Joshua Pound

Background: Breast cancer is the most common malignancy in women worldwide and complications of metastasis results in a high mortality rate and low treatment capability.² Metastasis to the brain occurs predominantly in cases of lung adenocarcinoma, breast carcinoma and melanoma with brain metastasis developing in 10-30% of women with metastatic breast cancer and can be 20-30% in HER2 positive breast cancers.² Diet and obesity play a direct role and are important risk factors for any type of cancer development but this is especially true in breast cancer development with cholesterol implicated in the progression of tumor growth. Recently, fibroblast growth factor 21 (FGF-21) has been shown to promote breast cancer progression by manipulating CD8+ T-Cell cholesterol metabolism leading to an increased probability of breast cancer metastasis and decreasing positive outcomes.^2,6 FGF-21 is secreted by tumors to function as an immune suppressor of host cells and can promote tumor progression and metastasis.²

Objective: In this narrative review, we explored the implications and mechanisms of FGF-21 on cancer metastasis and potential impact of inhibiting FGF-21 as a form of cancer treatment.

Search Methods: An online search in the PubMed database was conducted with articles being limited to the years 2019-2024 and including the following keywords: “fibroblast growth factor 21 or FGF-21”, “cancer metastasis”, “breast cancer”, “cancer metabolism”, “T-cell suppression”, “Immune checkpoint therapy”, “mTORC; PI3k; AKT; mTOR”, “cholesterol and cancer”, and finally “Cytotoxic T-Cell”.

Results: FGF-21 was found to be overexpressed in tumor cells and due to its lack of heparin-binding domain, this protein acts as an endocrine factor, affecting the tumor cell and other cells in the body.³ FGF-21 does not stimulate cell proliferation but changes cellular metabolism of cytotoxic T-cells, specifically cholesterol metabolism, leading to host immune suppression and cancer cell proliferation.³ FGF-21 exerts its biological effects via the FGF-receptor and activation of the AKT pathway.³ This leads to increased activation of the AKT-mTORC1 pathway and increased cholesterol synthesis via upregulation of the SREBP-1 protein.^3,5 This increased synthesis leads to overactivation of CD8+ T-cells and cholesterol stimulated exhaustion of the CD8+ T-cells, leading to decreased ability for the T-cells to synthesize and release IFN gamma and granzyme B, leading to T cell exhaustion and cancer cell proliferation.^{4,7 T}his results in poor prognosis of the host and improved tumor progression and survivability.³

Conclusion: FGF-21 knockout mice were utilized in multiple tumor cell lines to demonstrate that tumor progression was reduced in hosts with removal of FGF-21 and that knockout of FGF-21 increased CD8+ T-cell activation and restored granzyme B and IFN gamma release, leading to improved host immune response.³ Dual treatment with anti-FGF-21 and anti-PD1 blockade showed reduction of cancer cell proliferation as well as improved mouse survival compared to single treatment, indicating this as a combined therapy to improve survival and prevent tumor metastasis.^3,4 Overall, consideration should be given to the establishment of anti-FGF-21 drugs as a combined therapy treatment to prevent breast cancer metastasis and cancer cell proliferation.

Work Cited:

1. Hiebert PR, Granville DJ. Granzyme B in injury, inflammation, and repair. Trends Mol Med. 2012;18(12):732-741. doi:10.1016/j.molmed.2012.09.009
2. Hosonaga M, Saya H, Arima Y. Molecular and cellular mechanisms underlying brain metastasis of breast cancer. Cancer Metastasis Rev. 2020;39(3):711-720. doi:10.1007/s10555-020-09881-y
3. Hu C, Qiao W, Li X, et al. Tumor-secreted FGF-21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8⁺T cells. Cell Metab. Published online January 23, 2024. doi:10.1016/j.cmet.2024.01.005
4. Jorgovanovic D, Song M, Wang L, Zhang Y. Roles of IFN-γ in tumor progression and regression: a review. Biomark Res. 2020;8:49. Published 2020 Sep 29. doi:10.1186/s40364-020-00228-x
5. Liu C, Chikina M, Deshpande R, et al. Treg Cells Promote the SREBP1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of CD8+ T Cell-Derived Interferon-γ. Immunity. 2019;51(2):381-397.e6. doi:10.1016/j.immuni.2019.06.017
6. Lu J, Chen S, Bai X, et al. Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications. Biochem Pharmacol. 2023;218:115907. doi:10.1016/j.bcp.2023.115907
7. Ma X, Bi E, Lu Y, et al. Cholesterol Induces CD8+ T Cell Exhaustion in the Tumor Microenvironment. Cell Metab. 2019;30(1):143-156.e5. doi:10.1016/j.cmet.2019.04.002
8. Wang Y, Ye F, Liang Y, Yang Q. Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies. Br J Cancer. 2021;125(8):1056-1067. doi:10.1038/s41416-021-01424-8
9. Winslow T. Immune checkpoint inhibitors. National Cancer Institute. April 7, 2022. Accessed April 16, 2024. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors.