Human periostin gene expression in normal tissues, tumors and melanoma: evidences for periostin production by both stromal and melanoma cells

<p>Abstract</p> <p>Background</p> <p>Recently, periostin (<it>POSTN</it>), a gene encoding a protein with similarity to the fasciclin family and involved in cell survival and angiogenesis, has emerged as a promising marker for tumor progression in various types of human cancers. There is some controversy regarding both <it>POSTN </it>expression levels and the nature of periostin-producing cells within tumors. In this study, we used quantitative RT-PCR to assess periostin gene expression in normal tissues, primary cell cultures, tumor tissues and tumor cell lines.</p> <p>Results</p> <p>Periostin expression levels are highly variable in both normal tissues and tumors and strong <it>POSTN </it>overexpression is mostly detected in tumors from pancreas and liver. <it>POSTN </it>is not expressed in blood cancers. In melanoma samples, average periostin expression is not increased in primary tumors whereas <it>POSTN </it>overexpression was detected in about 60% of melanoma metastatic tumors in the liver or lymph nodes. Identification of the cellular source of periostin production in melanoma metastases -cancer cells or stroma- was assessed by comparing periostin expression in 23 newly-established melanoma cell lines and matched tumors. In contrast to the reduction by more than 99% of <it>COL6A3 </it>stromal marker mRNA in all cell lines, significant <it>POSTN </it>transcription was maintained in some melanoma cell lines, suggesting that both stromal cells and melanoma cells express periostin. The high level of periostin expression in primary cultures of skin fibroblasts suggests that fibroblasts may contribute for a large part to periostin production in melanoma-associated stroma. On the other hand, periostin expression in melanoma cells is probably acquired during the tumorigenic process as 1) normal melanocytes do not express <it>POSTN </it>and 2) melanoma cells from distinct metastases of the same patient were associated with very different levels of periostin expression.</p> <p>Conclusion</p> <p>Our comparative analysis suggests that, although periostin overexpression is clearly detected in some cancers, it is not a general feature of tumors. In melanoma, our study identifies both stromal and melanoma cells as sources of periostin production and correlates <it>POSTN </it>expression levels with increased primary tumor thickness and metastatic process development.</p

A Synopsis of Serum Biomarkers in Cutaneous Melanoma Patients

Many serum biomarkers have been evaluated in melanoma but their clinical significance remains a matter of debate. In this paper, a review of the serum biomarkers for melanoma will be detailed and will be discussed from the point of view of their practical usefulness. The expression of biomarkers can be detected intracellularly or on the cell membrane of melanoma cells or noncancer cells in association with the melanoma. Some of these molecules can then be released extracellularly and be found in body fluids such as the serum. Actually, with the emergence of new targeted therapies for cancer and the increasing range of therapeutic options, the challenge for the clinician is to assess the unique risk/response ratio and the prognosis for each patient. New serum biomarkers of melanoma progression and metastatic disease are still awaited in order to provide efficient rationale for followup and treatment choices. LDH as well as S100B levels have been correlated with poor prognosis in AJCC stage III/IV melanoma patients. However, the poor sensitivity and specificity of those markers and many other molecules are serious limitations for their routine use in both early (AJCC stage I and II) and advanced stages of melanoma (AJCC stage III and IV). Microarray technology and proteomic research will surely provide new candidates in the near future allowing more accurate definition of the individual prognosis and prediction of the therapeutic outcome and select patients for early adjuvant strategies

Contrasting frequencies of antitumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen

Melanoma patients have high frequencies of T cells directed against antigens of their tumor. The frequency of these antitumor T cells in the blood is usually well above that of the anti-vaccine T cells observed after vaccination with tumor antigens. In a patient vaccinated with a MAGE-3 antigen presented by HLA-A1, we measured the frequencies of anti-vaccine and antitumor T cells in several metastases to evaluate their respective potential contribution to tumor rejection. The frequency of anti–MAGE-3.A1 T cells was 1.5 × 10−5 of CD8 T cells in an invaded lymph node, sixfold higher than in the blood. An antitumor cytotoxic T lymphocyte (CTL) recognizing a MAGE-C2 antigen showed a much higher enrichment with a frequency of ∼10%, 1,000 times higher than its blood frequency. Several other antitumor T clonotypes had frequencies >1%. Similar findings were made on a regressing cutaneous metastasis. Thus, antitumor T cells were ∼10,000 times more frequent than anti-vaccine T cells inside metastases, representing the majority of T cells present there. This suggests that the anti-vaccine CTLs are not the effectors that kill the bulk of the tumor cells, but that their interaction with the tumor generates conditions enabling the stimulation of large numbers of antitumor CTLs that proceed to destroy the tumor cells. Naive T cells appear to be stimulated in the course of this process as new antitumor clonotypes arise after vaccination

The Athena x-ray optics development and accommodation

The Athena mission, under study and preparation by ESA as its second Large-class science mission, requires the largest X-ray optics ever flown, building on a novel optics technology based on mono crystalline silicon. Referred to as Silicon Pore Optics technology (SPO), the optics is highly modular and benefits from technology spin-in from the semiconductor industry. The telescope aperture of about 2.5 meters is populated by around 700 mirror modules, accurately co-aligned to produce a common focus. The development of the SPO technology is a joint effort by European industrial and research entities, working together to address the challenges to demonstrate the imaging performance, robustness and efficient series production of the Athena optics. A technology development plan was established and is being regularly updated to reflect the latest developments, and is fully funded by the ESA technology development programmes. An industrial consortium was formed to ensure coherence of the individual technology development activities. The SPO technology uses precision machined mirror plates produced using the latest generation top quality 12 inch silicon wafers, which are assembled into rugged stacks. The surfaces of the mirror plates and the integral support structure is such, that no glue is required to join the individual mirror plates. Once accurately aligned with respect to each other, the surfaces of the mirror plates merge in a physical bonding process. The resultant SPO mirror modules are therefore very accurate and stable and can sustain the harsh conditions encountered during launch and are able to tolerate the space environment expected during operations. The accommodation of the Athena telescope is also innovative, relying on a hexapod mechanism to align the optics to the selected detector instruments located in the focal plane. System studies are complemented by dedicated technology development activities to demonstrate the capabilities before the adoption of the Athena mission

Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE)

Identification of functional elements and regulatory circuits by Drosophila modENCODE

To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation

Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).This project was funded by the National Health and Medical Research Council (NHMRC; 1093017), the Walking On Sunshine Foundation, Anne Stanton, Nicola Laws and Lloyd Owen in Memorial and Civic Solutions. This study was also funded by Fight for Sight, Denmark. A.L.P. is supported by Highland Island Enterprise (HMS9353763). This work was supported by an NHMRC Program Grant (G.V.L., G.J.M., R.A.S. and N.K.H.). G.V.L. is supported by an NHMRC Practitioner Fellowship and The University of Sydney, Medical Foundation. R.A.S. is supported by an NHMRC Practitioner Fellowship. Support from Melanoma Institute Australia and The Ainsworth Foundation is also gratefully acknowledged. J.S.W. is supported by a NHMRC early career fellowship (1111678). N.W. is supported by an NHMRC Senior Research Fellowship (1139071). N.K.H. is supported by an NHMRC Senior Principal Research Fellowship (1117663)