Faculty Bibliography

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. It is important to target initiators, co-carcinogens and promoters, since by removing any one of them, tumor growth may be prevented. Identification of these agents is difficult. Epidemiological studies largely study cancer after it has occurred. It would be preferable to identify potential carcinogenic substances at an earlier stage before they have caused a large number of malignancies and thus become identifiable by epidemiology. During the past three decades, we have accumulated an impressive amount of evidence concerning molecular pathways that when altered contribute to malignant growth. It is time that we start applying this knowledge to the identification of human carcinogens. Here, we review the molecular changes that are required for carcinogenesis and propose some criteria that, in the absence of epidemiological evidence, can be used to identify agents that cause or contribute to human cancer development. In the absence of epidemiological evidence, a given agent should be considered a human carcinogen when: (1) the agent causes or contributes to the development of tumors in animals that are of the same type as those tumors associated with exposure to the agent in humans; (2) the agent transforms or contributes to the transformation of human cells in culture and these cells are of the same type from which associated human malignancies arise; (3) there is molecular evidence that the agent interferes with one or more key molecular pathways in human cells which leads to the formation of human cancer

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. In the past, the argument always has been whether the finding of SV40 in mesothelioma is credible enough to lead our thinking in another direction to help our patients. Unfortunately, the causality issues have been stuck to the issue like a remora on a shark. It is time to study the remora, but our priorities should be on taming the shark

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. The expression of the gene in the cell lines was determined by RT-PCR and correlated with the methylation status. Aberrant methylation was detected by MSP in 9 of 27 (33%) and 25 of 78 (32%) lung cancer cell lines and tumors, respectively, 11 of 18 (61%) and 17 of 38 (45%) breast cancer cell lines and tumors, respectively, and 1 of 25 (4%) MM tumors. DNA methylation was detected but rarely in the corresponding non-malignant tissues. In addition, the gene expression was restored in the methylated cell lines following 5-aza-2'-deoxycytidine treatment, confirming that the methylation was indeed responsible for the gene down-regulation. We also examined the relationship between the p57KIP2 methylation status and the clinicopathological features of the primary tumors, and found that there was no relationship between the p57KIP2 methylation status and any of the examined clinicopathological features. In summary, our results demonstrate that p57KIP2 methylation associated with the gene down-regulation is frequently present in lung and breast cancers and plays an important role at the molecular level in the pathogenesis of these cancers

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. This review will touch on the various steps in the translational pipeline, and highlight some of the most essential elements as well as possible roadblocks that can impact success of the program. Critical issues with regard to Institutional Review Board (IRB) and Health Insurance Portability and Accountability Act (HIPAA) compliance, data standardization, sample procurement, quality control (QC), quality assurance (QA), data analysis, preclinical models and clinical trials are addressed. The various facets of the translational pipeline have been incorporated into a fully integrated computational system, appropriately named Dx2Tx. This system readily allows for the identification of new diagnostic tests, the discovery of biomarkers and drugable targets, and prediction of optimal treatments based upon the underlying molecular basis of the disease

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. To this end, we studied the extent of changes in osteonectin (ON) protein levels induced in BEAS 2 B-cells by CSC treatment and its timing to changes occurring in the anchorage independent cloning efficiency. ON, a multimodular protein component of the extra-cellular matrix, has been implicated in tissue remodeling occurring in neoplastic and non-neoplastic conditions, but its role in lung carcinogenesis is incompletely characterized. To validate the in vitro findings, as in our previous reports, we studied resected lung tissue, to assess whether ON expression in neoplastic lung tissue differs from normal, and to determine its cellular localization. We found that CSC treatment of BEAS2-B cells results in a 7-16-fold increase in ON protein levels, that is associated with increased colony forming efficiency. ON is absent in normal lung; in contrast it is present in the majority (39/52) of non-small cell lung cancer (NSCLC). Here, its expression is restricted to peritumoral fibroblasts in squamous cell carcinoma and adenocarcinoma. In contrast, it is localized to tumor cells in pulmonary sarcomatoid carcinoma (8/10). Thus, up-regulated ON is linked in vitro to cell transformation and in vivo, it is frequently expressed in tumor-associated fibrosis, compatible with its proposed role in tissue remodelling. Increased ON expression by tumor cells appears to represent a marker of sarcomatoid NSCLC

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. Data that argue for considering lesser resection of selected early-stage lung cancers, as well as the need for more prospectively accumulated facts that arise from trial designs like the original randomized Lung Cancer Study Group Trial, are discussed

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. Recently aberrant methylation of TRAIL decoy receptors was reported in pediatric tumor cell lines and neuroblastomas. We examined the methylation and expression status of TRAIL receptor genes in cancers of breast, lung, mesothelioma, prostate, bladder, cervix, ovary, brain and in hematopoietic malignancies. Aberrant methylation of DcR1 or DcR2 was present in 70% of primary breast cancers, 31% of primary lung cancers, in 63% of primary malignant mesothelioma (MM), in 60% of prostate cancer, in 42% of bladder cancer, in 100% of cervical cancer, in 43% of ovarian cancer, in 41% of lymphoma, in 26% of leukemia and in 56% of multiple myeloma. Methylation of DR4 and DR5 was rare in all the tumor types examined. Methylation of all the 4 receptors was rare in non malignant tissues. In cell lines, aberrant methylation of DcR1 was present in 11 of 23 (48%) breast, 10 of 27 (37%) lung and 3 of 7 (43%) MM, whereas aberrant methylation of DcR2 was present in 17 of 23 (74%) breast, 13 of 27 (48%) lung and 5 of 7 (71%) MM. The concordance between loss of gene expression and aberrant methylation ranged from 70-100%. Treatment with 5-aza-2'-deoxycytidine restored DcR1 and DcR2 expression in 9 methylated cell lines confirming that aberrant methylation was the cause for silencing of DcR1 and DcR2 expression. Our results demonstrate that DcR1 and DcR2 genes are frequently methylated in various tumor types, and that the role of decoy receptors in tumor pathogenesis needs to be re-evaluated

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. Pemetrexed is a multitargeted antifolate that is being evaluated in many tumor types. Recent single-agent data and data in combination with cisplatin have suggested that pemetrexed has therapeutic benefits in patients with malignant mesothelioma. This article summarizes the data regarding pemetrexed in the treatment of malignant mesothelioma and the potential novel combinations involving the drug that may be used in the future for the treatment of the disease