uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Alafuzoff, Irina
Publications (10 of 103) Show all publications
Rauramaa, T., Saxlin, A., Lohvansuu, K., Alafuzoff, I., Pitkanen, A. & Soininen, H. (2018). Epilepsy in neuropathologically verified Alzheimer's disease. Seizure, 58, 9-12
Open this publication in new window or tab >>Epilepsy in neuropathologically verified Alzheimer's disease
Show others...
2018 (English)In: Seizure, ISSN 1059-1311, E-ISSN 1532-2688, Vol. 58, p. 9-12Article in journal (Refereed) Published
Abstract [en]

Purpose: Subjects with Alzheimer's disease (AD) have been shown to be at a higher risk for epilepsy. The vast majority of the previous studies have not included a full neuropathological examination. Methods: The objective of this study was to assess the prevalence of epilepsy and clinicopathological characteristics in a well-defined study group of 64 subjects with AD. We evaluated the clinicopathological findings in 64 subjects (mean age at death 85 +/- 8.6 years) from a longitudi-nal study cohort of patients with dementia. Results: Eleven out of the 64 subjects (17%) had a history of epilepsy, which is comparable to previous studies. The subjects with AD and epilepsy were significantly younger at the time of AD diagnosis and at the time of hospitalisation. In addition, their duration of AD was longer. Concomitant neuropathology in addition to AD was common in both groups and the ApoE genotypes did not differ significantly between the groups. Conclusion: The strength of this study is a thorough neuropathological examination of all study subjects. Our findings support the previous literature regarding the prevalence of epilepsy in subjects with AD. We have shown that the subjects with AD and epilepsy differ significantly from the subjects without epilepsy.

Place, publisher, year, edition, pages
W B SAUNDERS CO LTD, 2018
Keywords
Alzheimer, Dementia, Epilepsy, Autopsy, Neurodegeneration
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-360996 (URN)10.1016/j.seizure.2018.03.014 (DOI)000436884500003 ()29602145 (PubMedID)
Available from: 2018-09-26 Created: 2018-09-26 Last updated: 2018-09-26Bibliographically approved
Pyykko, O. T., Nerg, O., Niskasaari, H.-M., Niskasaari, T., Koivisto, A. M., Hiltunen, M., . . . Leinonen, V. (2018). Incidence, Comorbidities, and Mortality in Idiopathic Normal Pressure Hydrocephalus. World Neurosurgery, 112, E624-E631
Open this publication in new window or tab >>Incidence, Comorbidities, and Mortality in Idiopathic Normal Pressure Hydrocephalus
Show others...
2018 (English)In: World Neurosurgery, ISSN 1878-8750, E-ISSN 1878-8769, Vol. 112, p. E624-E631Article in journal (Refereed) Published
Abstract [en]

OBJECT: To investigate the incidence, comorbidities, mortality, and causes of death in idiopathic normal pressure hydrocephalus (iNPH). METHODS: A cohort of 536 patients with possible NPH from a defined population with a median follow-up time of 5.1 years, (range 0.04-19.9 years) was included in the study. Patients were evaluated by brain imaging and intraventricular pressure monitoring, with a brain biopsy specimen immunostained against amyloid-beta and hyper-phosphorylated tau. Hospital records were reviewed for vascular diseases and type 2 diabetes mellitus (T2DM). Death certificates and yearly population of the catchment area were obtained from national registries. RESULTS: A total of 283 patients had a clinical diagnosis of iNPH, leading to a median annual incidence of 1.58 iNPH patients per 100,000 inhabitants (range, 0.8-4.5). Alzeimer disease-related brain biopsy findings were less frequent in iNPH patients than in non-iNPH patients (P < 0.05). An overrepresentation of hypertension (52% vs. 33%, P < 0.001) and T2DM (23% vs. 13%, P = 0.002) was noted in iNPH patients. Age (hazard ratio [HR] 1.04/year, 95% confidence interval [CI] 1.03-1.06, P< 0.001) and T2DM (HR 1.63, 95% CI 1.23-2.16, P < 0.001) increased the risk of death in the iNPH patients and in the total population. iNPH was associated with decreased risk of death (HR 0.63, 95% CI 0.50-0.78, P < 0.001). The most frequent causes of death were cardiovascular and cerebrovascular disease. Dementia as a cause of death was more common in non-iNPH patients (27% vs. 10%, P < 0.001). CONCLUSIONS: Hypertension and T2DM are common in iNPH and the latter causes excess mortality in the affected patients.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2018
Keywords
Cause of death, Comorbidity, Incidence, Mortality, Normal pressure hydrocephalus, Survival
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-356808 (URN)10.1016/j.wneu.2018.01.107 (DOI)000432932700074 ()29374607 (PubMedID)
Available from: 2018-08-16 Created: 2018-08-16 Last updated: 2018-08-16Bibliographically approved
Libard, S., Laurell, K., Cesarini, K. G. & Alafuzoff, I. (2018). Progression of Alzheimer's Disease-Related Pathology and Cell Counts in a Patient with Idiopathic Normal Pressure Hydrocephalus. Journal of Alzheimer's Disease, 61(4), 1451-1461
Open this publication in new window or tab >>Progression of Alzheimer's Disease-Related Pathology and Cell Counts in a Patient with Idiopathic Normal Pressure Hydrocephalus
2018 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, no 4, p. 1451-1461Article in journal (Refereed) Published
Abstract [en]

We had an opportunity to assess the change observed in the brain regarding Alzheimer’s disease (AD)-related alterations, cell count, and inflammation that took place during a period of 21 months in a subject with a definite diagnosis of AD and idiopathic Normal Pressure Hydrocephalus (iNPH). Four neuronal markers, i.e., synaptophysin, microtubule associated protein 2, non-phosphorylated neurofilament H (SMI32), and embryonic lethal abnormal visual system proteins 3/4 HuC/HuD (HuC/HuD); three microglial markers CD68, Human Leucocytic Antigen DR, ionized calcium-binding adaptor molecule 1, glial fibrillary acidic protein (GFAP); and AD-related markers, hyperphosphorylated τ (HPτ) and amyloid-β (Aβ, Aβ40, Aβ42) were assessed. Morphometrically assessed immunoreactivity of all neuronal and all microglial markers and Aβ42 decreased parallel with an increase in the HPτ in the frontal cortex. The expression of GFAP was stable with time. The first sample was obtained during the therapeutic shunting procedure for iNPH, and the second sample was obtained postmortem. Negligible reactive changes were observed surrounding the shunt channel. In conclusion, in the late stage of AD with time, a neuronal loss, increase in the HPτ, and decrease in Aβ42 and microglia was observed, whereas the expression of GFAP was rather stable. The observations described here suggest that when a brain biopsy has been obtained from an adult subject with iNPH, the assessment of postmortem brain is of major significance.

Keywords
Amyloid-beta, astrocytes, hyperphosphorylated tau, idiopathic normal pressure hydrocephalus, immunohistochemistry, microglia, neurons
National Category
Neurosciences Neurology Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-346377 (URN)10.3233/JAD-170446 (DOI)000423364400018 ()29376849 (PubMedID)
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-03-23Bibliographically approved
Ygland, E., van Westen, D., Englund, E., Rademakers, R., Wszolek, Z. K., Nilsson, K., . . . Puschmann, A. (2018). Slowly progressive dementia caused by MAPT R406W mutations: longitudinal report on a new kindred and systematic review. Alzheimer's Research & Therapy, 10, Article ID 2.
Open this publication in new window or tab >>Slowly progressive dementia caused by MAPT R406W mutations: longitudinal report on a new kindred and systematic review
Show others...
2018 (English)In: Alzheimer's Research & Therapy, ISSN 0065-6755, E-ISSN 1758-9193, Vol. 10, article id 2Article, review/survey (Refereed) Published
Abstract [en]

Background: The MAPT c.1216C > T (p.Arg406Trp; R406W) mutation is a known cause of frontotemporal dementia with Parkinsonism linked to chromosome 17 tau with Alzheimer's disease-like clinical features. Methods: We compiled clinical data from a new Swedish kindred with R406W mutation. Seven family members were followed longitudinally for up to 22 years. Radiological examinations were performed in six family members and neuropathological examinations in three. We systematically reviewed the literature and compiled clinical, radiological, and neuropathological data on 63 previously described R406W heterozygotes and 3 homozygotes. Results: For all cases combined, the median age of onset was 56 years and the median disease duration was 13 years. Memory impairment was the most frequent symptom, behavioral disturbance and language impairment were less common, and Parkinsonism was rare. Disease progression was most often slow. The most frequent clinical diagnosis was Alzheimer's disease. R406W homozygotes had an earlier age at onset and a higher frequency of behavioral symptoms and Parkinsonism than heterozygotes. In the new Swedish kindred, a consistent imaging finding was ventromedial temporal lobe atrophy, which was evident also in early disease stages as a widening of the collateral sulcus with ensuing atrophy of the parahippocampal gyrus. Unlike previously published R406W carriers, all three autopsied patients from the novel family showed neuropathological similarities with progressive supranuclear palsy, with predominant four-repeat (exon 10+) tau isoform (4R) tauopathy and neurofibrillary tangles accentuated in the basal-medial temporal lobe. Amyloid-beta pathology was absent. Conclusions: Dominance of 4R over three-repeat (exon 10-) tau isoforms contrasts with earlier reports of R406W patients and was not sufficiently explained by the presence of H1/H2 haplotypes in two of the autopsied patients. R406W patients often show a long course of disease with marked memory deficits. Both our neuropathological results and our imaging findings revealed that the ventromedial temporal lobes were extensively affected in the disease. We suggest that this area may represent the point of origin of tau deposition in this disease with relatively isolated tauopathy.

Place, publisher, year, edition, pages
BioMed Central, 2018
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-350687 (URN)10.1186/s13195-017-0330-2 (DOI)000425762700002 ()29370822 (PubMedID)
Available from: 2018-05-21 Created: 2018-05-21 Last updated: 2018-05-21Bibliographically approved
Glimelius, B., Melin, B., Enblad, G., Alafuzoff, I., Beskow, A. H., Ahlström, H., . . . Sjöblom, T. (2018). U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.. Acta Oncologica, 57(2), 187-194
Open this publication in new window or tab >>U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
Show others...
2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed) Published
Abstract [en]

Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

National Category
Cancer and Oncology Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-325565 (URN)10.1080/0284186X.2017.1337926 (DOI)000423473200003 ()28631533 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-06-26 Created: 2017-06-26 Last updated: 2018-03-09Bibliographically approved
Velickaite, V., Giedraitis, V., Ström, K., Alafuzoff, I., Zetterberg, H., Lannfelt, L., . . . Ingelsson, M. (2017). Cognitive function in very old men does not correlate to biomarkers of Alzheimer's disease. BMC Geriatrics, 17(1), Article ID 208.
Open this publication in new window or tab >>Cognitive function in very old men does not correlate to biomarkers of Alzheimer's disease
Show others...
2017 (English)In: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 17, no 1, article id 208Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The Alzheimer's disease (AD) brain displays atrophy with amyloid-β (Aβ) and tau deposition, whereas decreased Aβ42 and increased tau are measured in cerebrospinal fluid (CSF). The aim of this study was to relate cognitive performance to the degree of brain atrophy, CSF biomarker levels and neuropathology in a cohort of aged men.

METHODS: Fifty-eight 86-92-year-old men from the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort underwent cognitive testing, brain computed tomography and lumbar puncture. Atrophy was graded with established scales. Concentrations of CSF Aβ42, t-tau and p-tau were measured by ELISA. Thirteen brains were examined post mortem.

RESULTS: Forty-six of the individuals were considered non-demented, whereas twelve were diagnosed with dementia, either at baseline (n = 4) or during follow-up (n = 8). When comparing subjects with and without dementia, there were no differences in the degree of atrophy, although the mini mental state examination (MMSE) scoring correlated weakly with the degree of medial temporal atrophy (MTA) (p = 0.04). Moreover, the CSF biomarker levels did not differ significantly between healthy (n = 27) and demented (n = 8) subjects (median values 715 vs 472 pg/ml for Aβ42, 414 vs 427 pg/ml for t-tau and 63 vs 60 pg/ml for p-tau). Similarly, there were no differences in the biomarker levels between individuals with mild (n = 24) and severe (n = 11) MTA (median values 643 vs 715 pg/ml for Aβ42, 441 vs 401 pg/ml for t-tau and 64 vs 53 pg/ml for p-tau). Finally, the neuropathological changes did not correlate with any of the other measures.

CONCLUSION: In this cohort of aged men only a weak correlation could be seen between cognitive performance and MTA, whereas the various neuroradiological, biochemical and neuropathological measures did not correlate with each other. Thus, AD biomarkers seem to be less informative in subjects of an advanced age.

Keywords
AD biomarkers, Advanced age, Brain atrophy, CSF biomarkers, Cognitive performance, Neuropathology
National Category
Neurology Geriatrics Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-329266 (URN)10.1186/s12877-017-0601-6 (DOI)000410449900002 ()28886705 (PubMedID)
Note

V. Velickaite and V. Giedraitis contributed equally.

Available from: 2017-09-11 Created: 2017-09-11 Last updated: 2017-12-06Bibliographically approved
Falk Delgado, A., Fahlström, M., Nilsson, M., Berntsson, S. G., Zetterling, M., Libard, S., . . . Larsson, E.-M. (2017). Diffusion kurtosis imaging of gliomas grades II and III: a study of perilesional tumor infiltration, tumor grades and subtypes at clinical presentation. Radiology and Oncology, 51(2), 121-129
Open this publication in new window or tab >>Diffusion kurtosis imaging of gliomas grades II and III: a study of perilesional tumor infiltration, tumor grades and subtypes at clinical presentation
Show others...
2017 (English)In: Radiology and Oncology, ISSN 1318-2099, E-ISSN 1581-3207, Vol. 51, no 2, p. 121-129Article in journal (Refereed) Published
Abstract [en]

Background. Diffusion kurtosis imaging (DKI) allows for assessment of diffusion influenced by microcellular structures. We analyzed DKI in suspected low-grade gliomas prior to histopathological diagnosis. The aim was to investigate if diffusion parameters in the perilesional normal-appearing white matter (NAWM) differed from contralesional white matter, and to investigate differences between glioma malignancy grades II and III and glioma subtypes (astrocytomas and oligodendrogliomas).

Patients and methods. Forty-eight patients with suspected low-grade glioma were prospectively recruited to this institutional review board-approved study and investigated with preoperative DKI at 3T after written informed consent. Patients with histologically proven glioma grades II or III were further analyzed (n=35). Regions of interest (ROIs) were delineated on T2FLAIR images and co-registered to diffusion MRI parameter maps. Mean DKI data were compared between perilesional and contralesional NAWM (student's t-test for dependent samples, Wilcoxon matched pairs test). Histogram DKI data were compared between glioma types and glioma grades (multiple comparisons of mean ranks for all groups). The discriminating potential for DKI in assessing glioma type and grade was assessed with receiver operating characteristics (ROC) curves.

Results. There were significant differences in all mean DKI variables between perilesional and contralesional NAWM (p=< 0.000), except for axial kurtosis (p=0.099). Forty-four histogram variables differed significantly between glioma grades II (n=23) and III (n=12) (p=0.003-0.048) and 10 variables differed significantly between ACs (n=18) and ODs (n=17) (p=0.011-0.050). ROC curves of the best discriminating variables had an area under the curve (AUC) of 0.657-0.815.

Conclusions. Mean DKI variables in perilesional NAWM differ significantly from contralesional NAWM, suggesting altered microstructure by tumor infiltration not depicted on morphological MRI. Histogram analysis of DKI data identifies differences between glioma grades and subtypes.

Keywords
diffusion kurtosis imaging (DKI), glioma, perilesional, tumor infiltration, grade, subtype
National Category
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-323762 (URN)10.1515/raon-2017-0010 (DOI)000401697000001 ()
Funder
Swedish Cancer Society
Available from: 2017-06-09 Created: 2017-06-09 Last updated: 2017-06-09Bibliographically approved
Laiterä, T., Paananen, J., Helisalmi, S., Sarajärvi, T., Huovinen, J., Laitinen, M., . . . Hiltunen, M. (2017). Effects of Alzheimer's Disease-Associated Risk Loci on Amyloid-β Accumulation in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients. Journal of Alzheimer's Disease, 55(3), 995-1003
Open this publication in new window or tab >>Effects of Alzheimer's Disease-Associated Risk Loci on Amyloid-β Accumulation in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients
Show others...
2017 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 55, no 3, p. 995-1003Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer's disease (AD) patients, diffuse aggregates of amyloid-β (Aβ) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aβ is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aβ-related cellular processes. Apart from the apolipoprotein E ɛ4 allele (APOE4), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing the combined effects.

OBJECTIVE: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aβ in the brain samples of iNPH patients.

METHODS: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aβ pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aβ deposition.

RESULTS: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aβ in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aβ deposition.

CONCLUSION: Novel AD-associated risk genes have no significant effect on Aβ accumulation in the brain of iNPH patients. However, APOE4 affects the Aβ deposition in the brain of iNPH and AD patients in a similar manner.

Keywords
Alzheimer’s disease, amyloid-β, apolipoprotein E, genome wide association studies, idiopathic normal pressure hydrocephalus
National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-319086 (URN)10.3233/JAD-160554 (DOI)000390766600012 ()27802227 (PubMedID)
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2018-09-24Bibliographically approved
Jiang, Y., Marinescu, V. D., Xie, Y., Jarvius, M., Maturi, N. P., Haglund, C., . . . Uhrbom, L. (2017). Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin. Cell reports, 18(4), 977-990
Open this publication in new window or tab >>Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin
Show others...
2017 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 4, p. 977-990Article in journal (Refereed) Published
Abstract [en]

The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

Keywords
cancer stem cell, cell of origin, central nervous system, drug response, glioblastoma, glioma, mouse model, neural stem cell, oligodendrocyte precursor cell, self-renewal
National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-319084 (URN)10.1016/j.celrep.2017.01.003 (DOI)000396474300013 ()28122246 (PubMedID)
Funder
Swedish Cancer Society, 110363 140385 150628Swedish Research Council, 90283201 C0259101 B0310101 E0331401Swedish Childhood Cancer Foundation, PROJ11/057 PR2014-0143Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2017-11-29Bibliographically approved
Roy, A., Libard, S., Weishaupt, H., Gustavsson, I., Uhrbom, L., Hesselager, G., . . . Tchougounova, E. (2017). Mast Cell Infiltration in Human Brain Metastases Modulates the Microenvironment and Contributes to the Metastatic Potential. Frontiers in Oncology, 7, Article ID 115.
Open this publication in new window or tab >>Mast Cell Infiltration in Human Brain Metastases Modulates the Microenvironment and Contributes to the Metastatic Potential
Show others...
2017 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 7, article id 115Article in journal (Refereed) Published
Abstract [en]

Metastatic brain tumors continue to be a clinical problem, despite new therapeutic advances in cancer treatment. Brain metastases (BMs) are among the most common mass lesions in the brain that are resistant to chemotherapies, have a very poor prognosis, and currently lack any efficient diagnostic tests. Predictions estimate that about 40% of lung and breast cancer patients will develop BM. Despite this, very little is known about the immunological and genetic aberrations that drive tumorigenesis in BM. In this study, we demonstrate the infiltration of mast cells (MCs) in a large cohort of human BM samples with different tissues of origin for primary cancer. We applied patient-derived BM cell models to the study of BM cell-MC interactions. BM cells when cocultured with MCs demonstrate enhanced growth and self-renewal capacity. Gene set enrichment analyses indicate increased expression of signal transduction and transmembrane proteins related genes in the cocultured BM cells. MCs exert their effect by release of mediators such as IL-8, IL-10, matrix metalloprotease 2, and vascular endothelial growth factor, thereby permitting metastasis. In conclusion, we provide evidence for a role of MCs in BM. Our findings indicate MCs' capability of modulating gene expression in BM cells and suggest that MCs can serve as a new target for drug development against metastases in the brain.

Keywords
IL-10, IL-8, brain metastases, mast cell, matrix metalloprotease 2, vascular endothelial growth factor
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-343584 (URN)10.3389/fonc.2017.00115 (DOI)000402502800001 ()28626727 (PubMedID)
Funder
Swedish Research Council, 522-2009-2452Swedish Cancer Society, CAN 2014/580
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-09-04Bibliographically approved
Organisations

Search in DiVA

Show all publications