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Oncogenesis | Maspin was classified as a breast cancer suppressor on the basis of functional and observational (immunohistochemical - IHC) studies. However, as more model systems, tumour types and corresponding normal tissues were analysed, the situation became more complex. Several microarray analyses of different human cancers indicated that maspin was frequently strongly expressed in tumour over normal tissue. Furthermore, strong and frequent expression was seen in some instances in pre-neoplastic lesions. Clearly, some tumours in a range of tissues express maspin and some do not, the subcellular localisation of the protein is variable, as is the methylation status of the promoter. Expression may correlate to some degree with the clinical behaviour or characteristics of particular tumours but in many cases the data from different studies of the same diseases and tissues appear to be contradictory. One point that must be borne in mind is that a gene can be associated with good prognostic factors and improved survival and yet it can still be driving the malignant phenotype in the tumours in which it is expressed. In summary, many questions concerning the pathological role of maspin in human cancer remain unanswered. |
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Entity | Breast cancer |
Note | The terminal duct-lobular system of the breast comprises two specialised epithelial cell types, inner luminal secretory cells and outer contractile myoepithelial cells. It is thought that most breast tumours arise from cell types located within this structure. SERPINB5 is strongly expressed in the outer oestrogen receptor (ER) negative myoepithelial cells, where it is frequently located in both the nucleus and the cytoplasm. The luminal cells appear not to express maspin. The largest study (1068) of maspin expression in breast tumours scored a nuclear signal in 96% of carcinomas and a cytoplasmic signal in 35%. The nuclear staining was correlated with ER and progesterone receptor (PR) positivity whilst the cytoplasmic staining was associated with ER and PR negativity. It has been suggested that breast cancer initiates and is maintained from an aberrant adult stem cell. Maspin expression levels in tumours may therefore reflect a tendency for the tumour initiating stem cell component to differentiate towards cells which lack or retain maspin expression. These lesions may behave differently clinically in a way which is or is not directly related to maspin expression. This would not exclude the possibility that maspin is associated with some aspect of the multipotent stem cell phenotype nor that it might be involved in the actual differentiation process of particular cell types. |
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Entity | Lung cancer |
Note | Lung cancers generally arise from a component of the bronchial epithelium (BE). This pseudostratified lining of the airways comprises multipotent basal cells and specialised differentiated apical cells. The basal cells represent a reserve component of the epithelium which can differentiate into each of the mature cell types. Alveolar, stromal and normal differentiated epithelial cells are all typically negative for maspin expression. However, strong nuclear staining is seen in all airway basal cells (Figure: A, B). Maspin appears to be strongly expressed, generally in the cytoplasm and nucleus, in >95% of squamous cell carcinomas (Figure C) and 30-50% of adenocarcinomas. The expression of maspin is linked to the degree of promoter methylation and allele-specific transcript analysis suggests that in approximately 50% of lesions, expression in the tumour is predominantly driven from one chromosomal allele. Maspin is strongly and presumably inappropriately expressed in a significant fraction of pre-neoplastic bronchial lesions and a small fraction of histologically non-neoplastic epithelia (Figure D). The observation that maspin is strongly expressed apparently appropriately in the normal stem cell-like basal component of the BE and that this expression appears to be down-regulated in the differentiated BE cells might suggest that the protein has a role in some aspect of maintenance of the basal cell (perhaps lung stem cell) phenotype and that a failure to inactivate maspin appropriately during differentiation may contribute to bronchial neoplasia. |
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| The images show an immunohistochemical analysis of maspin expression in histologically normal lung (A, B, D) and NSCLC (C) tissues. The tumour cells (C) show intense nuclear and cytoplasmic staining. Panels A and B show typical staining patterns for normal bronchial tissue. Stromal cells are negative, basal epithelial cells in the airway epithelia in the normal sections show strong predominantly nuclear staining whilst apical epithelial cells are negative. A small number of hyperplastic epithelia show strong nuclear/cytoplasmic expression of maspin (D). |
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Entity | Gastric cancer |
Note | IHC reports are to some extent contradictory and this may reflect differing aetiologies. However, several studies suggest that maspin is strongly expressed in gastric carcinoma over normal mucosa. It has been reported that 80% of primary tumours and all gastric normal mucosa (GNM) with intestinal metaplasia (IM) show dense and diffuse cytoplasmic immunoreactivity while in contrast, GNM without IM show only weak or no staining. They further demonstrated that the GNM with IM show maspin promoter hypermethylation of one parental allele which would be consistent with expression occurring from a single allele in a clonal expansion, either as a result of an aberrant demethylation event or else as a consequence of a failure to methylate appropriately one parental allele at some time during the differentiation process from a maspin expressing precursor. An alternative explanation, that SERPINB5 is developmentally imprinted in a GM with IM precursor, seems less likely but is nevertheless possible. Both alleles were hypermethylated in GNM without IM and both were generally hypomethylated in tumours. |
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Entity | Pancreatic cancer |
Note | Maspin is strongly expressed in most if not all pancreatic adenocarcinomas whereas normal pancreatic tissue appears to be negative or only weakly positive. |
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Entity | Prostate cancer |
Note | Whilst maspin expression in prostatic cancer was reportedly correlated with a less aggressive pathological and histological tumour grade, the protein was found to be expressed frequently in high grade prostate intraepithelial neoplasia, an observation which would be consistent with a role for maspin in pre-malignancy of the prostate. |
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Entity | Melanoma |
Note | Maspin appears to be expressed in a small fraction of primary melanomas but not normal melanocytes. This expression is correlated with the methylation status of the promoter. |
Disease | Melanoma |
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Entity | Thyroid |
Note | Maspin expression has been reported in a large fraction of: papillary thyroid carcinomas, undifferentiated carcinomas and poorly differentiated carcinomas but only rarely in well differentiated tumours and not at all in normal thyroid, follicular adenomas or follicular carcinomas. The expression of maspin in thyroid carcinomas was therefore closely associated with a lack of differentiation of the tumour cells. |
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Entity | Ovarian cancer |
Note | Whilst normal ovarian surface epithelia have low levels of expression, maspin appears to be strongly expressed in a large fraction of primary tumours (37%). Tumours with high levels of maspin were more likely to be invasive and show cytoplasmic staining. Maspin over-expression was further associated with higher tumour grade, the presence of ascites and shorter survival. However, somewhat paradoxically, introduction of wild-type maspin into two ovarian cancer cell lines reduced their invasiveness. |
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Entity | Bladder cancer |
Note | Maspin does not appear to be expressed in normal transitional cells of the bladder. However, a sizable fraction of tumours show strong nuclear and cytoplasmic expression; which is significantly correlated with muscle-invasive over non-invasive bladder cancer. |
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