Current Proteomics - Volume 10, Issue 3, 2013

Research and practice in neuro-endocrine(NE) markers is focused on the detection and diagnosis of neuroendocrine tumors (NETs), as epithelial neoplasms arise in many organs and are clinically characterised by an intriguingly disperse behaviour, ranging from the almost invariably benign cases of carcinoids to the highly aggressive ones of small cell carcinomas. In addition to specific hormonal peptides, NETs produce (and release) “general” NE markers, which constitute the distinctive evidence of their differentiation. The present review will focus on these “general” NE markers, belonging to six categories (see Table 1). The markers belonging to the Granins family (chromogranins and secretogranins) are stored in the cytoplasmic secretory granules and their most prominent component (Chromogranin A), a specific marker of NE differentiation, is currently detected by immunohistochemistry on tumor sections and by ELISA procedures in the plasma. Membrane-related proteins (such as synaptophysin) and cytoplasmic proteins (such as Neuron-specific Enolase and Protein-Gene product 9,5) are also important diagnostic markers. Cell membrane-associated proteins (eg. Somatostatin receptors) and Transcription factors are also markers of interest in NETs. In addition, special interest is presently dedicated to biomarkers such as phospho-mTOR and MGMT, potentially predictive of responsiveness to selected drugs and of use in the selection of NET cases potentially responsive to tailored therapy. In fact, the mammalian target of rapamycin (mTOR) represents a potential target for treatment, while differences in MGMT expression might explain the sensitivity of some neuroendocrine tumors to temozolomide-based therapies.

This review will focus on the elements of the skin’s immune system, immune cells and/or non-immune cells that support immune mechanisms, molecules with immune origin and/or immune functions that are involved in skin carcinogenesis. All these immune elements are compulsory in the development of skin tumors and/or sustainability of the neoplastic process. In this light, recent data gathered in this review will acknowledge all immune elements that contribute to skin tumorigenesis; moreover, they can serve as immune biomarkers. These immune markers can contribute to the diagnostic improvement, prognosis forecast, therapy monitoring, and even personalized therapeutical approach in skin cancer. Immune processes that sustain tumorigenesis in non-melanoma and melanoma skin cancers are described in the framework of recent data.

Oral squamous cell carcinoma (OSCC) is the most frequent malignancy of the oral cavity, highly invasive with unfavourable prognosis and unimproved 5-year survival rate for at least two decades. Comprehensive analysis of the proteome in OSCC patients (tissue tumor, blood and saliva) was extensively performed in the last years in order to identify reliable biomarkers for early detection, prognosis or treatment efficacy. We discuss herein the up-dated recent data regarding neoplastic / stromal interactions related biomarkers such as cadherins, catenins, matrix metalloproteinases, snai1, snai2, desmoglein 3, ezrin, zyxin, ILK, EMMPRIN, bone sialoprotein, dentin sialophosphoprotein, osteopontin, fascin, podoplanin, calreticulin. These molecules are involved either in cell-cell adhesion, cell-extracellular matrix interactions or regulation of matrix metalloproteinases that are expressed in OSCC, most of them in correlation with tumor aggressivity. The pattern of the expression of most of these biomolecules in correlation with prognosis and/or histopathologic parameters with previously proven prognostic significance (such as tumor stage or presence of lymph node metastases) recommend them as possible biomarkers; however, considering the multitude of the studies involving several of this markers and the inhomogeneous results, further investigations are required in order to validate them for daily practice use.

Digestive tract cancers – gastric-, colorectal-, pancreatic-, hepatocarcinoma- and esophageal are some of the most frequent cancers; they are characterized by invasivity, metastatic potential and bad outcomes. This group includes several of the most critical cancers (those ranked 2nd-4th in cancer related mortality), and, despite all efforts, they remain with low survival rates and lack of success of therapies. Discovery of novel biomarkers may improve disease characterization and make optimized or personalized therapies possible. The novel biomarkers are expected to provide, hopefully, less invasive or non-invasive diagnostic tools to make possible earlier detection of disease, and, also, they will provide more reliable selection in the drug discovery process, and provide guidance for personalized medicine. Deregulation of protein expression and genetic alterations were demonstrated in various cancers, including digestive. Investigations in tissue samples provided a considerable amount of knowledge, identifying altered expressions of proteins associated with tumorigenesis and tumour progression. Over-expression of some tumour-inducing or tumour promoting proteins was demonstrated, as well as expression down-regulation of several tumor suppressor genes. Often mutated and polymorphic alleles were demonstrated to occur in various cancers with high incidence. Several protein biomarkers were also demonstrated to be differentially expressed in groups of patients showing different responsivities to therapies. Both individual proteins and sets of multiple proteins were set up as candidate biomarkers for diagnostics or monitoring, offered relevant insights on the tumorigenic mechanisms. Proteins and other molecules (mRNAs, miRNAs, lncRNAs) are also providing potential candidates for multifactorial panels of biomarkers.

Omics are wide concepts used to define metadata in life sciences and are increasing in number with the development of science. Thus the era of omics started with genomics, which studies the genome; followed by proteomics which focuses on proteins and metabolomics which covers the field of metabolites. Cellomics deals with "the study of cells" or "the knowledge of cellular phenotype and function". One of the main areas of cellomics application is cancer. As there is considerable amount of overlapping between these concepts, we studied papers published between 2005-2013, dealing with cellomics and cancer and found 192 articles, and further classified them in 3 main categories: A: wide genomic and proteomic data analyses; B: cellomics pattern analyses in different kinds of oncologic diseases; C: general cell behavior applied in oncology or studies of atypical cancer cells in different kinds of tumors. 83 papers were clustered in cluster A, 65 in cluster B and 60 in cluster C, 16 papers were included in more than one cluster as they focused on theme of overlapping. Cluster B and C were further sub clustered regarding cancer type and research field. The papers covered a wide range of oncologic diseases: colon-rectal, gastric, breast cancer, ovarian, lung, all types of leukemia, prostate cancer, brain tumors etc; a wide range of cellular mechanisms: cell proliferation, cell migration, cell death, cell adhesion, cell counting, apoptose, phosphorylation, DNA damage, DNA ploidity, DNA sequencing, free circulating DNA etc. Samples used for the study were mainly plasma and tissue but saliva, feces, urine, exhaled breath concentrate etc were also reported for the study. Regarding techniques, papers focused on: flow cytometry, tissue microarray, antibody microarray, reverse phase protein microarray, single nucleotide polymorphism; and also on mass spectrometry: MALDI-TOF-MS, SELDI-TOF-MS, liquid chromatography-tandem mass spectrometry (LC-MS/MS) etc. The article emphasizes the need for standardization. With the emergence of omics fields, there are now no boundary between cellomics, genomics and proteomics. The genes codify processes and proteins as well as cells; as cells are under DNA control and are influenced through RNA protein synthesis, therefore the determination of proteins as the cells as well as the determination of DNA might be referred to as being genomic, proteomic or cellomic.

High grade gliomas represent one of the most aggressive and treatment-resistant types of human cancer, with only 1–2 years median survival rate for patients with grade IV glioma. The treatment of glioblastoma is a considerable therapeutic challenge; combination therapy targeting multiple pathways is becoming a fast growing area of research. This review offers an up-to-date perspective of the literature about current molecular therapy targets in high grade glioma, that include angiogenic signals, tyrosine kinase receptors, nodal signaling proteins and cancer stem cells related approaches. Simultaneous identification of proteomic signatures could provide biomarker panels for diagnostic and personalized treatment of different subsets of glioblastoma. Personalized medicine is starting to gain importance in clinical care, already having recorded a series of successes in several types of cancer; nonetheless, in brain tumors it is still at an early stage.

Mycobacterium tuberculosis is the causative agent of tuberculosis, an old formidable scourge of global public health. Despite decades of intensive studies on the biology and physiology of M.tuberculosis, the function of about one-quarter open reading frame (ORF) of the M.tuberculosis genome remains elusive. In order to determine the size of M.tuberculosis proteome during normal in vitro growth, shotgun proteomic profiling and cross-reference to available multi-omics data were performed. We identified 2817 M.tuberculosis ORFs, about 70% of the predicted encoding capacity. More interestingly, 228 novel proteins which had not been predicted by the 1998 genomic annotation were found. These novel proteins participated in various cellular events including intracellular growth, persistence and dormancy. The proteins with potential value in diagnostic biomarker, drug target and host immune response targets were thoroughly aligned with available transcriptional data. One unexpected discovery is the absence of the key components involved in the base-excision repair pathway which was crucial for M.tuberculosis survival. These data provided fresh insights into the biology of this old pathogen.