its anticancer effects and found that Tg6F altered lipid metabolism in the small intestine, which in turn altered gene expression and the type of immune cells present in both the intestine and the lung. In particular, the Tg6F supplements increased the expression of genes in a pathway that boosts white blood cells patrolling for cancer and decreased gene expression in a pathway that facilitates cancer growth.
The findings, Dr. Reddy says, illuminate the mechanisms by which “good” cholesterol may reduce cancer risk and underscore how important the small intestine is in exerting immune effects in distant organs. These results suggest that oral compounds may have therapeutic value for treating lung cancer in humans. The team next plans to study if Tg6F also inhibits tumor growth in other organs of the body.
“Treating the Intestine with Oral ApoA-I Mimetic Tg6F Reduces Tumor Burden in Mouse Models of Metastatic Lung Cancer,” Scientific Reports, June 13, 2018.
