Levels of Circulating Fibroblast Growth Factor 23 (FGF23) and Prognosis in Cancer Patients with Bone Metastases

Mansinho, André; Ferreira, Arlindo R.; Casimiro, Sandra; Alho, Irina; Vendrell, I.; Costa, Andreia; Abreu, Catarina; Pulido, Catarina; Macedo, Daniela; Pacheco, Teresa R.; Correia, Lurdes; Costa, Luís

doi:10.3390/ijms20030695

Cited by 22 publications

(14 citation statements)

References 16 publications

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“…Genomic aberrations in the FGF19 subfamily members have rarely been associated with a role in cancer progression, with the exception of an SNP in FGF23 that has been linked to increased risk of prostate cancer [ 169 ]. Although not directly linked to the SNP, FGF23 overexpression has also been associated with reduced overall survival and shortened time to occurrence of bone metastases [ 170 ] A large proportion of endometrial cancers are associated with metabolic disorders, including obesity. FGF21 and FGF23 expression have been implicated in endometrial cancer due to their association with increased expression of leptin (LEP), a hormone produced in adipose tissue.…”

Section: Fgf Signaling Diversity In Cancermentioning

confidence: 99%

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Ferguson

Smith

Francavilla

2021

Cells

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Increasing evidence indicates that success of targeted therapies in the treatment of cancer is context-dependent and is influenced by a complex crosstalk between signaling pathways and between cell types in the tumor. The Fibroblast Growth Factor (FGF)/FGF receptor (FGFR) signaling axis highlights the importance of such context-dependent signaling in cancer. Aberrant FGFR signaling has been characterized in almost all cancer types, most commonly non-small cell lung cancer (NSCLC), breast cancer, glioblastoma, prostate cancer and gastrointestinal cancer. This occurs primarily through amplification and over-expression of FGFR1 and FGFR2 resulting in ligand-independent activation. Mutations and translocations of FGFR1-4 are also identified in cancer. Canonical FGF-FGFR signaling is tightly regulated by ligand-receptor combinations as well as direct interactions with the FGFR coreceptors heparan sulfate proteoglycans (HSPGs) and Klotho. Noncanonical FGFR signaling partners have been implicated in differential regulation of FGFR signaling. FGFR directly interacts with cell adhesion molecules (CAMs) and extracellular matrix (ECM) proteins, contributing to invasive and migratory properties of cancer cells, whereas interactions with other receptor tyrosine kinases (RTKs) regulate angiogenic, resistance to therapy, and metastatic potential of cancer cells. The diversity in FGFR signaling partners supports a role for FGFR signaling in cancer, independent of genetic aberration.

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Section: Fgf Signaling Diversity In Cancermentioning

confidence: 99%

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Ferguson

Smith

Francavilla

2021

Cells

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“…Because bone is the main site of FGF23 production, malignancies typically affecting or arising from bone may have a link to FGF23. In patients with bone metastasis due to different solid tumors, a higher FGF23 plasma concentration is associated with shorter survival and shorter time to skeletal-related events ( Mansinho et al, 2019 ). Patients with myelodysplastic syndrome (MDS) characterized by impaired hematopoiesis in the bone marrow have a higher FGF23 plasma concentration that is associated with anemia and lower bone mineralization ( Weidner et al, 2020 ).…”

Section: Fgf23 and Cancermentioning

confidence: 99%

Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

Ewendt

Feger

Föller

2021

Front. Cell Dev. Biol.

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Together with fibroblast growth factors (FGFs) 19 and 21, FGF23 is an endocrine member of the family of FGFs. Mainly secreted by bone cells, FGF23 acts as a hormone on the kidney, stimulating phosphate excretion and suppressing formation of 1,25(OH)2D3, active vitamin D. These effects are dependent on transmembrane protein αKlotho, which enhances the binding affinity of FGF23 for FGF receptors (FGFR). Locally produced FGF23 in other tissues including liver or heart exerts further paracrine effects without involvement of αKlotho. Soluble Klotho (sKL) is an endocrine factor that is cleaved off of transmembrane Klotho or generated by alternative splicing and regulates membrane channels, transporters, and intracellular signaling including insulin growth factor 1 (IGF-1) and Wnt pathways, signaling cascades highly relevant for tumor progression. In mice, lack of FGF23 or αKlotho results in derangement of phosphate metabolism and a syndrome of rapid aging with abnormalities affecting most organs and a very short life span. Conversely, overexpression of anti-aging factor αKlotho results in a profound elongation of life span. Accumulating evidence suggests a major role of αKlotho as a tumor suppressor, at least in part by inhibiting IGF-1 and Wnt/β-catenin signaling. Hence, in many malignancies, higher αKlotho expression or activity is associated with a more favorable outcome. Moreover, also FGF23 and phosphate have been revealed to be factors relevant in cancer. FGF23 is particularly significant for those forms of cancer primarily affecting bone (e.g., multiple myeloma) or characterized by bone metastasis. This review summarizes the current knowledge of the significance of FGF23 and αKlotho for tumor cell signaling, biology, and clinically relevant parameters in different forms of cancer.

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“…Choudhary et al reported for the first time that the presence of prostate cancer cells significantly stimulates the expression of FGF23 by osteocytes [ 82 ]. Interestingly, other researchers suggested that FGF23 may play a role in cancer [ 84 , 85 , 86 ]. For example, FGF23 may act as an autocrine, paracrine and/or endocrine growth factor in prostate cancer progression, but the relative importance of each factor depends on tumor expression level, tumor site, and underlying disease state [ 85 ].…”

Section: Osteocytes: Their Physiology and Possible Contributions Tmentioning

confidence: 99%

“…Mansinho et al assigned a negative prognostic meaning to FGF: low baseline serum FGF23 levels correlated with longer overall survival and onset of SREs in metastasis-bearing patients [ 84 ].…”

Section: Osteocytes: Their Physiology and Possible Contributions Tmentioning

confidence: 99%

Bone, a Secondary Growth Site of Breast and Prostate Carcinomas: Role of Osteocytes

Maroni

Bendinelli

2020

Cancers

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Bone is the primarily preferred site for breast and prostate cancer to metastasize. Bone metastases are responsible for most deaths related to breast and prostate cancer. The bone’s particular microenvironment makes it conducive for the growth of cancer cells. Studies on bone metastasis have focused on the interaction between cancer cells and the bone microenvironment. Osteocytes, the most common cell type of bone tissue, have received little attention in bone metastasis, although they are master signal sensors, integrators, and skeleton transducers. They play an important role in regulating bone mass by acting on both osteoblasts and osteoclasts, through the release of proteins such as sclerostin, Dickkopf-1 (DKK-1), and fibroblast growth factor 23 (FGF23). Osteocytes have been extensively re-evaluated, in light of their multiple functions: with different experimental approaches, it has been shown that, indeed, osteocytes are actively involved in the colonization of bone tissue by cancer cells. The present review focuses on recent research on the role that osteocytes play in bone metastasis of breast and prostate cancers. Moreover, the studies here summarized open up perspectives for new therapeutic approaches focused on modulating the activity of osteocytes to improve the condition of the bone metastatic patients. A better understanding of the complex interactions between cancer cells and bone-resident cells is indispensable for identifying potential therapeutic targets to stop tumor progression and prevent bone metastases.

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Levels of Circulating Fibroblast Growth Factor 23 (FGF23) and Prognosis in Cancer Patients with Bone Metastases

Cited by 22 publications

References 16 publications

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

Bone, a Secondary Growth Site of Breast and Prostate Carcinomas: Role of Osteocytes

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