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Updated: May 28, 2025

The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia
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Published on: November 30, 2016

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A tumor-secreted protein utilizes glucagon release to cause host wasting

Guangming Ding1,2, Yingge Li1,2, Chen Cheng1,2

  • 1Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, Hubei, China.

Cell Discovery
|February 9, 2025
PubMed

Insights

Malignant tumors promote systemic organ wasting by increasing adipokinetic hormone (Akh) or glucagon production. This occurs via a Pvf1-Pvr signaling pathway that enhances neural activity in hormone-producing cells.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Cancer Biology

Background:

  • Tumor-host interactions are crucial in cancer progression and cachexia.
  • The mechanisms by which tumors induce systemic organ wasting are not fully understood.
  • Adipokinetic hormone (Akh) is a catabolic hormone with known roles in energy metabolism.

Purpose of the Study:

  • To investigate how tumors induce systemic host wasting.
  • To identify the key hormones and signaling pathways involved in tumor-induced cachexia.
  • To explore potential therapeutic targets for mitigating organ wasting in cancer patients.

Main Methods:

  • Utilized a conserved yki3SA-tumor model in Drosophila.
  • Employed RNAi screening and Gal4-LexA dual expression system.
  • Investigated the Pvf1-Pvr signaling axis and its downstream effects on Akh production and innervation.

Main Results:

  • yki3SA-gut tumors increase Akh production, leading to systemic wasting (muscle dysfunction, lipid loss, hyperglycemia, ovary atrophy).
  • Tumors secrete Pvf1, which activates Pvr on Akh-producing cells (APCs), promoting Akh production via Mmp2-dependent ECM remodeling and enhanced cholinergic innervation.
  • Similar mechanisms involving glucagon and PDGFR (Pvr homolog) were confirmed in mammals, with blockade ameliorating organ wasting.

Conclusions:

  • Tumors remotely induce systemic host wasting by promoting neural-associated Akh/glucagon production.
  • The Pvf1-Pvr signaling axis is a key mediator of tumor-induced cachexia.
  • Targeting glucagon or PDGFR signaling may offer therapeutic strategies against cancer-related organ wasting.

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