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Background The biological mechanisms underlying cancer cell motility and invasiveness remain unclear, although it has been hypothesized that they involve some type of epithelial-mesenchymal transition (EMT). Methods We used xenograft models of human cancer cells in immunocompromised mice, profiling the harvested tumors separately with species-specific probes and computationally analyzing the results. Results Here we show that human cancer cells express in vivo a precise multi-cancer invasion-associated gene expression signature that prominently includes many EMT markers, among them the transcription factor Slug, fibronectin, and α-SMA. We found that human, but not mouse, cells express the signature and Slug is the only upregulated EMT-inducing transcription factor. The signature is also present in samples from many publicly available cancer gene expression datasets, suggesting that it is produced by the cancer cells themselves in multiple cancer types, including nonepithelial cancers such as neuroblastoma. Furthermore, we found that the presence of the signature in human xenografted cells was associated with a downregulation of adipocyte markers in the mouse tissue adjacent to the invasive tumor, suggesting that the signature is triggered by contextual microenvironmental interactions when the cancer cells encounter adipocytes, as previously reported. Conclusions The known, precise and consistent gene composition of this cancer mesenchymal transition signature, particularly when combined with simultaneous analysis of the adjacent microenvironment, provides unique opportunities for shedding light on the underlying mechanisms of cancer invasiveness as well as identifying potential diagnostic markers and targets for metastasis-inhibiting therapeutics.

Simona O. Dima1, Cristiana Tanase2, Radu Albulescu2, Anca Botezatu3 and Irinel Popescu1 1Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute of Digestive Disease and Liver Transplantation, Bucharest, 2Biochemistry and Proteomics Department, “Victor Babes” National Institute of Pathology, Bucharest, 3Viral Genetic Engineering Laboratory, Romanian Academy ‘Stefan S. Nicolau’ Virology Institute, Bucharest, Romania

Digestive cancers (e.g., gastric, colorectal, pancreatic or hepatocarcinoma) are among the most frequently reported cancers in the world, and are characterized by invasivity, metastatic potential and poor outcomes. This group includes some of the most critical cancers (among them, are those ranked second to forth in cancer-related mortality) and, despite all sustained efforts, they maintain a profile of low survival rates and lack successful therapies. Discovery of biomarkers that improve disease characterization may make optimized or personalized therapy possible. Novel biomarkers are expected to provide, hopefully, less-invasive or noninvasive diagnostic tools that make possible earlier detection of disease. Also, they may provide a more reliable selection instrument in the drug discovery process. miRNAs, short noncoding RNAs, have emerged in the last few years as significant regulators of cellular activities, controlling protein expression at the post-transcriptional level, with a significant implication in pathology in general and, of most relevance, in cancers. Deregulation of miRNA expression levels and some genetic alterations were demonstrated in various cancers, including digestive cancers. Investigations in tissue samples have provided a considerable amount of knowledge, identifying altered expressions of miRNAs associated with tumorigenesis and tumor progression. Overexpression of some tumor-inducing or tumor-promoting miRNAs was demonstrated, as well as the downregulation of tumor-suppressor miRNAs. Both individual miRNAs, as well as sets of multiple miRNAs, were set up as candidate biomarkers for diagnostics or monitoring, offering relevant insights into tumorigenic mechanisms. Circulating miRNAs were demonstrated as valuable instruments in tumor diagnosis and the prognosis of digestive cancers (affecting the esophagus, stomach, intestine, colorectum, liver and pancreas), and are being investigated thoroughly in order to generate and validate less-invasive diagnostic tools with enhanced sensitivity.

Skin melanoma, a life-threatening disease, has a recently reported worldwide increase in incidence, despite primary prevention. Skin melanoma statistics emphasize the need for finding markers related to the immune response of the host. The mechanisms that are able to over-power the local immune surveillance comprise molecules that can be valuable markers for diagnosis and prognosis. This article summarizes the immune markers that can monitor the disease stage and evaluate the efficacy of therapeutic interventions. Recent data regarding immunotherapy are presented in the context of tumor escape from immune surveillance and the immune molecules that are both targets and a means of monitoring. Perspectives for developing immune interventions for skin melanoma management and the position of tissue or soluble immune markers as a diagnostic/prognostic panel are evaluated. State-of-the-art technology is emphasized for developing immune molecular signatures for a complex characterization of the patient's immunological status.

Pancreatic cancer represents a major challenge for research studies and clinical management. No specific tumor marker for the diagnosis of pancreatic cancer exists. Therefore, extensive genomic, transcriptomic, and proteomic studies are being developed to identify candidate markers for use in high-throughput systems capable of large cohort screening. Understandably, the complex pathophysiology of pancreatic cancer requires sensitive and specific biomarkers that can improve both early diagnosis and therapeutic monitoring. The lack of a single diagnostic marker makes it likely that only a panel of biomarkers is capable of providing the appropriate combination of high sensitivity and specificity. Biomarker discovery using novel technology can improve prognostic upgrading and pinpoint new molecular targets for innovative therapy.

The assessment of caveolin-1 (Cav-1) as a marker of tumor aggressiveness in pancreatic ductal adenocarcinoma (PDAC). In this study, we examined the expression of Cav-1 in 34 human PDAC tissue samples and the associated peritumoral tissues by immunohistochemistry and western blot. Additionally, we correlated Cav-1 expression with other tissue (Ki-67, p53) and serum (CA 19-9) tumor markers. In the tumor-derived tissue, both tumor cells and blood vessels expressed Cav-1. In contrast, in peritumoral tissue, Cav-1 expression was confined mainly to blood vessels and was only occasionally expressed in ductal or parenchymal cells. Western blot analysis confirmed the overexpression of Cav-1 in pancreatic tumors compared with peritumoral tissue. Cav-1 expression in tumor tissues was correlated with both the Ki-67 LI (r = 0.95, P

Aims: Apaf-1 (apoptotic protease-activating factor 1), is commonly known as an indicator of apoptosis regulation. It is the core protein of the apoptosome and its dosage is also critical in various cancer types. The aim of our study was to investigate the expression of Apaf-1 and cathepsin B (as caspase-dependent and non-caspase-dependent) effectors of cell death, in order to correlate them with the invasivity of pituitary adenoma. Design: Immunohistochemical analysis was performed on 30 paraffin-embeded pituitary adenomas: 21 functioning and 9 non-functioning; 22 with local invasiveness, 16 invasive in cavernous sinus; 4 were recidives. The following antibodies were used: Apaf-1– rabbit polyclonal (1:100), cathepsin B – mouse monoclonal NCL-Cath-B (CB131) (1:40), and Ki67– MIB1 (1:50). Apoptosis was measured as apoptotic index by TUNEL method. Results: A positive relation between high proliferation and high apoptotic index in invasive adenomas was revealed. The loss of Apaf-1 expression was observed in most of the invasive adenoma with increased Ki67 proliferative index. In low-grade invasive tumors Apaf-1 was expressed in variable degree with a zonal distribution. Most of the non-invasive adenoma presented positive Apaf-1 reaction, with zonal or diffuse aspect. On the contrary, cathepsin B was commonly expressed with a granular pattern, routinely lying on the plasma membrane, in invasive pituitary tumors. In cells undergoing apoptosis, cathepsin B appeared diffusely re-distributed in the cytosol. A negative correlation between Apaf-1 and invasiveness was noted. On the other hand, a positive correlation between cathepsin-B and invasiveness was recorded. Conclusion: These data demonstrated an inverse correlation between Apaf-1 and cathepsin B expressions. Shifting the balance between cell death mediators might result in changes in tumor behavior.