Distinct DNA methylation profiles in malignant mesothelioma, lung adenocarcinoma, and non-tumor lung.

DNA methylation markers provide a powerful tool to make diagnoses based on genetic material obtained directly from tumors or from "remote" locations such as sputum, pleural fluid, or serum. In particular when limited cell numbers are available, amplifyable DNA markers can provide a very sensitive tool for cancer detection and classification. Malignant mesothelioma (MM), an aggressive cancer strongly associated with asbestos exposure, can be difficult to distinguish from adenocarcinoma of the lung when limited material is available.

Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection.

Malignant mesothelioma (MM) is associated with asbestos exposure and the presence of SV40 viral sequences. Recently, we reported that SV40 infection of human mesothelial cells (HM) causes aberrant methylation of the tumor suppressor gene (TSG) RASSF1A. We investigated methylation of 12 genes by methylation-specific PCR in 63 MMs, six MM cell lines, and two foci of SV40-infected HM.

Evidence of an important role for SV40 in mesothelioma.

The discovery of SV40 DNA in human mesothelioma has evolved from a finding that originally was dismissed as polymerase chain reaction contamination to one that has won approval for a National Cancer Institute Rapid Access to Intervention Development grant to vaccinate SV40-positive tumors with a vaccinia mTag construct. As the credibility of these findings has become imprinted in the literature, the burden of phenomenon dismissal has become more difficult for investigators who have based their arguments on critically flawed validation studies. Mesothelioma is a disease for which novel strategies of detection or treatment should be encouraged, and it is as dangerous as a hungry shark.

Translation research: from accurate diagnosis to appropriate treatment.

This review article focuses on the various aspects of translational research, where research on human subjects can ultimately enhance the diagnosis and treatment of future patients. While we will use specific examples relating to the asbestos related cancer mesothelioma, it should be stressed that the general approach outlined throughout this review is readily applicable to other diseases with an underlying molecular basis. Through the integration of molecular-based technologies, systematic tissue procurement and medical informatics, we now have the ability to identify clinically applicable "genotype"-"phenotype" associations across cohorts of patients that can rapidly be translated into useful diagnostic and treatment strategies.

Aberrant methylation of p57KIP2 gene in lung and breast cancers and malignant mesotheliomas.

The p57KIP2 gene belongs to the Cip/Kip family of CDK inhibitors and has been demonstrated to be a tumor suppressor gene, being inactivated in various types of human cancers. We analyzed the methylation and expression status of p57KIP2 in lung and breast cancers, and in malignant mesotheliomas (MMs). The promoter region of p57KIP2 was determined by methylation-specific PCR (MSP) in samples of lung and breast cancer, and of MM.

Multistep and multifactorial carcinogenesis: when does a contributing factor become a carcinogen?

Our greatest successes in fighting cancer derive from the identification and removal or inactivation of carcinogenic substances, and from the identification and removal of pre-malignant lesions. In comparison, our successes at treating already formed malignancies have been minimal. Therefore, emphasis should be put in identifying and removing pre-malignant lesions, and in the identification and removal of those agents that cause or contribute to cancer development.

Aberrant methylation of HIN-1 (high in normal-1) is a frequent event in many human malignancies.

HIN-1 (high in normal-1) is a putative cytokine with growth inhibitory activities and is downregulated by aberrant methylation in breast cancers. We studied HIN-1 methylation status in many types of adult and pediatric malignancies and cell lines. We examined the expression of HIN-1 mRNA in 52 cell lines and the promoter methylation status in the cell lines and in over 800 primary tumors representing 17 tumor types using methylation specific PCR.

Computerized tomographic nodule heterogeneity: present and future impact on indications for sublobar resections.

With the advent of lung cancer screening, many nodules are being detected that are subsequently proven to be lung cancer. These nodules have different radiographic appearances and different biologic characteristics regarding their invasiveness and propensity for metastasis. These solid and part-solid nodules are now having surgeons reassess issues of lung sparing for early-stage lung cancer by not only considering smaller nodules as potentially appropriate for wedge resection or segmentectomies, but are also requiring surgeons to stratify these lesions by radiographic appearance.

Increased osteonectin expression is associated with malignant transformation and tumor associated fibrosis in the lung.

Chemical transformation of the SV-40 immortalized bronchial epithelial cell line BEAS2-B induces alterations in molecules involved in cell cycle control, including up-regulation of EGFR and cyclin E [Oncogene 13 (1996) 1983; Clin Cancer Res 8 (2002) 54]. The finding that these changes also occur in vivo, in both pre-invasive and invasive lung cancer [Cancer Res 55 (1995) 1365; Cancer Res 59 (1999) 2470], proves this to be a suitable model to study lung carcinogenesis. The current study tested the hypothesis that chemical treatment of BEAS2-B with Cigarette Smoke Condensate (CSC) may affect levels of gene products involved in cell adhesion and tissue remodeling.

Novel combinations using pemetrexed in malignant mesothelioma.

Malignant mesothelioma is an uncommon malignancy that is locally invasive and rapidly fatal. The majority of patients with mesothelioma are not candidates for curative surgical resection. Chemotherapy has yielded only modest results in these patients.

Integration of multimodality approaches in the management of malignant pleural mesothelioma.

More than half a century after the first descriptions of mesothelioma as a pathologic entity, satisfactory treatment is still elusive. Although relatively uncommon, the incidence of mesothelioma will most likely increase over the next 10-20 years. Advances have been made in understanding the pathogenesis, diagnosis, and staging, but they have not translated into markedly improved survival.

Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types.

TNF-related apoptosis-inducing ligand (TRAIL) selectively induces programmed cell death (apoptosis) in various cancer cells but not in normal cells. TRAIL is known to bind to 4 different receptors, 2 proapoptotic (DR4 and DR5), and 2 potentially antiapoptotic receptors lacking death domains (DcR1 and DcR2). Aberrant promoter methylation and resultant silencing of tumor suppressor genes play an important role in the pathogenesis of many tumor types.

Gene expression profiles predict survival and progression of pleural mesothelioma.

Purpose: Clinical outcomes for malignant pleural mesothelioma (MPM) patients having surgery are imprecisely predicted by histopathology and intraoperative staging. We hypothesized that gene expression profiles could predict time to progression and survival in surgically cytoreduced pleural mesothelioma of all stages.

Experimental Design: Gene expression analyses from 21 MPM patients having cytoreductions and identical postoperative adjuvant therapy were performed using the U95 Affymetrix gene chip.

Disseminated malignant solitary fibrous tumor of the pleura.

Solitary fibrous tumor (SFT) of the pleura typically forms a localized pleura-based mass, and most are benign. A rare case of disseminated malignant SFT of the pleura is reported. The patient was a 71-year-old man who presented with complaints of shortness of breath to his primary care physician.

Mutation analysis of the BRAF codon 599 in malignant pleural mesothelioma by enriched PCR-RFLP.

BRAF encodes a RAS-regulated serine/threonine kinase that mediates the pathway for cell growth and malignant transformation. Point mutations of BRAF were reported recently in 66% of melanomas, over 30% of thyroid papillary and low-grade ovarian cancers, and a smaller percentage of other human cancers. Mutations in malignant cells were reported to occur only in exons 11 and 15.

Expression of human MutT homologue (hMTH1) protein in primary non-small-cell lung carcinomas and histologically normal surrounding tissue.

In situ, oxidation of deoxyguanosine yields 8-hydroxy-2'-deoxyguanosine (8-oxo-dG), which is mutation prone and results in a G:C --> T:A transversion following DNA replication. Another pathway to the formation of DNA containing 8-oxo-dG is by the misincorporation of 8-oxo-dGTP via DNA polymerase. Human MutT homologue (hMTH1), an 8-oxo-dGTPase, prevents misincorporation of this oxidized nucleotide by hydrolyzing 8-oxo-dGTP to 8-oxo-dGMP.

A phase I study of Foscan-mediated photodynamic therapy and surgery in patients with mesothelioma.

Background: Photodynamic therapy (PDT) is a light-based cancer treatment that, in the correct setting, can be delivered intraoperatively as an adjuvant therapy. A phase I clinical trial combining surgical debulking with Foscan-mediated PDT was performed in patients with malignant pleural mesothelioma. The purpose of the study was to define the toxicities and to determine the maximally tolerated dose (MTD) of Foscan-mediated PDT.

Immunohistochemistry frequently detects c-Kit expression in pulmonary small cell carcinoma and may help select clinical subsets for a novel form of chemotherapy.

The presence of c-Kit immunoreactivity in gastrointestinal stromal tumor (GIST), currently guides treatment with the selective c-Kit inhibitor STI571 (or Gleevec) in clinical trials and establishes a precedent of immunohistochemistry-guided treatment decisions. Thus, the optimization of detection conditions for c-Kit and the determination of its incidence in other malignancies have clinical bearing. Aims of our study were: 1) to determine the incidence of c-Kit expression in formalin-fixed paraffin-embedded tissue (FFPE) in pulmonary small cell carcinoma (SCC) and non small cell carcinoma (NSCC), pulmonary carcinoid, and malignant mesothelioma (MM); and 2) to test the feasibility of c-Kit determination using commercially available antibodies and routine immunohistochemical settings, comparing the performance of two commercially available antibodies, Dako and Santa Cruz.

Notch-1 induction, a novel activity of SV40 required for growth of SV40-transformed human mesothelial cells.

We show that SV40 infection of human mesothelial cells directly causes overexpression of Notch-1, a key cell regulatory gene. Notch-1 induction is achieved at the transcriptional level and requires both the SV40 large T-antigen and the small t-antigen. Notch-1 upregulation is maintained in SV40-transformed human mesothelial clones and in SV40-positive mesotheliomas and derived cell lines.

Human lung cancer cells and tissues partially recapitulate the homeobox gene expression profile of embryonic lung.

The fetal cell features of tumor cells suggest that neoplasia arises through a process of defective ontogeny. Homeobox (HOX) genes code for transcription factors that orchestrate organogenesis patterning and maintain tissue homeostasis. Thus, if detective ontogeny is a mechanism in cancer development, it can be hypothesized that tumor cells should express the HOX genes normally expressed by the embryonic cells of that tissue.