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Progranulin Oncogenic Network in Solid Tumors

Elisa Ventura,Giacomo Ducci,Reyes Benot Dominguez,V. Ruggiero,A. Belfiore,Elena Sacco,M. Vanoni,R. Iozzo,A. Giordano,A. Morrione

Published 2023 in Cancers

ABSTRACT

Simple Summary The growth factor progranulin plays an important pro-tumorigenic role in several solid tumors and a growing number of studies suggest diagnostic and prognostic values for progranulin in many tumor types. Progranulin exerts its pro-tumorigenic action by affecting both tumor cells and the tumor microenvironment. However, the details of progranulin pro-oncogenic function are not fully elucidated and recent evidence suggests a strong context-dependency of progranulin signaling. In this review, we will summarize the current evidence supporting the progranulin pro-oncogenic role, with a particular focus on what is currently known about progranulin molecular mechanisms of action in cancer. 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.

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