Progranulin Oncogenic Network in Solid Tumors

Our plain-English summary of Progranulin Oncogenic Network in Solid Tumors, by E. Ventura, G. Ducci, R. Benot Dominguez, et al (Cancers, 2023).

The study

• Authors: E. Ventura, G. Ducci, R. Benot Dominguez, V. Ruggiero, A. Belfiore, E. Sacco, M. Vanoni, R.V. Iozzo, A. Giordano, A. Morrione
• Journal: Cancers
• Published: 2023;15(6)
• Type of article: Review
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Progranulin is a pleiotropic growth factor with important physiological roles in embryogenesis and maintenance of adult tissue homeostasis. While-progranulin deficiency is associated with a broad range of pathological conditions affecting the brain, such as frontotemporal dementia and neuronal ceroid lipofuscinosis, progranulin upregulation characterizes many tumors, including brain tumors, multiple myeloma, leiomyosarcoma, mesothelioma and epithelial cancers such as ovarian, liver, breast, bladder, adrenal, prostate and kidney carcinomas. The increase of progranulin levels in tumors might have diagnostic and prognostic significance. In cancer, progranulin has a pro-tumorigenic role by promoting cancer cell proliferation, migration, invasiveness, anchorage-independent growth and resistance to chemotherapy. In addition, progranulin regulates the tumor microenvironment, affects the function of cancer-associated fibroblasts, and modulates tumor immune surveillance. However, the molecular mechanisms of progranulin oncogenic function are not fully elucidated. In bladder cancer, progranulin action relies on the activation of its functional signaling receptor EphA2. Notably, more recent data suggest that progranulin can also modulate a functional crosstalk between multiple receptor-tyrosine kinases, demonstrating a more complex and context-dependent role of progranulin in cancer. Here, we will review what is currently known about the function of progranulin in tumors, with a focus on its molecular mechanisms of action and regulation.

In plain English

This article was a review, not a new study. The authors summarized published research on progranulin, a growth factor protein, in solid tumors, including mesothelioma, with a focus on its molecular mechanisms of action and regulation. They described earlier studies reporting that progranulin is raised in many solid tumors, where it was reported to promote tumor cell growth, movement, invasion and tumor formation. It has also been suggested as a marker for diagnosis or outcome in several cancers. For mesothelioma, the authors described their own earlier laboratory work in mesothelioma cells. That work reported that EphA2, the progranulin receptor identified in bladder cancer, was not the major progranulin receptor in these cells. Progranulin acted instead through the receptors EGFR and RYK, and it affected FAK, a protein involved in cell movement. The authors noted that a first-in-human phase 1 trial of an anti-progranulin antibody, AG01, began in February 2022 in patients with advanced solid tumors, including mesothelioma patients. The authors concluded that progranulin's actions depend strongly on tumor context, so progranulin-based treatments might need tailoring. They said it is unknown whether progranulin activates EGFR directly.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published research
• Who was studied: Published studies of progranulin in solid tumors (cell, animal and patient studies) across many cancer types, including mesothelioma, reviewed with a focus on progranulin's molecular mechanisms of action and regulation; no new subjects were studied and no numbers of studies are given
• Exposure: No asbestos or other environmental or occupational exposure was studied; the subject is the growth factor protein progranulin
• Main results:
  • Reviewed studies reported that progranulin is upregulated in many solid tumors and promotes tumor cell proliferation, migration, invasion, adhesion, tumor formation in living animals and maintenance of cancer stem cells
  • Progranulin's raised levels in tumors compared with normal tissue were described as suggesting it could serve as a biomarker for several cancer types
  • The authors' own earlier work in mesothelioma cells reported that EphA2 was not the major progranulin signaling receptor and that progranulin acted through EGFR and RYK
  • The authors' earlier work reported that in mesothelioma, progranulin regulated FAK phosphorylation and focal adhesion turnover, a step in cell movement
  • In bladder cancer, progranulin was described as binding to and activating the receptor EphA2
  • Other researchers suggested that progranulin may promote blood vessel formation in mesothelioma independently of VEGF
  • A first-in-human phase 1 trial of the anti-progranulin antibody AG01 started in February 2022 in patients with advanced solid tumors, including mesothelioma patients
• The authors' conclusion: The authors concluded that progranulin's mechanisms of action are highly context dependent and involve multiple receptor tyrosine kinases, so progranulin-based therapies might have to be tailored to specific tumor contexts
• Limitations the authors state:
  • The authors stated that the molecular mechanisms of progranulin's role in cancer are not fully understood
  • In mesothelioma, the authors stated that it is unknown whether progranulin acts on EGFR directly or indirectly
  • The authors stated they could not cite all relevant work in the field

Topics

Medical terms in this study, explained in our Lexicon: Myeloma, Mesothelioma, Carcinoma, Chemotherapy, Tumor Microenvironment, Fibroblast.

Related studies

• Complexity of progranulin mechanisms of action in mesothelioma — E. Ventura, C. Xie, et al. (2022)
• A Pan-Cancer Analysis of the Oncogenic Role of Twinfilin Actin Binding Protein 1 in Human Tumors — G. Huo, Y. Wang, et al. (2021)
• Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas — N.C. Campanella, E.C. Silva, et al. (2020)
• ESCO2's oncogenic role in human tumors: a pan-cancer analysis and experimental validation — Y. Huang, D. Chen, et al. (2024)
• A pan-cancer analysis of the oncogenic function of HMGB1 in human tumors — H.M. Yang, X.N. Zhao, et al. (2024)
• A pancancer analysis reveals the oncogenic role of glutaminase 1 (GLS1) in tumor metabolism and immune evasion: a bioinformatics analysis — J. Liu, S. Hong, et al. (2025)

Browse more research in Cancers, or return to medical research.