| 1. |
- Hagerstrand, Daniel, et al.
(författare)
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Identification of a SOX2-dependent subset of tumor- and sphere-forming glioblastoma cells with a distinct tyrosine kinase inhibitor sensitivity profile
- 2011
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Ingår i: Neuro-Oncology. - : Oxford University Press (OUP). - 1522-8517 .- 1523-5866. ; 13:11, s. 1178-1191
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Tidskriftsartikel (refereegranskat)abstract
- Putative cancer stem cells have been identified in glioblastomas and are associated with radio- and chemoresistance. Further knowledge about these cells is thus highly warranted for the development of better glioblastoma therapies. Gene expression analyses of 11 high-grade glioma cultures identified 2 subsets, designated type A and type B cultures. The type A cultures displayed high expression of CXCR4, SOX2, EAAT1, and GFAP and low expression of CNP, PDGFRB, CXCL12, and extracellular matrix proteins. Clinical significance of the 2 types was indicated by the expression of type A-and type B-defining genes in different clinical glioblastoma samples. Classification of glioblastomas with type A- and type B-defining genes generated 2 groups of tumors composed predominantly of the classical, neural, and/or proneural subsets and the mesenchymal subset, respectively. Furthermore, tumors with EGFR mutations were enriched in the group of type A samples. Type A cultures possessed a higher capacity to form xenograft tumors and neurospheres and displayed low or no sensitivity to monotreatment with PDGF-and IGF-1-receptor inhibitors but were efficiently growth inhibited by combination treatment with low doses of these 2 inhibitors. Furthermore, siRNA-induced downregulation of SOX2 reduced sphere formation of type A cultures, decreased expression of type A-defining genes, and conferred sensitivity to monotreatment with PDGF-and IGF-1receptor inhibitors. The present study thus describes a tumor-and neurosphere-forming SOX2-dependent subset of glioblastoma cultures characterized by a gene expression signature similar to that of the recently described classical, proneural, and/or neural subsets of glioblastoma. The findings that resistance to PDGF-and IGF-1-receptor inhibitors is related to SOX2 expression and can be overcome by combination treatment should be considered in ongoing efforts to develop novel stem cell-targeting therapies.
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| 2. |
- Johansson, Ann-Charlotte, et al.
(författare)
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Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells
- 2012
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Ingår i: Molecular Cancer Research. - : American Association for Cancer Research. - 1541-7786 .- 1557-3125. ; 10:9, s. 1158-1168
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Tidskriftsartikel (refereegranskat)abstract
- A growing body of evidence suggests that components of the tumor microenvironment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Here, we investigated the possible influence of CAFs on the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to cetuximab, an antagonistic epidermal growth factor receptor (EGFR) antibody. Cetuximab treatment caused a reduction in the proliferation rate of HNSCC cell lines, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were cocultured with CAFs in a transwell system, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. Media that had been conditioned by CAFs offered protection from cetuximab treatment in a concentration-dependent manner, suggesting that the resistance to treatment was mediated by CAF-derived soluble factors. The coculture of HNSCC cell lines with CAFs resulted in an elevated expression of matrix metalloproteinase-1 (MMP-1) in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMP inhibitor. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results identify a novel CAF-dependent modulation of cetuximab sensitivity and suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy.
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| 3. |
- Lindh, Maja Bradic
(författare)
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Mechanisms determining efficacy of tyrosine kinase-targeting anti-cancer drugs
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The expanding field of cancer research and the introduction of multiple molecular biology techniques have significantly improved cancer drug discovery, presented new drugs, including tyrosine kinase inhibitors, and thereby gave new hope to the cancer patients and their oncologists. Using this knowledge it is now becoming increasingly possible to determine outcome of malignant disease more accurately, to estimate response to specific therapies and to get closer to the ideal of personalized targeted therapy adjusted to each patient, and to the specific cancer type and its unique genetic profile. This thesis tries to explain some mechanisms lying behind the sensitivity or the resistance to new targeted therapies of two cancer types: glioblastoma (GBM) and colorectal cancer (CRC). The IGF-1- and PDGF- receptor tyrosine kinases are widely expressed in GBMs and involved in their self-sustained proliferation, glioblastoma tissue invasion, resistance to apoptotic stimuli, insensitivity to growth control signals and are thus potential therapeutical targets. The first study of the thesis analyzed the sensitivity of GBM cultures to the IGF-1 receptor inhibitor NVP-AEW541. This small molecule caused variable reduction in growth of GBM cultures, allowing grouping of cultures as “responders” and “non-responders” . Use of the IGF-1 receptor siRNA gave very similar result. The sensitivity to NVP-AEW541 was significantly reduced in cultures with PIK3CA mutations or ligand-independent Akt phosphorylation and in a “responder cell culture” treated with PTEN siRNA as well. Combination treatments with either PI3 kinase- or mTOR-inhibitors together with NVP- AEW541 resulted in prominent reduction in growth of “non-responders”. In the second study, the prognostic or predictive potential of PDGFRs status was evaluated, as a translational part of the randomized CSTI571BDE40 trial, which compared hydroxyurea monotherapy and a combination of hydroxyurea and imatinib, a small molecule targeting PDGFRs in recurrent glioblastoma patients. Both PDGFR alpha protein expression and phosphorylation correlated with worse outcome, but did not define a group that showed benefit from the combination therapy with hydroxyurea and imatinib. The third study deals with putative cancer stem cells, associated with radio- and chemo-resistance of GBMs. Gene expression analyses of 11 GBM cell cultures identified two subsets - designated type I and type II cultures. The type I cultures showed high expression of CXCR4, SOX2, EAAT1 and GFAP and low expression of CNP, PDGFRB, CXCL12 and extracellular matrix proteins. Type I cultures had a higher capacity to form xenograft tumors and neurospheres, displayed low or no sensitivity to mono-treatment with PDGF- and IGF-1-receptor inhibitors, but were growth inhibited by combination treatment with low concentrations of the two inhibitors. SOX2 down-regulation conferred sensitivity to PDGF- and IGF-1-receptor inhibitors. The fourth study describes the influence of one part of the tumor microinviroment, activated fibroblasts, on sensitivity of colorectal cancer cells to cetuximab, a monoclonal EGFR-targeting antibody. LIM1215 colorectal cancer cells were growth-inhibited by cetuximab. However, when co-cultured with PDGF stimulated fibroblasts they become significantly less sensitive to cetuximab with regard to inhibition of growth, migration and invasion. LIM1215 cells co-cultured with activated fibroblasts displayed increased c-met phosphorylation suggesting fibroblast-produced HGF as a mediator of the protective effects of fibroblasts.
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| 4. |
- Mezheyeuski, Artur, et al.
(författare)
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Digitalized multiparametric analyses of tumor stroma for identification of low perivascular PDGFBR expression and low vessel density as independent prognosis markers for stage IV CRC
- 2014
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Ingår i: Journal of Clinical Oncology. - Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. Belarusian State Med Univ, Dept Pathol, Minsk, Byelarus. Akad Univ Hosp, Uppsala, Sweden. Odense Univ Hosp, Dept Oncol, DK-5000 Odense, Denmark. Oslo Univ Hosp, Dept Genet, Inst Canc Res, Oslo, Norway. Oslo Univ Hosp, Dept Oncol, Oslo, Norway. Univ Oslo, Oslo, Norway. Haukeland Hosp, N-5021 Bergen, Norway. Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Stockholm, Sweden. Dept Surg, Uppsala, Sweden. Karolinska Inst, Dept Neurosci, Sci Life Lab, Stockholm, Sweden. : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 32:15
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Mezheyeuski, Artur, et al.
(författare)
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Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:27, s. 41948-41958
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Tidskriftsartikel (refereegranskat)abstract
- Perivascular cells (PC) were recently implied as regulators of metastasis and immune cell activity. Perivascular heterogeneity in clinical samples, and associations with other tumor features and outcome, remain largely unknown.Here we report a novel method for digital quantitative analyses of vessel characteristics and PC, which was applied to two collections of human metastatic colorectal cancer (mCRC).Initial analyses identified marker-defined subsets of PC, including cells expressing PDGFR-β or α-SMA or both markers. PC subsets were largely independently expressed in a manner unrelated to vessel density and size. Association studies implied specific oncogenic mutations in malignant cells as determinants of PC status. Semi-quantitative and digital-image-analyses-based scoring of the NORDIC-VII cohort identified significant associations between low expression of perivascular PDGFR-α and -β and shorter overall survival. Analyses of the SPCRC cohort confirmed these findings. Perivascular PDGFR-α and -β remained independent factors for survival in multivariate analyses.Overall, our study identified host vasculature and oncogenic status as determinants of tumor perivascular features. Perivascular PDGFR-α and -β were identified as novel independent markers predicting survival in mCRC. The novel methodology should be suitable for similar analyses in other tumor collections.
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| 6. |
- Paulsson, Janna, et al.
(författare)
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Prognostic but not predictive role of platelet-derived growth factor receptors in patients with recurrent glioblastoma
- 2011
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 128:8, s. 1981-1988
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor receptor (PDGFR) signaling has been implicated in the pathogenesis of glioblastomas and represents a target for the tyrosine kinase inhibitor imatinib. To examine the prognostic or predictive role of PDGFRs in recurrent glioblastomas, expression was examined in tumor samples of 101 patients of CSTI571BDE40, a randomized trial comparing hydroxyurea monotherapy and a combination of hydroxyurea and imatinib. Furthermore, PDGFRa phosphorylation was investigated using in situ proximity ligation assay. PDGFRa protein was expressed in 33% of tumors and was associated with male sex, young age, presence of R132H mutated isocitrate dehydrogenase 1 protein and short median survival (142 vs. 187 days, p = 0.028). Tumor PDGFRa phosphorylation was also associated with short survival (p = 0.030). The subset of patients with PDGFRa positive glioblastoma did not have longer survival on treatment with hydroxyurea and imatinib compared with hydroxyurea monotherapy. In conclusion, both PDGFRa protein expression and phosphorylation status had a prognostic role in recurrent glioblastomas but did not define a group that showed benefit from the combination therapy consisting of hydroxyurea and imatinib.
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| 7. |
- Pena, Cristina, et al.
(författare)
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STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer
- 2013
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 74:4, s. 1287-1297
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis. Cancer Res; 73(4); 1287-97.
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