Cancer Cachexia: Might This Molecule Hold the Key?

Posted on July 22, 2014 by Dr. Francis Collins

Caption: Structure of parathyroid hormone-related protein (PTHrP), which has been implicated in cancer-related cachexia.
Source: The Protein Data Bank

No matter how much high-calorie food they eat or nutritionally fortified shakes they drink, many people with cancer just can’t seem to maintain their body weight. They lose muscle and fat, sometimes becoming so weak that they can’t tolerate further treatment. Called cachexia, this progressive wasting syndrome has long troubled patients and their families, as well as baffled scientists searching for ways to treat or perhaps even prevent it.

Some previous studies [1-3] have observed that humans and mice suffering from cachexia have “activated” brown fat. This type of fat, as I explained in a previous post, has the ability to convert its chemical energy into heat to keep the body warm. Intrigued by these hints, a team led by Bruce Spiegelman of the Dana-Farber Cancer Institute and Harvard Medical School in Boston recently decided to explore whether tumor cells might secrete molecules that spur similar brown fat-like activity, causing a gradual depletion of the body’s energy stores.

Using Lewis lung carcinoma (LLC) cells, which cause tumors and cachexia when injected into mice, the NIH-funded team identified four proteins that boosted heat production in mouse fat cells grown in laboratory dishes. Further studies revealed that one of these proteins, called parathyroid hormone-related protein (PTHrP), seemed to be responsible for triggering a phenomenon called “browning.”

Many white adipose tissues, which store fat in large droplets and are often thought of as the bad fat tissue, contain pockets of so-called beige cells. Under the correct circumstances, these beige cells become active and behave like brown fat, burning lipids and producing heat. Not only did PTHrP trigger browning in mouse white fat tissue, but it boosted by 200-fold the activity of theUcp1 gene, which is critical for heat production in beige cells [4].

This ability of PTHrP to boost heat production and induce browning suggested that it might play a key role in triggering cachexia. To test the hypothesis, Spiegelman and his colleagues injected an antibody into the LLC mice that blocked the activity of PTHrP. In a remarkably clear-cut demonstration, the antibody prevented fat and muscle loss in the tumor-laden mice. These mice also had better muscle function and strength compared to the control group. In contrast, the untreated mice developed severe cachexia.

When PTHrP was injected into healthy mice, it didn’t cause muscle wasting or activate genes related to muscle atrophy. But when PTHrP was injected into mice with tumors, the protein accelerated muscle loss. This suggests that, in order to cause muscle wasting, PTHrP may require another yet-to-be-identified ‘X factor’ secreted from tumor cells.

Caption: In mice, Lewis lung carcinoma cells secrete a protein called PTHrP, which causes white fat to ‘brown,’ generating heat. PTHrP, together with another unknown tumor-secreted ‘X-factor,’ also triggers muscle atrophy, or wasting.
Credit: Bruce Spiegelman, Harvard Medical School; Nature

To determine whether PTHrP plays a role in human cachexia, the researchers tested blood samples from 47 patients with metastatic non-small cell lung cancer or colon cancer to see if levels of this protein affected body composition. Indeed, the 17 patients who had detectable levels of PTHrP in their bloodstream turned out to have significantly less muscle mass than the 30 patients with undetectable PTHrP levels—and their bodies were also burning their energy stores more rapidly.

These findings suggest that PTHrP may provide a way to identify which cancer patients at greatest risk of developing cachexia. In addition, these results raise the possibility that molecules that block or lower PTHrP levels may help to reduce or prevent the cachexia associated with cancer—and possibly even similar progressive wasting associated with other conditions, such as heart failure and kidney disease.

Finally, some of you are probably wondering if because of its fat-burning activity, PTHrP might be useful for spurring weight loss in obese or overweight people. That’s probably not a possibility because PTHrP is also critical for controlling calcium levels in the body. Too much of this protein causes calcium to be stripped from the bones, leading to high levels of calcium in the bloodstream that can cause kidney stones and disrupt the functions of the heart and brain.

References:

[1] Brown adipose tissue in cancer patients: possible cause of cancer-induced cachexia. Shellock FG, Riedinger MS, Fishbein MC. J Cancer Res Clin Oncol. 1986;111(1):82-5.

[2] Increased brown adipose tissue activity in children with malignant disease. Bianchi A, Bruce J, Cooper AL, Childs C, Kohli M, Morris ID, Morris-Jones P, Rothwell NJ. Horm Metab Res. 1989 Nov;21(11):640-1.

[3] Increased gene expression of brown fat uncoupling protein (UCP)1 and skeletal muscle UCP2 and UCP3 in MAC16-induced cancer cachexia. Bing C, Brown M, King P, Collins P, Tisdale MJ, Williams G. Cancer Res. 2000 May 1;60(9):2405-10.

[4] Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Kir S, White JP, Kleiner S, Kazak L, Cohen P, Baracos VE, Spiegelman BM. Nature. 2014 Jul 13. [Epub ahead of print]

Link:

Spiegelman Lab

NIH support: National Institute of Diabetes and Digestive and Kidney Diseases