The Thomsen-Friedenreich (TF) antigen: a critical review on the structural, biosynthetic and histochemica aspects of a pancarcinoma-associated antigen

Within the family of blood-group related carbohydrate antigens the Thomsen-Friedenreich (TF) antigen (or T antigen) is an outstanding member by attracting scientific interest for more than 65 years and by having retained its significance as object of current biomedical research; in particular, as a pancarcinoma-associated antigen. In accordance with its constant or even growing attraction scientists have searched for specific reagents which would allow the unambiguous and sensitive detection of the Thomsen-Friedenreich antigen on cells or tissues. While at the beginning, immunohistochemical work on TF antigen expression was restricted by the limited specificity of plant lectins (peanut lectin) a significant progress has been possible since the introduction of the hybridoma technique. The respective monoclonal antibodies display distinct fine specificities and cellular staining patterns in immunohistochemistry and have contributed to controversia1 discussions on the organ-characteristic and tumor-associated expression of the TF antigen in some organs. It is the aim of this survey to summarize in the context of its structural and biosynthetic aspects the current knowledge on the tissue expression of the TF antigen as based on the use of peanut agglutinin and monoclonal antibodies and to discuss the findings with regard to their biomedical relevance, in particular, with emphasis on their value in tumor diagnosis

MUC1 (EMA) expressing plasma cells in bone marrow infiltrated by plasma cell myeloma

MUC1 (also called: epithelial membrane antigen, EMA) represents a mucin molecule strongly expressed in various epithelia and epithelial neoplasms. Its expression correlates with clinical and pathological factors as well as prognosis in some tumor types. Additionally, MUC1 was detected in normal haematopoietic cell lines and neoplasms, especially subgroups of human lymphomas including plasma cell myeloma. Therefore, the expression of MUC1 in trephine biopsies exhibiting infiltrates of plasma cell myeloma were investigated immunohistochemically. An immunoreactivity of two monoclonal antibodies (EMA and HMFG-2) was observed in about 50% of the cases. In cases exhibiting a so-called packed marrow, EMA immunoreactivity was reduced. However, MUC1 positivity did not correlate with the cytologic grade of differentiation, the fibre content of the marrow, or survival probability of the patients. However, its strong expression in a certain percentage of cases of plasma cell myeloma may be of therapeutic impact, since new therapeutic strategies include the enrichment of MUC1- specific T cells or MUC1 vaccination

lmmunoreactivity of Thomsen-Friedenreich ,TF, antigen in human neoplasms. The importance of carrier-specific glycotope expression on MUC

On the basis of their known fine specificities we evaluated the immunohistochemical marker qualities of two monoclonal antibodies (mabs) defining the tumor-associated TF disaccharide GalBl-3GalNAc. This antigen is expressed in certain tumors in correlation with prognosis and metastasis. The reactivity of one of these mabs (A78-G/A7) depends on clustered TF disaccharides (glycosylation at vicinal Ser~Thr positions) while the other - rnab BW835 - has been characterized to bind specifically to TF disaccharide linked to a motif within the MUCl repeat. Therefore, rnab BW835 represents an interesting tool for the identification of tumor-associated glycoforms of MUC1, which are involved in tumor progression and metastasis, but also in the recognition of tumor cells by cytotoxic T cells. As references the TF-binding lectins from peanut (PNA) and Arrocarpus integrifolia (jacalin) were applied. The binding patterns of these immunoreagents were strikingly distinct. Mab BW835 showed a significantly stronger reactivity than rnab A78-G/A7, especially in gastric, mammary, pancreatic, thyreoideal, renal and bladder carcinomas. PNA and jacalin receptors exhibited an expression in the majority of all cancer types, with the exception of seminoma and glioblastoma/ sarcoma. These results can be explained by the broader fine specificities of the lectins. Furthermore, a strong expression of MUC1-bound TF antigen is indicated by the staining pattern of rnab BW835. The marker qualities of both antigens, TF and MUC1, are combined in the binding specificity of BW835, and hence this antibody may have a high impact for the immunodetection of these tumor-associated antigens

Do we need complex image features to personalize treatment of patients with locally advanced rectal cancer?

Radiomics has shown great potential for outcome prognosis and presents a promising approach for improving personalized cancer treatment. In radiomic analyses, features of different complexity are extracted from clinical imaging datasets, which are correlated to the endpoints of interest using machine-learning approaches. However, it is generally unclear if more complex features have a higher prognostic value and show a robust performance in external validation. Therefore, in this study, we developed and validated radiomic signatures for outcome prognosis after neoadjuvant radiochemotherapy in locally advanced rectal cancer (LARC) using computed tomography (CT) and T2-weighted magnetic resonance imaging (MRI) of two independent institutions (training/validation: 94/28 patients). For the prognosis of tumor response and freedom from distant metastases (FFDM), we used different imaging features extracted from the gross tumor volume: less complex morphological and first-order (MFO) features, more complex second-order texture (SOT) features, and both feature classes combined. Analyses were performed for both imaging modalities separately and combined. Performance was assessed by the area under the curve (AUC) and the concordance index (CI) for tumor response and FFDM, respectively. Overall, radiomic features showed prognostic value for both endpoints. Combining MFO and SOT features led to equal or higher performance in external validation compared to MFO and SOT features alone. The best results were observed after combining MRI and CT features (AUC = 0.76, CI = 0.65). In conclusion, promising biomarker signatures combining MRI and CT were developed for outcome prognosis in LARC. Further external validation is pending before potential clinical application

Immunoreactivity of Lewis blood group and mucin peptide core antigens: Correlations with grade of dysplasia and malignant transformation in the colorectal adenoma-carcinoma sequence

Previous studies on the immunoreactivity of various mucin peptide and carbohydrate antigens in neoplastic colorectal tissues led to at least in part contradictory results. Therefore, we investigated a series of 42 adenomas and 44 carcinomas applying monoclonal antibodies (mabs) directed against Lewis blood group antigens (sialyl-Lea, Lex, sialyl-Lex, Ley) as well as mucin peptide cores (MUC1, MUC2 and MUC5AC) by i m m u n o h i s t o c h e m i s t r y. A statistically significant positive correlation between the development of highgrade dysplasia in colorectal adenomas and the immunoreactivity of Le y and MUC1 epitopes was observed, whereas MUC2 exhibited a significant negative correlation. The reactivity of the other epitopes did not show an association with the progression of malignant transformation. Colorectal carcinomas were subdivided according to their histopathological subtype. The immunohistochemical staining resulted in a significantly stronger MUC2 reactivity of mucinous vs. tubular adenocarcinomas. Immunoreactivity of the MUC1-specific mab, which does not react with the fully glycosylated peptide core, showed a statistically nonsignificant inverse tendency, whereas all carbohydrate antigens displayed a strong expression in both tumor subtypes. Furthermore, correlations between mucin peptide and carbohydrate epitope labelling were evaluated. Progression of the adenoma-carcinoma sequence was accompanied by an increase of Ley as well as MUC1 antigen and an increase of all Lewis antigens compared to MUC2 immunoreactivity. On the other hand, mucinous carcinomas exhibited an inverse pattern. In conclusion, these results demonstrate that Ley a n d MUC1 immunoreactivity correlate with malignant transformation in the colorectum, whereas MUC2 represents a marker for low-grade dysplasia and the subtype of mucinous carcinomas

Clinicopathological significance of MMP-2 and its specific inhibitor TIMP-2 in gastric cancer

Matrix metalloproteinases (MMPs) can degrade type IV collagen of extracellular matrices and basal membranes and thus play a key role in the migration of malignant cells. In vivo, MMPs are inhibited by tissue inhibitors of metalloproteinases (TIMPs). Since in a previous study we showed that the expression of MMP-2 correlates with clinicopathological parameters in gastric cancer, we have now investigated a possible correlation of MMP-2 and TIMP-2 expression with survival in gastric cancer, as well as the possible association of TIMP-2 with clinicopathological parameters. Tissue samples were obtained from 116 gastric cancer patients who underwent gastrectomy with extended lymphadenectomy. MMP-2 and TIMP-2 expression was analysed using immunohistochemical staining and was graded semiquantitatively (score 0 – 3). High epithelial MMP-2 immunoreactivity was significantly associated with tumor stage and poor survival using the Kaplan-Meier log-rank statistical method (log-rank statistics). However, using Cox regression analysis, high epithelial MMP-2 immunoreactivity was not an independent prognostic factor. TIMP-2 showed no association with survival in gastric cancer, but the intensity of TIMP-2 staining in tumor cells correlated significantly with tumor differentiation based on the WHO and Lauren and Ming classifications, as well as with presence of distant metastasis. Our results show that high epithelial MMP-2 expression in gastric cancer is associated with poor survival, although it is not an independent prognostic factor, and that aggressive forms of gastric cancer are associated with low TIMP-2 expression