BAG3 induces α-SMA expression in human fibroblasts and its over-expression correlates with poorer survival in fibrotic cancer patients

Our plain-English summary of BAG3 induces α-SMA expression in human fibroblasts and its over-expression correlates with poorer survival in fibrotic cancer patients, by M. De Marco, N. Del Papa, F. Reppucci, et al (Journal of Cellular Biochemistry, 2022).

The study

• Authors: M. De Marco, N. Del Papa, F. Reppucci, V. Iorio, A. Basile, A. Falco, R. Iaccarino, S. Brongo, F. De Caro, M. Capunzo, M.C. Turco, A. Rosati, L. Marzullo
• Journal: Journal of Cellular Biochemistry
• Published: 2022;123(1):91-101
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Hypoxia and angiogenesis in solid tumors are often strictly linked to the development of fibrotic tissues, a detrimental event that compromises the antitumor immunity. As a consequence, tumor aggressiveness and poor patient prognosis relate to higher incidence of tissue fibrosis and stromal stiffness. The molecular pathways through which normal fibroblasts are converted in cancer-associated fibroblasts (CAFs) have a central role in the onset of fibrosis in tumor stroma, thus emerging as a strategic target of novel therapeutic approaches for cancer disease. Several studies addressed the role of BAG3 in sustaining growth and survival of cancer cell and also shed light on the different mechanisms in which the intracellular protein is involved. More recently, new pieces of evidence revealed a pivotal role of extracellular BAG3 in pro-tumor cell signaling in the tumor microenvironment, as well as its involvement in the development of fibrosis in tumor tissues. Here we report further data showing the presence of the BAG3 receptor (Interferon-induced transmembrane protein [IFITM]-2) on the plasma membrane of normal dermal fibroblasts and the activity of BAG3 as a factor able to induce the expression of α-smooth muscle actin and the phosphorylation of AKT and focal adhesion kinase, that sustain CAF functions in tumor microenvironment. Furthermore, in agreement with these findings, bag3 gene expression has been analyzed by high throughput RNA sequencing databases from patients-derived xenografts. A strong correlation between bag3 gene expression and patients' survival was found in several types of fibrotic tumors. The results obtained provide encouraging data that identify BAG3 as a promising therapeutic target to counteract fibrosis in tumors.

© 2021 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals LLC.

In plain English

This laboratory study does not discuss asbestos. It concerns BAG3, a protein some tumor cells release, and whether it acts on normal human skin (dermal) fibroblasts, cells involved in scar-like tissue (fibrosis) around tumors. The authors reported that these fibroblasts carried the BAG3 receptor, IFITM-2, on their surface. Adding BAG3 cut binding of an anti-IFITM-2 antibody by about 75% at equal amounts and blocked it completely at a tenfold excess. Fibroblasts given increasing amounts of BAG3 for 16 hours showed more α-smooth muscle actin, a marker of activated fibroblasts, and BAG3 also triggered activation (phosphorylation) of the signaling protein FAK. Using public gene-expression databases of patients' tumors grown in mice (xenografts), the authors reported higher bag3 levels in several tumor types, including mesothelioma, than in lymphomas. In survival data split at median bag3 expression, higher bag3 was linked with poorer overall survival in pancreatic cancer (176 patients), head and neck cancer (414), mesothelioma (81) and liver cancer (362). The authors concluded that BAG3 is a promising treatment target against tumor fibrosis. Six authors hold shares in BIOUNIVERSA s.r.l.

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: Laboratory cell-culture experiments plus analysis of existing public gene-expression and survival databases
• Who was studied: Commercially obtained normal human dermal fibroblasts. Database analyses of patient-derived tumor xenografts in mice. Survival data from the GEPIA2 database for pancreatic cancer (N = 176), head and neck squamous cell carcinoma (N = 414), mesothelioma (N = 81) and liver cancer (N = 362) patients.
• Exposure: No asbestos exposure was studied. Fibroblasts were treated with laboratory-made (recombinant) human BAG3 protein at various concentrations, including 4 μg/ml for 16 h, with or without an anti-BAG3 antibody.
• Main results:
  • The BAG3 receptor IFITM-2 was found on the surface of human fibroblasts
  • In fibroblasts, an equal-amount mixture of BAG3 with anti-IFITM-2 antibody reduced the antibody signal by about 75%. A 10-fold excess of BAG3 completely displaced antibody binding.
  • The level of α-smooth muscle actin rose in normal human dermal fibroblasts treated with increasing concentrations of recombinant BAG3 for 16 h
  • Recombinant BAG3 induced phosphorylation of FAK in fibroblasts, and an anti-BAG3 antibody inhibited this effect
  • In the patient-derived xenograft databases, bag3 expression was higher in several cancers, including head and neck cancer, pancreatic cancer, mesothelioma and lung cancers, than in nonfibrotic cancers such as lymphomas (p < .001; R = 0.72)
  • Pancreatic cancer patients (N = 176): higher bag3 expression was associated with poorer survival (p = .032)
  • Head and neck squamous cell carcinoma patients (N = 414): patients with low bag3 expression had longer overall survival than those with higher expression (p = .034)
  • Mesothelioma patients (N = 81): the authors reported a significant correlation between bag3 levels and survival. No p-value is printed in the text.
  • Liver hepatocellular cancer patients (N = 362): similar results (p = .0041)
  • Several solid tumors, including pancreatic, head and neck, bladder and ovarian cancers, showed a high rate of bag3 gene amplification. Glioma and small cell lung cancer showed frequent bag3 deletions.
• The authors' conclusion: The authors concluded that their data identify BAG3 as a promising therapeutic target against tumor fibrosis. They named head and neck squamous cell carcinoma, mesothelioma and liver hepatocellular cancer as fibrotic tumors presumably more responsive to anti-BAG3 therapy.
• Limitations the authors state:
  • The authors noted that patient-derived xenograft models lack interaction between cancer cells and immune cells

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Fibroblast, Hypoxia, Angiogenesis, Prognosis, Fibrosis, Tumor Microenvironment.

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