Metastasis-inducing proteins are widely expressed in human brain metastases and associated with intracranial progression and radiation response.
Understanding the factors that drive recurrence and radiosensitivity in brain metastases would improve prediction of outcomes, treatment planning and development of therapeutics. We investigated the expression of known metastasis-inducing proteins in human brain metastases.



Immunohistochemistry on metastases removed at neurosurgery from 138 patients to determine the degree and pattern of expression of the proteins S100A4, S100P, AGR2, osteopontin (OPN) and the DNA repair marker FANCD2. Validation of significant findings in a separate prospective series with the investigation of intra-tumoral heterogeneity using image-guided sampling. Assessment of S100A4 expression in brain metastatic and non-metastatic primary breast carcinomas.



There was widespread staining for OPN, S100A4, S100P and AGR2 in human brain metastases. Positive staining for S100A4 was independently associated with a shorter time to intracranial progression after resection in multivariate analysis (hazard ratio for negative over positive staining=0.17, 95% CI: 0.04-0.74, P=0.018). S100A4 was expressed at the leading edge of brain metastases in image guided sampling and overexpressed in brain metastatic vs non-brain metastatic primary breast carcinomas. Staining for OPN was associated with a significant increase in survival time after post-operative whole-brain radiotherapy in retrospective (OPN negative 3.43 months, 95% CI: 1.36-5.51 vs OPN positive, 11.20 months 95% CI: 7.68-14.72, Log rank test, P<0.001) and validation populations.



Proteins known to be involved in cellular adhesion and migration in vitro, and metastasis in vivo are significantly expressed in human brain metastases and may be useful biomarkers of intracranial progression and radiosensitivity.
Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.|Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Rasheed
R
Zakaria
Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Angela
A
Platt-Higgins
Department of Neuropathology, The Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
Nitika
N
Rathi
Department of Neuropathology, The Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
Daniel
D
Crooks
Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
Andrew
A
Brodbelt
Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
Emmanuel
E
Chavredakis
Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
David
D
Lawson
Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.|Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
Michael D
MD
Jenkinson
Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Philip S
PS
Rudland
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000532:radiotherapy* / Q000556:secondary*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061705:Image-Guided Biopsy; D008297:Male; D008875:Middle Aged; D009088:Mucoproteins; D009363:Neoplasm Proteins / Q000378:metabolism*; D015513:Oncogene Proteins; D053495:Osteopontin / Q000378:metabolism*; D011379:Prognosis; D011446:Prospective Studies; D011506:Proteins / Q000378:metabolism*; D012189:Retrospective Studies; D000071999:S100 Calcium-Binding Protein A4 / Q000378:metabolism*; D016019:Survival Analysis; D055815:Young Adult
C502296:AGR2 protein, human; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D009088:Mucoproteins; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D011506:Proteins; D000071999:S100 Calcium-Binding Protein A4; C103003:S100P protein, human; C506895:SPP1 protein, human; D053495:Osteopontin; C077591:S100A4 protein, human