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- Hellman, Kristina, et al.
(författare)
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Differential tissue-specific protein markers of vaginal carcinoma
- 2009
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Ingår i: British Journal of Cancer. - : Cancer Research UK. - 0007-0920 .- 1532-1827. ; 100:8, s. 1303-1314
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Forskningsöversikt (refereegranskat)abstract
- The objective was to identify proteins differentially expressed in vaginal cancer to elucidate relevant cancer-related proteins. A total of 16 fresh-frozen tissue biopsies, consisting of 5 biopsies from normal vaginal epithelium, 6 from primary vaginal carcinomas and 5 from primary cervical carcinomas, were analysed using two-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry. Of the 43 proteins identified with significant alterations in protein expression between non-tumourous and tumourous tissue, 26 were upregulated and 17 were downregulated. Some were similarly altered in vaginal and cervical carcinoma, including cytoskeletal proteins, tumour suppressor proteins, oncoproteins implicated in apoptosis and proteins in the ubiquitin-proteasome pathway. Three proteins were uniquely altered in vaginal carcinoma (DDX48, erbB3-binding protein and biliverdin reductase) and five in cervical carcinoma (peroxiredoxin 2, annexin A2, sarcomeric tropomyosin kappa, human ribonuclease inhibitor and prolyl-4-hydrolase beta). The identified proteins imply involvement of multiple different cellular pathways in the carcinogenesis of vaginal carcinoma. Similar protein alterations were found between vaginal and cervical carcinoma suggesting common tumourigenesis. However, the expression level of some of these proteins markedly differs among the three tissue specimens indicating that they might be useful molecular markers.
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| 2. |
- Hellman, Kristina
(författare)
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Vaginal carcinoma : studies on etiology and prognostic factors
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Primary carcinoma of the vagina (PCV) is a rare disease, with poor survival, mostly affecting elderly women. Due to its rarity the established knowledge originates from studies based on small materials, therefore little is known regarding the genesis, natural history and factors predicting the prognosis. PCV is supposed to have similar aetiology and natural history as cervical carcinoma, which however mostly occurs at younger ages. Clinical stage is described as the most important prognostic factor. Against this background the objectives of this thesis were focused on the understanding of the genesis of PCV and its prognostic factors. The material in the retrospective studies (paper 1 and 11) is the largest so far published on PCV. A hypothesis was that factors influencing the age at onset of PCV should be connected directly or indirectly with the genesis of the disease. Epidemiological, clinical and histopathological variables were evaluated in relation to age at diagnosis in a retrospective study or 341 cases of PCV, diagnosed 1956 - 1996. According to the statistical analysis the independent predictor for young age at diagnosis was a history of cervical dysplasia and for old age at diagnosis late menarche. Parity >4 as well as nulliparity, smoking and unstable marital status were background factors more common than in the general Swedish female population, but not correlated with age at diagnosis. Clinical and histopathological prognostic factors were evaluated retrospectively in 314 patients with squamous cell carcinoma of the vagina. The 5year discase-specific survival rate was 45 % and in stage 175%. In the multivariate analysis there were only three factors that independently could predict poor survival: high age at diagnosis, large tumors (>4cm) and advanced stage. Common background factors with no prognostic significance were prior hysterectomy, other gynecological malignancies and pelvic irradiation. The immunohistochemical expression of laminin-5gamma2 chain, an epithelial basement membrane protein, implicated in tumour cell invasion, was investigated in 59 cases of primary vaginal malignancies. All epithelial tumours showed gamma2 chain immunoreactivity. High expression of the 72 chain was a good predictor of poor survival in the univariate analysis, but not in the multivariate analysis. A positive correlation between tumour size and gamma2 chain expression could also be observed. Comparative genomic hybridization (CGH) of 16 primary vaginal carcinomas revealed that 70% carry relative copy number increases that map to chromosome arm 3q. The pattern of genomic imbalances was strikingly similar to the one observed in advanced cervical tumours. Most PCV were aneuploid, showed high proliferative activity, low p53 and increased p21 expression. Human papilloma virus was detected in 2/8 cases. In the univariate analysis age at diagnosis, tumour size, and laminin-5 expression were identified as predictors or prognosis. Protein expression patterns in six samples from primary vaginal cancers, in five from normal vaginal tissue and in five primary cervical cancers, were analyzed using twodimensional polyacrylamide gel electrophoresis (2-DE). A total of 23 protein spots were significantly differentially expressed among cervical and vaginal carcinoma. By using these 23 proteins in cluster analysis all samples could be classified into three distinct groups (normal vaginal tissue, vaginal- and cervical carcinoma). There might be a possibility to identify tumour-specific markers among the differentially expressed proteins. In conclusion this thesis supports the theory of related aetiology and tumorigenesis for vaginal and cervical carcinoma. Crude clinical variables (stage, tumour size and age at diagnosis) turned out to be independent predictors of prognosis. PCV appears to be an aggressive tumour characterized by high genomic instability, aneuploidy and high proliferative activity.
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| 6. |
- Strömberg, Thomas, et al.
(författare)
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IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells.
- 2006
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 107:2, s. 669-78
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Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence suggests the insulin-like growth factor-1 receptor (IGF-1R) to be an important mediator of tumor-cell survival and resistance to cytotoxic therapy in multiple myeloma (MM). Recently, members of the cyclolignan family have been shown to selectively inhibit the receptor tyrosine kinase (RTK) activity of the IGF-1R beta-chain. The effects of the cyclolignan picropodophyllin (PPP) were studied in vitro using a panel of 13 MM cell lines and freshly purified tumor cells from 10 patients with MM. PPP clearly inhibited growth in all MM cell lines and primary MM samples cultured in the presence or absence of bone marrow stromal cells. PPP induced a profound accumulation of cells in the G(2)/M-phase and an increased apoptosis. Importantly, IGF-1, IGF-2, insulin, or IL-6 did not reduce the inhibitory effects of PPP. As demonstrated by in vitro kinase assays, PPP down-regulated the IGF-1 RTK activity without inhibiting the insulin RTK activity. This conferred decreased phosphorylation of Erk1/2 and reduced cyclin dependent kinase (CDK1) activity. In addition, the expression of mcl-1 and survivin was reduced. Taken together, we suggest that interfering with the IGF-1 RTK by using the cyclolignan PPP offers a novel and selective therapeutic strategy for MM.
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