A study led by scientists at the Korean Research Institute of BioScience and Biotechnology (KRIBB) in Daejeon is the first to demonstrate that Dilp8/INSL3-Lgr3/8-NUCB, neuropeptide y (NPY) signaling may be a potential therapeutic target in cancer anorexia and cachexia, which is associated with increased cancer mortality.

The study also suggested that tumor-derived Dilp8/INSL3 induced anorexia by regulating feeding hormones through the Lgr3/Lgr8 receptor in Drosophila and mammals, and showed that insulin-like 3 peptide (INSL3) levels were significantly increased in serum from pancreatic cancer patients.

Anorexia is particularly common in late-stage cancer patients, causing progressive weight loss and contributing to cancer-related mortality. It is also a linked to cancer-associated cachexia, which severely impacts quality of life (QoL).

"Anorexia is considered to be one of the main manifestations of cachexia, which is characterized by loss of muscle mass and function with or without adipose tissue atrophy," said study leader Kweon Yu.

"Cachexia is a debilitating syndrome that not only drastically reduces the patient's QoL, but also contributes to approximately 20% of cancer-related mortality," said the professor and principal researcher in the Disease Target Structure Research Center at KRIBB.

In a study in advanced cancer patients, more than 60% showed anorexia despite not receiving chemotherapy, suggesting anorexia development is independent of treatment.

However, at present the molecular mechanisms underlying cancer anorexia remain largely unknown and no effective treatments are available.

"There is no available treatment for preventing cancer anorexia, so it is important that our study has indicated that Dilp8/INSL3-Lgr3/8-NUCB, NPY signaling is a promising target for treating cancer anorexia," Yu told BioWorld Science.

In cancer anorexia-cachexia syndrome, secreted tumor-derived cytokines play a key role in inter-organ/tissue communication, the systemic coordination and integration of which is important, both in health and in pathologies including cancer and metabolic syndrome.

Evidence suggests that tumors elicit inflammatory responses and metabolic dysfunction in muscle and fat through activation of systemic proinflammatory cytokines, which act as tumor-derived hormones mediating muscle wasting in mouse cancer models and cancer patients.

Recent studies have shown that ImpL2, a Drosophila homologue of mammalian insulin-like growth factor binding protein (IGFBP), is secreted from tumors, impairing muscle function and tissue wasting by inhibiting IGF-like signaling in Drosophila.

Such Drosophila cancer models reveal how tumor-secreted cytokines cause cachexia-like tissue wasting, demonstrating that Drosophila is a good model with which to elucidate the mechanisms of tumor-host interaction.

This prompted the new Korean study, in which the authors established a Drosophila cancer anorexia model by overexpressing the known oncogene yorkie, they reported in the February 8, 2021, edition of Nature Cell Biology.

The researchers then demonstrated that tumor-derived Dilp8, a Drosophila homologue of mammalian INSL3, was secreted from tumor tissues and induced anorexia through the Lgr3 receptor in the brain.

"Using molecular genetic techniques, we demonstrated that Dilp8 was secreted from tumor tissues and induced anorexia via the Lgr3 receptor in the brain in Drosophila fruit flies, mouse models and in studies in cancer patients," said Yu.

Activated Dilp8-Lgr3 signaling was then shown to upregulate anorexigenic nucleobindin 1 (NUCB1) and downregulate the appetite-stimulating (orexigenic) short neuropeptide F (sNPF) and NPF expression in the brain.

Therefore, "in the normal physiological condition, Dilp8/INSL3-Lgr3 signaling is not active, but it is active in cancer and induces anorexia," Yu said.

In cancer, the researchers also demonstrated that protein expression of Lgr3 and NUCB1 was significantly upregulated in neurons expressing sNPF and NPF.

Colon vs. lung

Interestingly, "INSL3 and NUCB1 were upregulated in colon cancer-implanted mice but not in lung cancer-implanted mice, suggesting that not all cancer types induce cancer anorexia by this signaling," noted Yu.

Moreover, INSL3 levels were shown to be increased in tumor-implanted mice, while INSL3-treated mouse hypothalamic cells showed Nucb2 upregulation and Npy downregulation.

"We found that colon cancer-implanted mice showed anorexia and an INSL3 level more than double that in those in lung cancer-implanted mice," said Yu.

"In mouse hypothalamic cells containing high Lgr8 receptor leves, INSL3 treatment induced anorexic Nucb2 upregulation and orexic Npy downregulation."

Food consumption was significantly reduced in INSL3-injected mice, while higher serum INSL3 levels increased anorexia in pancreatic cancer patients. "Mice receiving intracerebrospinal INSL3 injection showed an approximately 30% reduction in food consumption, while higher INSL3 levels were associated with anorexia in pancreatic cancer patients," Yu said.

These findings suggest that tumor-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding hormones through the Lgr3/Lgr8 receptor in Drosophila and mammals and that "the Dilp8/INSL3-Lgr3/8-NUCB, NPY signaling is a potential drug target for treating cancer anorexia in humans."