| 1. |
- Magnusson, Kristina, 1979-
(författare)
-
Protein Expression Profiling of Cancer Biomarkers
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Human Protein Atlas project is a Swedish research initiative that uses antibody-based proteomics for large scale protein profiling in human tissues and cells. Affinity-purified antibodies are produced within the project and used for immunohistochemical staining on tissue micro arrays (TMAs) in order to map the human proteome and publish the result in a protein atlas (www.proteinatlas.org). In this thesis, TMAs were used for analysis of protein expression patterns in order to identify and explore potential biomarkers of clinical relevance.In Paper I, protein expression of SATB2 was studied in colorectal cancer. The results show that SATB2 is a sensitive and specific biomarker for colorectal cancer, staining 85% of all investigated tumors. Moreover, SATB2 in combination with CK20 showed positivity in 97% of all colorectal carcinomas and is therefore suitable as a complementary tool in clinical differential diagnostics of cancer.In Paper II, ANLN was explored as a prognostic biomarker for breast cancer. A high nuclear fraction of ANLN in breast cancer was significantly correlated to large tumor size, high histological grade, hormone receptor negative tumors, high proliferation rate and poor prognosis. Furthermore, ANLN depletion in breast cancer cell lines resulted in cell cycle arrest and cellular senescence with altered cell morphology.In Paper III, young age at breast cancer diagnosis was investigated as an independent risk factor for poor prognosis. TMAs were produced from a selection of patients from a previously defined register-based cohort. The analysis shows that young women with luminal B tumors have a 2.2-fold higher risk of dying of breast cancer compared to older women.In Paper IV, vascular expression of CD93 was explored by image analysis of the tissue-based breast cancer cohort produced in Paper III. The analysis shows that young women with breast cancer display a significantly higher CD93-positive vessel area in their tumors. High CD93-positive vessel area was significantly associated with hormone receptor negative tumors, grade, Ki-67, EGFR and a poor prognosis.In conclusion, this thesis shows that protein expression profiling using TMAs is an important tool for identifying and exploring potential novel biomarkers for cancer.
|
|
| 2. |
- Ghanipour, Lana
(författare)
-
Colorectal Cancer : Aspects of Heredity, Prognosis and Tumour Markers
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is one of the most common cancer types and leading causes of cancer death worldwide. Since CRC is a heterogenic disease, there is a demand for increased knowledge of the underlying genetic and epigenetic mechanisms. The aim of this thesis was to investigate heredity and potential tumour markers in relation to prognosis. In paper I, survival of patients with CRC and a positive family history of CRC in first-degree relatives was analysed. Patients with colon cancer and positive family history of CRC had improved survival compared to patients with negative family history. This improvement in survival could not be explained by known clinico-pathological factors. In paper II, we investigated the prognostic value of Tryptophanyl t-RNA synthetase (TrpRS) in tissues from patients operated for CRC. Low protein expression of TrpRS in primary tumour tissues correlated with increased risk of recurrence and poorer survival. In paper III, the prognostic value of microsatellite instability (MSI) and the correlation to heredity for CRC in first-degree relatives was investigated. Patients with proximal colon cancer and MSI had improved cancer specific survival. There were no correlation between MSI and heredity. In paper IV, we evaluated the potential use of proximity ligation assay (SP-PLA) in patients with CRC, by simultaneous analysis of 35 proteins in only 5 μl plasma. SP-PLA is a suitable method for protein detection and might give valuable guidance in pursuing new prognostic and predictive tumour markers. However, none of the markers selected for present SP-PLA analyses gave better prognostic information than CEA. In conclusion, heredity is related to better survival independent of MSI in patients with CRC and MSI is associated with better prognosis in proximal colon cancer. Detection and increased knowledge of molecular mechanism in CRC is important, however it needs to be further investigated and validated in clinical use.
|
|
| 3. |
- Backman, Max, et al.
(författare)
-
Infiltration of NK and plasma cells is associated with a distinct immune subset in non‐small cell lung cancer
- 2021
-
Ingår i: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 255:3, s. 243-256
-
Tidskriftsartikel (refereegranskat)abstract
- Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and showed only poor association with specific mutations. The previously defined immune phenotypic patterns, desert, inflamed, and immune excluded, comprised 30, 13, and 57% of cases, respectively. Notably, mRNA immune activation and high estimated tumor mutational load were unique only for the inflamed pattern. However, in the unsupervised cluster analysis, including all immune cell markers, these conceptual patterns were only weakly reproduced. Instead, four immune classes were identified: (1) high immune cell infiltration, (2) high immune cell infiltration with abundance of CD20+ B cells, (3) low immune cell infiltration, and (4) a phenotype with an imprint of plasma cells and NK cells. This latter class was linked to better survival despite exhibiting low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, CTLA4). This compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC reveals two previously unrecognized immune classes. A refined immune classification, including traits of the humoral and innate immune response, is important to define the immunogenic potency of NSCLC in the era of immunotherapy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
|
|
| 4. |
- Backman, Max, 1987-, et al.
(författare)
-
Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer
- 2023
-
Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 185, s. 40-52
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Immune cells in the tumour microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterise the spatial im-mune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC).Methods: We established a multiplexed fluorescence imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4-Eff), CD4 regulatory cells (CD4-Treg), CD8 effector cells (CD8-Eff), CD8 regulatory cells (CD8-Treg), B-cells, natural killer cells, natural killer T-cells, M1 macrophages (M1), CD163 thorn myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs).Results: CD4-Eff cells, CD8-Eff cells and M1 macrophages were the most abundant immune cells invading the tumour cell compartment and indicated a patient group with a favourable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4-Eff, CD4-Treg, CD8-Treg, B-cells and pDCs) were independently associated with longer survival. However, when these immune cells were located close to CD8-Treg cells, the favourable impact was attenuated. In the multivariable Cox regression model, including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8-Treg-B-cells, CD8-Eff-cancer cells and B-cells-CD4-Treg) demonstrated positive prognostic impact, whereas short M2-M1 distances were prognostically unfavourable.Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is crucial for diagnostic use.
|
|
| 5. |
|
|
