the hpv-pathogen iss study aims at systematically analysing 13 different biomarkers in defined retrospective cross-sectional and prospective cohorts of hiv positive and negative women branca costa et al

the hpv-pathogen iss study aims at systematically analysing 13 different biomarkers in defined retrospective cross-sectional and prospective cohorts of hiv positive and negative women branca costa et al. 2004 until now several markers have been analysed in retrospective cross-sectional and prospective analyses including erk1 survivin vegfc 67 kd-laminin receptor nucleosid diphosphate kinase nm23-h1 mmp2 and timp-2 e-cadherin and nf-kappa-b. survivin: it is involved both in cell cycle and apoptosis regulation wheatley and mcneish 2005 survivin gene expression is usually repressed by wild type p53. as such its over-expression indirectly indicates e6 mediated p53 degradation. survivin was found to be an early marker of cervical carcinogenesis expression strength increased with lesion grade branca giorgi et al. 2005 vegf: it is upregulated by e6 independent from p53. vegf overexpression was found to be an early marker of cin and correlated linearly with lesion grade branca giorgi et al. 2006 matrix metalloproteinases and tissue inhibitors of metalloproteinases: proteins with potential usefulness as molecular markers or prognostic indicators are the family of matrix metalloproteinases mmps and tissue inhibitors of metalloproteinases timps mmps belong to the family of endogenous proteases that degrade the extracellular matrix including collagen elastin and gelatin and are considered to be critical for the development and invasion of tumors. both mmp-2 and mmp-9 are important matrix metalloproteinase known to be involved in the breakdown of the basement membrane a pre-requisite for invasion of cancer lein jung et al. 2000 e-cadherin: a defining characteristic of malignant cells is the ability to migrate from their niche and become invasive and metastatic and a critical step in this process is the loss of cell-cell adhesion hanahan and weinberg 2011 a prime example in human carcinomas is the loss of epithelial adherens junction transmembrane protein e-cadherin berx and van roy 2009 the inhibition of e-cadherin promotes cellular migration and e-cadherin loss promotes the epithelial-to-mesenchymal transition emt hanahan and weinberg 2011 accordingly loss of e-cadherin has been demonstrated in carcinomas of the breast gastrointestinal tract pancreas and numerous others berx and van roy 2009 as well as in cervical scc vessey wilding et al. 1995 chen liu et al. 2003 fadare reddy et al. 2005 2.18.3 tumour-associated antigens taas a family of tumour-associated antigens taas has been identified and their encoding genes have been extensively investigated. the ideal taas should be 1 non-self i.e. a foreign antigen like hpv proteins or not tolerized 2 expressed only in the tumor 3 common to all tumors of this type 4 required for tumor viability so that it cannot be lost e.g. e6 and e7 since cervical cancer cells die in their absence 5 immunogenic and 6 cell surface i.e. can be targeted by antibody among them cancer testis antigens ctas are expressed in a limited number of normal tissues as well as in various malignant tumors of unrelated histological origin including cervical cancers and are being vigorously pursued as targets for new therapeutic strategies. they are also being evaluated because of their role in oncogenesis and the recapitulation of portions of the germ line gene-expression program which might contribute characteristic features to the neoplastic phenotype such as immortality invasiveness immune evasion hypomethylation and metastatic capacity. the discovery of taas one of the most controversial issues in immunology for over a century has been whether an effective immune response can be elicited against malignant tumors parish 2003 based on recent immunological developments there is no doubt that the immune system can recognize and eliminate malignant cells. in 1967 frank macfarlane burnet introduced a general hypothesis suggesting that lymphocytes are continually patrolling tissues and eliminating transformed cells presumably via recognition of taas a process he called immunosurveillance burnet 1967 it is known today that the immune system is capable of discriminating between benign and malignant cells based on specific recognition of aberrantly expressed proteins or peptide fragments in the context of major histocompatibility complex mhc thus the proteins encoded by abnormally expressed genes of a tumour cell may represent potential targets for immune cells serving as tumour-associated rejection or regression antigens. with the exception of melanoma few candidate taas have been described for human malignancies van der bruggen traversari et al. 1991 lewis reilly et al. 2003 the introduction of a genetic approach of t-cell epitope cloning and subsequently an innovative method through the serological analysis of recombinant tumor cdna expression libraries with autologous serum serex has greatly expanded the identification of a promising class of taas called cancer testis antigens ctas another method used in the search for taas is acid elution of peptides from tumour-cell surface mhc i molecules. pools of peptides are produced fractioned with high pressure liquid chromatography and sequenced van bleek and nathenson 1990 parker shields et al. 1995 taas that are over-expressed or up-regulated in cancer cells can also be identified by analysis of differentially expressed genes in tumour cells compared to their counterpart normal cells. serial analysis of gene expression sage is a useful approach to determine the expression of a high number of genes simultaneously.