Treating intestine with ‘good’ cholesterol compound inhibits lung tumor growth in mice
A compound that mimics the main protein in high-density lipoprotein (HDL, or "good") cholesterol significantly reduced the number of tumors in the lungs of mice, reports a team of UCLA researchers. 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 wasn't totally clear which immune and genetic mechanisms were responsible for the connection. In the new study, the researchers set out to determine whether 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).
The team used a mouse model of lung cancer, injecting cancer cells into the tail veins of mice. 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.
The team also looked at how the compound was exerting its anti-cancer 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 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. The results suggest that oral compounds may have therapeutic value for treating lung cancer in humans. The team next plans to look at whether Tg6F also inhibits tumor growth in other organs of the body.
Arnab Chattopadhyay, project scientist in UCLA's department of medicine, is the study's first author. Srinivasa Reddy, professor-in-residence in the departments of medicine, molecular and medical pharmacology, and obstetrics and gynecology, is senior author. Other UCLA-affiliated authors are: Xinying Yang, Pallavi Mukherjee, Dawoud Sulaiman, Hannah Fogelman, Victor Grijalva, Steven Dubinett, Tonya Wasler, Manash Paul, Ramin Salehi-Rad, Julia Mack, M. Luisa Iruela-Arispe, Mohamad Navab and Alan Fogelman.
The study was published in Scientific Reports, a Nature journal.
This work was supported in part by a U.S. Public Health Service grant and the Castera, Laubisch and Milt Grey funds at UCLA.
Alan Fogelman, Navab and Reddy are principals at Bruin Pharma. Alan Fogelman is also an officer at Bruin Pharma.