In our large-scale retrospective study we sought to investigate the prognostic impact of a set of biomarkers in non-GIST STS patients. These markers are known to participate in the process of EMT in epithelial tumors 
, but bear other important biological functions as well. Moreover, the EMT concept has not received general acceptance 
. STSs are of mesenchymal origin and can demonstrate a range of behavior patterns, varying from almost benign to highly aggressive tumors. TGF-β1, fascin, NF-kB p 105 and PKC-ζ showed significant unfavorable influence on survival in the univariate analyses. Besides, high expression of TGF-β1 was a significant independent negative prognostic indicator of DSS. To our knowledge this is the first prognostic evaluation of these biomarkers in whole-array non-GIST STSs.
TGF-β is a multifunctional cytokine known to induce G1 arrest in order to end proliferation, induce differentiation, or promote apoptosis in normal cells, thus being a natural tumor-suppressive agent. Though in tumorigenesis this mediator initiates EMT through activation of Smad and non-Smad signalling pathways 
. Such pro-neoplastic action becomes possible through either blockade of the TGF-β pathway with receptor-inactivating mutations, or selective inactivation of the tumor-inhibiting arm of this pathway 
. Another possibility is TGF-β induced systemic immune suppression 
. The TGF-β pathway activation has been shown to negatively influence prognosis both in epithelial 
and in mesenchymal bone 
and soft tissue tumors 
. The latter studies, however, are devoted to one particular STS type, while investigations of TGF-β1 expression by whole-array human STS with concern to impact on survival are not reported. In the present study, TGF-β1 was found to be a crucial prognostic marker. It had an independent significantly negative prognostic effect on DSS in non-GIST STS.
TGF-β was called the Jekyl and Hyde of cancer 
for its ability to modulate its action from tumor promoter to tumor suppressor. The factors responsible for such transition remain unclear. The candidates are both tumour-cell-autonomous TGF-β signalling 
itself, and factors in the tumor microenvironment. Among the latter, inflammatory cells and cancer-associated fibroblasts 
, as well as angiogenetic factors 
, are considered the most potent modulators of TGF-β action. In previous studies, we have investigated the prognostic value of both inflammatory cells 
and angiogenetic factors in STSs 
, and further plan to explore their interactions with TGF-β.
Fascin and E-cadherin are both related to cell motility and cell adhesiveness and important factors in the progression and metastasis of cancers 
. Fascin is reported to be overexpressed in sarcomatoid, in contrast to conventional, non-small cell lung carcinoma 
. In leiomyomatous tumors of the uterus it was associated with higher malignancy grade 
. We found fascin expression to be associated with a shorter STS survival in univariate analyses, but not in multivariate. E-cadherin, being responsible for epithelial cell junction, is rarely expressed in STS, except for synovial and epithelioid sarcomas, as well as mesothelioma, which naturally express both epithelial and mesenchymal markers. As could be expected, E-cadherin was in this study expressed aberrantly in a minority of STS and failed to demonstrate any association with survival.
NF-kB 1 (p50 and its precursor p105) is one of five members of the NF-kB family. These are transcription proteins responsible for control of inflammation, regulation of cell cycle and cell proliferation. NF-kB is constitutively activated in various tumor cells where it promotes cell proliferation, survival, metastasis, inflammation, invasion, and angiogenesis 
. Its influence on tumorigenesis is rather controversial. Indeed, while the majority of the investigators confirm that this marker augments tumor invasiveness and metastasis resulting in shorter DSS, in a recent study by Al-Saad et al., NF-kB p 105 was reported to have a favourable impact on DSS in operable non-small cell lung carcinoma patients 
. We found NF-kB p 105 expression in STS to indicate a poor prognosis.
Par-6 and PKC-ζ (one of four atypical PKCs) belong to the Par3/Par-6/aPKC polarity complex that governs diverse cell functions such as localization of embryonic determinants and establishment of tissue and organ during the embryonal period and regulation of cell polarity and the asymmetric division of cells in mature organisms 
. Both Par-6 and PKC-ζ have been identified as EMT-associated biomarkers 
and found to enhance proliferation, migration and invasiveness in cell cultures 
. We were unable to retrieve studies on Par-6 expression in human tumor tissue through PubMed searches. Cornford et al. reported that PKC-ζ expression was significantly higher in prostatic carcinomas than in non-neoplastic prostate tissue 
. In STS, we observed that PKC-ζ expression was a significant indicator of shorter DSS.
Vimentin is an acknowledged marker of higher aggressivity in epithelial tumors. Its negative influence on patient survival has been demonstrated in several human cancers including breast 
, gastric 
and oral squamous cell carcinoma 
. The STSs which by definition express vimentin are not generally investigated for the prognostic importance of its grade of expression. In our material, all tumor cells were positive for vimentin, but at varying degrees. All STSs were dichotomized as strongly positive tumors or not, but there was no difference in survival between these two groups of patients.
In conclusion, we have characterized the STS phenotype with respect to tumor aggressiveness and DSS. We found also that all the tumors included in the non-GIST STS group shared this phenotype at different degrees. Moreover, our findings are in agreement with results of a number of studies that have investigated the roles of these markers in other, especially epithelial, tumors. This makes us to believe that the processes we have explored in the study are universal and are not a feature of one or several distinct entities.
Although the precise molecular interactions resulting in STS tumor cell dedifferentiation are still unclear, our findings may help to identify a subgroup of patients with aggressive tumors which require adjuvant therapy. Moreover, the biomarkers indicating such aggressiveness can represent molecular targets with the future development of small-molecule targeted therapy.