Pivotal protein identified in ‘endless wound-healing’ that fatally scars kidneys

Fibrosis, a non-stop injury-repair process, raises cancer risk, but also kills by itself

MD Anderson News Release 01/28/13

HOUSTON – Cancer behaves like a wound that never mends, constantly drawing on the body’s injury- repair response to thrive and grow.

“Fibrosis is wound-healing that never stops. The body thinks an injury exists when it doesn’t, so it just keeps going, producing scars that clog an organ’s system and destroy its functional tissue until it fails,” says Raghu Kalluri, Ph.D., M.D., an expert in the microenvironment that surrounds and supports cells and its influence on health and disease.

“Fibrosis is almost a tumor-like growth minus the cancer cells,” Kalluri says. Most solid tumors are 75 to 95 percent fibrotic material. As the new chair of The University of Texas MD Anderson Cancer Center Department of Cancer Biology, Kalluri has an intense interest in both processes.

Not only is fibrosis a known risk factor for cancer development, it’s also an accomplished, less famous, killer in its own right, Kalluri notes.

“Cirrhosis of the liver is nothing but fibrosis. In diabetes, 40 percent of all deaths are caused by kidney failure from fibrosis, which also is the leading cause of death from lupus,” Kalluri says. “Pulmonary fibrosis is incurable. Scleroderma, hardening of the skin, also is fibrotic disease.”

“Put them all together and you have a major disease area that probably affects half a billion people worldwide,” Kalluri says. “Developing a drug specific to fibrosis would greatly reduce deaths from all of these diseases.”

To do that, you first have to understand the molecular details of the process.

Nature Medicine paper uncovers fibrosis protector
Kalluri and colleagues reported Sunday in advance online publication at Nature Medicine that a protein known as HE4 stifles other proteins that destroy collagen and other matrix material, supportive tissue that provides a scaffold for the healing process but also is the predominant scar material in fibrosis.

In effect, HE4 takes down a stop sign on the road leading to endless wound-healing. Kalluri spent 16 years, from assistant professor to full professor, at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston before coming to MD Anderson in June.  Research for the Nature Medicine paper was conducted in Boston along with collaborators in Germany.

Fibroblasts are specialized cells that produce collagen, among other things, which reconnects damaged tissue and forms a framework for tissue repair.  When the job is done, proteins called proteases degrade collagen as healing winds down. Kalluri and colleagues discovered that HE4 inhibits the proteases from destroying collagen.

Impact of HE4 found in fibrotic mouse and human kidneys
In a series of mouse model experiments, the team found:

  • Activity of the HE4 gene, a known protease inhibitor, increases 37-fold in collagen-making fibrosis-associated fibroblasts taken from fibrotic kidneys compared to control kidneys.
  • Two proteases, PRSS35 and PRSS23, not previously connected to fibrosis degrade collagen.
  • HE4 blocked collagen I destruction by those and other proteases in fibrotic kidneys.
  • Neutralizing HE4 with an antibody reduced fibrosis in three mouse models of kidney damage --ureteral blockage, immune system damage, and injury -- with reductions in collagen I content ranging from 60 to 80 percent.

High levels of HE4 found in blood of patients with kidney disease
The team analyzed human samples of fibrotic kidneys and blood levels of HE4 in patients with biopsy-confirmed fibrosis and found:

  • Expression of HE4 and the newly identified proteases is greatly increased in fibrosis-associated fibroblasts in human fibrotic kidneys.
  • HE4 is secreted by fibrosis-associated fibroblasts.
  • Levels of HE4 in the blood of patients with chronic kidney disease are elevated to more than three times the level found in healthy controls.

HE4 has the potential to serve as a biomarker to predict kidney fibrosis, which begins to do damage long before it is usually detected, Kalluri says. A large-scale patient analysis will be needed to validate the team’s findings.
Interestingly, a tool is readily at hand. The U.S. Food and Drug Administration recently approved an HE4 blood detection test to diagnose and monitor recurrence and progression of ovarian cancer. A high concentration of HE4 identifies high-risk patients with ovarian and endometrial cancers.

Co-authors with Kalluri are first author Valerie LeBleu, Ph.D., Yingqi Teng, Ph.D., Joyce O’Connell and Hikaru Sugimoto, Ph.D., all of the Department of Medicine at Beth Israel Deaconess Medical Center, Boston; David Charytan, M.D., of the Department of Medicine, Renal Division, of Brigham and Women’s Hospital, Boston; and Gerhard Müller, M.D. and Claudia Müller, Ph.D. of the Department of Nephrology and Rheumatology, Georg-August University Medical Center, Gottingen, Germany.

Funding was provided by grants from the National Institutes of Health (DK55001, DK081976, CA125550, CA155370, CA151925 and CA163191) the Harvard Stem Cell Institute; NIH research training grants in gastroenterology, cardiovascular biology and cell and development biology (2T32DK007760-11, 2T32DK007760-11 and GM07226) and the U.S. Department of Defense Breast Cancer Predoctoral Traineeship Award.