54 Researchers at the University of Colorado Anschutz and Indiana University School of Medicine have identified a biological process that may help explain why colorectal cancer can cause severe muscle and bone loss, particularly in advanced disease. The condition, known as cancer cachexia, can leave patients weak, make everyday activities more difficult, and reduce their ability to tolerate cancer treatment. The study was published today in Nature Communications. Researchers found that colorectal cancer cells can send a signal to the liver, prompting it to produce a protein called IGFBP1. Once released into the bloodstream, IGFBP1 can contribute to muscle and bone loss. In laboratory and mouse studies, blocking IGFBP1 helped preserve muscle and bone and improved muscle strength, even when the cancer itself remained. “Our findings show that cancer can affect muscle and bone through a conversation between the tumour and the liver,” said Andrea Bonetto, PhD, associate professor in the Department of Pathology and a member of the CU Anschutz. “This gives us a new way to think about cancer-related wasting and a potential target for protecting patients from its effects.” The researchers found that colorectal cancer cells produce a protein called FGF21, which sends a signal to the liver. In response, the liver produces more IGFBP1, which enters the bloodstream and can contribute to muscle and bone loss throughout the body. IGFBP1 levels were about twice as high in people with colorectal cancer as in healthy individuals, with particularly high levels among patients whose cancer had spread to the liver. The findings build on earlier observations that circulating IGFBP1 is elevated in colorectal cancer patients and that liver-derived factors contribute to systemic wasting, particularly when the disease reaches the liver. Laboratory experiments showed that IGFBP1 can cause muscle cells to shrink and increase the development of cells involved in bone breakdown. When researchers blocked IGFBP1 in laboratory and preclinical models of colorectal cancer, the models retained more muscle and bone and showed greater muscle strength. Blocking the cancer-produced signal also reduced the liver’s production of IGFBP1, helping to protect against muscle and bone loss. Importantly, blocking this pathway did not consistently reduce the amount of cancer in the models, indicating that the mechanism operates independently of direct tumour growth control. This suggests the approach could have a different goal from traditional cancer treatments. Rather than directly targeting the tumour, it could help protect the body from some of the damage caused by cancer. “Since clinical and preclinical evidence already shows that preserving muscle mass can prolong life in cancer, our goal here is not necessarily to attack the tumour directly,” said Bonetto. “It is to understand whether we can protect the patient from the damage cancer causes throughout the body, ultimately improving quality of life and survival.” The findings suggest that the FGF21–IGFBP1 pathway could eventually become a target for treatments designed to prevent or reduce cancer-related muscle and bone loss. Neutralising IGFBP1 or interrupting the upstream FGF21 signal could offer a complementary strategy focused on protecting patients rather than solely on tumour eradication. However, the research is still in its early stages, and further studies are needed to determine whether blocking this pathway is safe and effective in people. This will be particularly important because FGF21 and IGFBP1 also play roles in normal bodily functions, including metabolism. Careful evaluation of safety, dosing, timing, and long-term effects will therefore be essential before the approach can move towards clinical use. “Our next challenge is to determine whether this pathway can be safely targeted in patients,” Bonetto said. “If we can preserve muscle and bone, we may be able to help people remain stronger, more mobile and better able to tolerate cancer treatment.” The study underscores the importance of examining communication between organs in cancer, positioning the liver as a key intermediary in the development of cachexia. Cancer cachexia remains a major challenge in advanced colorectal cancer, where muscle wasting and bone loss can significantly affect patient outcomes. If therapies targeting this pathway prove successful, they could help patients maintain strength, mobility, and their ability to tolerate treatment.