FN14 and GRP94 expression are prognostic/predictive biomarkers of brain metastasis outcome that open up new therapeutic strategies

Abstract

Brain metastasis is a devastating problem in patients with breast, lung and melanoma tumors. GRP94 and FN14 are predictive biomarkers over-expressed in primary breast carcinomas that metastasized in brain. To further validate these brain metastasis biomarkers, we performed a multicenter study including 318 patients with breast carcinomas. Among these patients, there were 138 patients with metastasis, of whom 84 had brain metastasis. The likelihood of developing brain metastasis increased by 5.24-fold (95%CI 2.83–9.71) and 2.55- (95%CI 1.52–4.3) in the presence of FN14 and GRP94, respectively. Moreover, FN14 was more sensitive than ErbB2 (38.27 vs. 24.68) with similar specificity (89.43 vs. 89.55) to predict brain metastasis and had identical prognostic value than triple negative patients (p < 0.0001). Furthermore, we used GRP94 and FN14 pathways and GUILD, a network-based disease-gene prioritization program, to pinpoint the genes likely to be therapeutic targets, which resulted in FN14 as the main modulator and thalidomide as the best scored drug. The treatment of mice with brain metastasis improves survival decreasing reactive astrocytes and angiogenesis, and down-regulate FN14 and its ligand TWEAK. In conclusion our results indicate that FN14 and GRP94 are prediction/prognosis markers which open up new possibilities for preventing/treating brain metastasis.

Risk factors for breast cancer brain metastases: a systematic review

“…Additional primary tumor markers found to associate with BCBM progression by more than one study included Ki67, EGFR, FOXC1 and CK5/6. Although different IHC staining cut-offs were used across studies, Metastatic status 4 [33,38,53,70] 3 [33,38,53] 2 Primary metastatic status M0, SHR:2.64 p = 0.007 [33]; Extracranial distant metastases, AHR=28.46, p < 0.001 [38] Number of nonbrain metastatic sites 6 [29,33,55,70,74,79] 3 [29,33,70] 5 >1 OR: 1.76, p < 0.001 [29]; ≥3, HR = 2.712, p < 0.0001 [55]; <1, sHR: 1.77 p = 0.04 [70] 1 Abnormal serum levels, HR: 3.51 p = 0.005 [64] p16 expression on metastatic lymph nodes 1 [69] 1 [69] 1 High score p = 0.01 [69] CRYAB expression 1 [63] 1 HR:1.2 p = 0.021 [63] 3q gene signature 1 [76] 1 HR: 1.61 p = 0.001 [76] GRP94 Status 2 [35,62] 1 Strong positive vs. negative [35] FN14 Status 2 [35,62] 1 Strong positive vs. negative [35] CTC status 1 [34] 1 Undetectable CTC status OR: 6.17 p = 0.001 [34] SNPs 1 [72] 1 AKT1 -RS3803304, SHR: 2.72 p = 0.008, AKT2 -RS3730050, SHR: 2.06 p = 0.041, PDK1 -RS11686903 SHR: 2.38 p = 0.001, PI3KR1 -RS706716, SHR: 2.42 p = 0.025 [72] HR -Hazard Ratio; OR -Odds Ratio; NS -Non Significant; NR -Not Reported; SHR -Subhazard ratio; IDC -Infiltrating ductal carcinoma; CTC -C...…”

Molecular and cellular stratagem of brain metastases associated with melanoma (Review)

“…Active molecules, such as astrocytic-derived microRNAs are secreted as exosomes and they target malignant PTEN expression in order to promote BM. Astrocytic exosome inhibition can prevent BM (41). A multicentre study on 318 patients with breast cancer (84 with BM) highlighted that fibroblast growth factor-inducible protein 14 (FN14) and GRP94 are prediction/prognosis markers that can be used as therapeutic targets in BM patients (42).…”

TWEAK/Fn14 signaling in tumors

“…80 The treatment of mice with brain metastasis of breast carcinoma improves survival and downregulates TWEAK and Fn14 expression in tumors. 80 Moreover, Fn14 protein is related to human glioma tumor grade. 81 Fn14 expression is also an independent prognostic factor in gastric cancer, non-small cell lung cancer, and hepatocellular carcinoma.…”