Current concepts in bronchioloalveolar carcinoma biology.
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Adenocarcinoma, Bronchiolo-Alveolar↗
Biomedical subjects
David M Jablons
Publications and source records attributed to David M Jablons.
Wnt inhibitory factor-1, a Wnt antagonist, is silenced by promoter hypermethylation in malignant pleural mesothelioma.
Wnt inhibitory factor-1 (WIF-1) is a secreted protein that antagonizes Wnt signaling. We recently demonstrated the importance of aberrant activation of the Wnt signaling pathway in various cancers including malignant pleural mesothelioma. In this study, we revealed downregulated WIF-1 expression in cell lines and primary tissue when compared to normal mesothelial cell lines and adjacent pleura, respectively. We observed hypermethylation in four of four mesothelioma cell lines, but not in two normal mesothelial cell lines. In primary tissue samples, we observed methylation in three paired tumor specimens compared to their adjacent normal pleura and methylation in eight of nine unpaired tumor tissue samples. Taken together, our studies suggest that WIF-1 silencing due to its promoter hypermethylation is an important mechanism underlying the constitutively activated Wnt signaling in mesothelioma. New therapies toward inhibition of the Wnt pathway through WIF-1 might be promising for the future treatment of malignant mesothelioma.
Adaptor Proteins, Signal Transducing↗
Wnt signaling activation and WIF-1 silencing in nasopharyngeal cancer cell lines.
Aberrant activation of Wingless-type (Wnt) signaling pathway plays a critical role in oncogenesis of various human cancers. Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist of Wnt signaling and acts through direct binding to Wnt in the extracellular space. Recently, we reported Wnt signaling in various human malignancies. In addition, we identified in lung cancer that WIF-1 is silenced due to promoter hypermethylation. In this study, we found constitutive activation of Wnt signaling and WIF-1 silencing in nasopharyngeal carcinoma (NPC) cell lines. Furthermore, by utilizing methylation-specific PCR and sequence analysis, we demonstrated that frequent hypermethylation of the WIF-1 promoter correlates with WIF-1 silencing in NPC cell lines. Our results indicate that aberrant Wnt signaling is a common event in NPC carcinogenesis linked with WIF-1 silencing in at least cell lines. Strategies targeting these molecules should be potentially promising in treating NPC.
Adaptor Proteins, Signal Transducing↗
Clinical patterns of metastasis.
In human solid cancer, lymph node status is the most important indicator for clinical outcome. Recent developments in the sentinel lymph node concept and technology have resulted in a more precise way of examining micrometastasis in the sentinel lymph node and the role of lymphovascular system in the facilitation of cancer metastasis. Different patterns of metastasis are described with respect to different types of solid cancer. Expect perhaps for papillary carcinoma and sarcoma, the overwhelming evidence is that solid cancer progresses in an orderly progression from the primary site to the regional lymph node or the sentinel lymph node in the majority of cases with subsequent dissemination to the systemic sites. The basic mechanisms of cancer metastasis through the lymphovascular system form the basis of rational therapy against cancer. Beyond the clinical patterns of metastasis, it is imperative to understand the biology of metastasis and to characterize patterns of metastasis perhaps due to heterogeneous clones based on their molecular signatures.
Animals↗
Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer.
We describe here the existence of a heregulin-HER3 autocrine loop, and the contribution of heregulin-dependent, HER2-mediated HER3 activation to gefitinib insensitivity in non-small cell lung cancer (NSCLC). ADAM17 protein, a major ErbB ligand sheddase, is upregulated in NSCLC and is required not only for heregulin-dependent HER3 signaling, but also for EGFR ligand-dependent signaling in NSCLC cell lines. A selective ADAM inhibitor, INCB3619, prevents the processing and activation of multiple ErbB ligands, including heregulin. In addition, INCB3619 inhibits gefitinib-resistant HER3 signaling and enhances gefitinib inhibition of EGFR signaling in NSCLC. These results show that ADAM inhibition affects multiple ErbB pathways in NSCLC and thus offers an excellent opportunity for pharmacological intervention, either alone or in combination with other drugs.
ADAM Proteins↗
Tumor fluoro-2-deoxy-D-glucose avidity on positron emission tomographic scan predicts mortality in patients with early-stage pure and mixed bronchioloalveolar carcinoma.
OBJECTIVE: Bronchioloalveolar carcinoma is a clinically heterogeneous subtype of non-small cell lung carcinoma that frequently has low 2-[18F]fluoro-D-glucose (FDG) uptake on positron emission tomographic scanning. We investigated whether tumor FDG avidity was associated with worse survival among patients with completely resected node-negative pure and mixed bronchioloalveolar carcinoma. METHODS: We performed a cohort study of 36 patients who had completely resected pure and mixed bronchioloalveolar carcinoma between 1998 and 2004, who had no hilar or mediastinal lymph node metastases, and who had undergone a preoperative positron emission tomographic scan. Tumor FDG avidity was defined as a standardized uptake value of 2.5 or greater. Survival analysis was performed with a proportional hazards model. RESULTS: Of 36 patients studied, 26 patients (72%) were alive and 10 patients (28%) were dead after a median follow-up of 31 months (interquartile range 17-41 months). Seventeen patients (47%) had FDG-avid tumors, and 19 patients (53%) had non-avid tumors. Three-year survival was 49% in the FDG-avid group and 95% in the non-avid group (P = .005). FDG avidity had a hazard ratio of death of 8.6 (95% confidence interval 1.4-244.7, P = .02) after adjusting for tumor size, the presence of multifocal bronchioloalveolar carcinoma, and the presence of histologically mixed bronchioloalveolar carcinoma. CONCLUSIONS: Preoperative tumor FDG standardized uptake value of 2.5 or greater on positron emission tomography is a powerful predictor of long-term mortality in patients with lymph node-negative pure and mixed bronchioloalveolar carcinoma who undergo complete surgical resection. Patients with a high level of FDG uptake (standardized uptake value > or = 2.5) may benefit from adjuvant chemotherapy or more frequent clinical follow-up.
Adenocarcinoma, Bronchiolo-Alveolar↗
Bronchioloalveolar carcinoma: a review.
Bronchioloalveolar carcinoma (BAC) is classified as a subset of lung adenocarcinoma but has a distinct clinical presentation, tumor biology, response to therapy, and prognosis compared with other subtypes of non-small-cell lung carcinoma (NSCLC). Bronchioloalveolar carcinoma disproportionately affects women, never-smokers, and Asians and is characterized by growth along alveolar septae without evidence of stromal, vascular, or pleural invasion. Although pure BAC accounts for approximately 4% of lung cancers, tumors with histologically mixed BAC and adenocarcinoma account for > 20% of all NSCLCs, and the incidence of BAC might be increasing. Bronchioloalveolar carcinoma histology is most commonly found in small lesions identified incidentally on chest radiographs or computed tomography scans and might represent a precursor lesion to invasive adenocarcinoma. As with other subsets of NSCLC, surgical resection is the only potentially curative treatment. Patients with unresectable BAC are more likely to respond to the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib than patients with other subtypes of NSCLC. Stage for stage, patients with BAC have a higher rate of long-term survival but might have an increased rate of intrathoracic recurrence than patients with other subtypes of NSCLC.
Adenocarcinoma, Bronchiolo-Alveolar↗
Wnt2 as a new therapeutic target in malignant pleural mesothelioma.
Malignant mesothelioma of the pleura (MPM) is a highly aggressive neoplasm with a poor prognosis and limited treatment options. A better understanding of its pathogenesis is essential to developing alternative therapeutic strategies. We previously demonstrated that the Wnt signaling pathway is activated in MPM through the overexpression of disheveled proteins. To extend our knowledge of Wnt signaling activation in MPM, we performed Wnt-specific microarrays in normal pleura and MPM. We found that the most common event in MPM was the upregulation of Wnt2. We inhibited Wnt2 by siRNA and a monoclonal anti-Wnt2 antibody and analyzed their effects on apoptosis and downstream signaling effectors. We then assessed the antiproliferative effects of the Wnt2 antibody and Alimta, one of the current standard treatments of MPM. We confirmed Wnt2 overexpression at the mRNA and protein level in MPM cell lines and tissues. We then demonstrated that inhibition of Wnt2 by siRNA or a monoclonal antibody induces programmed cell death in MPM cells. We next analyzed the effects of the anti-Wnt2 antibody and of Alimta on MPM cell proliferation. We found that although Wnt2 antibody by itself had less antiproliferative potency than Alimta, the two in combination had substantially more activity than Alimta alone. We thus propose that inhibition of Wnt2 is of therapeutic interest in the development of more effective treatments for MPM.
Antibodies, Monoclonal↗
A novel in vitro model of human mesothelioma for studying tumor biology and apoptotic resistance.
Like many tumors, malignant mesothelioma exhibits significant chemoresistance and resistance to apoptosis in vivo that is not seen in current in vitro models. To study the mechanisms of this multicellular resistance, biologically relevant in vitro models are necessary. Therefore, we characterized and tested human mesothelioma tissue grown in vitro as tumor fragment spheroids. After 5-10 d in culture, fragments from each of 15 human mesothelioma tumors rounded into spheroids. The tumor fragment spheroids maintained multiple characteristics of the original tumors for up to 3 mo including the presence of viable mesothelioma cells, macrophages, and a collagen-rich stroma. In 14-d-old spheroids, mesothelioma cells showed the same proliferation rate and expression of a death receptor, DR5, as in the original tumor. To determine responses to treatment, we treated tumor fragment spheroids grown from three separate tumors with agents, TNF-related apoptosis-inducing ligand (TRAIL) plus cycloheximide, that induced near total apoptosis in three human mesothelioma cell lines (M28, REN, MS-1) grown as monolayers (94 +/- 6% apoptosis; mean +/- SEM). Compared with mesothelioma cells in monolayers, mesothelioma cells in the spheroids were resistant to TRAIL plus cycloheximide (32 +/- 4% apoptosis; mean +/- SEM). Apoptotic resistance of mesothelioma cells was significantly reduced by inhibiting either the PI3K/Akt pathway with LY294002 (47 +/- 6% apoptosis) or the mTOR pathway with rapamycin (50 +/- 17% apoptosis). We conclude that human mesothelioma can be maintained in vitro in a biologically relevant model that exhibits apoptotic resistance, thereby permitting study of its tumor biology and of novel approaches to therapy.
Apoptosis↗
Inhibition of Wnt16 in human acute lymphoblastoid leukemia cells containing the t(1;19) translocation induces apoptosis.
The Wnt family of secreted glycoproteins is widely involved in cell proliferation, differentiation and oncogenesis. Many Wnt signaling genes are upregulated and activated in chronic lymphocytic leukemia. Less is known concerning acute leukemia. One subtype of acute lymphoblastoid leukemia (ALL) is characterized by a t(1;19) chromosomal translocation resulting in a fusion protein E2A-Pbx1 that promotes transformation and leukemogenesis. Wnt16 has been shown to be targeted by E2A-Pbx1. We performed a differential gene expression array in acute leukemia cell lines displaying or not displaying the t(1;19) translocation. We found that Wnt16 and many Wnt signaling-related genes were upregulated in the translocation-containing cells. As two isoforms of Wnt16, Wnt16a and Wnt16b, have been recently identified, we demonstrated by using RT-PCR and Western blot that Wnt16b (and not Wnt16a) is overexpressed in t(1;19)-containing cell lines. We then directly addressed the role played by both isoforms in this type of leukemia. Using specific short interfering RNA (siRNA) and an anti-Wnt16 antibody, we showed that targeted-Wnt16b inhibition leads to apoptotic cell death. We also demonstrated that Wnt16b mediates its effect through the canonical Wnt pathway involving dishevelled-2, beta-catenin and survivin. We thus propose that Wnt16 plays an important role in leukemogenesis, raising its therapeutic interest.
Apoptosis↗
Efficacy of Wnt-1 monoclonal antibody in sarcoma cells.
BACKGROUND: Sarcomas are one of the most refractory diseases among malignant tumors. More effective therapies based on an increased understanding of the molecular biology of sarcomas are needed as current forms of therapy remain inadequate. Recently, it has been reported that Wnt-1/beta-catenin signaling inhibits apoptosis in several cancers. In this study, we investigated the efficacy of a monoclonal anti-Wnt-1 antibody in sarcoma cells. METHODS: We treated cell lines A-204, SJSA-1, and fresh primary cultures of lung metastasis of sarcoma with a monoclonal anti-Wnt-1 antibody. Wnt-1 siRNA treatment was carried out in A-204. We assessed cell death using Crystal Violet staining. Apoptosis induction was estimated by flow cytometry analysis (Annexin V and PI staining). Cell signaling changes were determined by western blotting analysis. RESULTS: We detected Wnt-1 expression in all tissue samples and cell lines. Significant apoptosis induction was found in monoclonal anti-Wnt-1 antibody treated cells compared to control monoclonal antibody treated cells (p < 0.02). Similarly, we observed increased apoptosis in Wnt-1 siRNA treated cells. Blockade of Wnt-1 signaling in both experiments was confirmed by analyzing intracellular levels of Dishevelled-3 and of cytosolic beta-catenin. Furthermore, the monoclonal anti-Wnt-1 antibody also induced cell death in fresh primary cultures of metastatic sarcoma in which Wnt-1 signaling was active. CONCLUSION: Our results indicate that Wnt-1 blockade by either monoclonal antibody or siRNA induces cell death in sarcoma cells. These data suggest that Wnt-1 may be a novel therapeutic target for the treatment of a subset of sarcoma cells in which Wnt-1/beta-catenin signaling is active.
Adaptor Proteins, Signal Transducing↗
Wnt signaling in lung cancer.
Wnt signaling has recently emerged as a critical pathway in lung carcinogenesis as already demonstrated in many cancers and particularly in colorectal cancer. We critically discuss in this review the individual components of the Wnt pathway and their role in lung cancer development. We propose that activation of the Wnt-mediated signal occurs in a different manner in lung cancer than in colorectal cancer. In lung cancer, mutations of APC or beta-catenin are rare and the Wnt pathway appears to be activated upstream of beta-catenin. We identified at least three mechanisms of activation: overexpression of Wnt effectors such as Dvl, activation of a non-canonical pathway involving JNK and repression of Wnt antagonists such as WIF-1. The respective relevance of each event and their likely relationship remain unclear. Nevertheless, we propose that many of the studied components of the Wnt pathway may serve as potential targets in the search for therapeutic agents and we can reasonably argue that blockade of Wnt pathway may lead to new treatment strategies in lung cancer.
Adaptor Proteins, Signal Transducing↗
Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations.
Aberrant Wnt signaling, mainly through mutations of APC and in some cases of CTNNB1 or AXIN2, has been found in the majority of colorectal cancers. Recently, frequent promoter hypermethylation was identified to cause silencing of the secreted frizzled-related protein (sFRP) family in colorectal cancer. Restoration of sFRP in colorectal cancer cells attenuates Wnt signaling even in the presence of downstream mutations. Here we show that Wnt inhibitory factor-1 (WIF-1), a different secreted antagonist of Wnt signaling, is also silenced by promoter hypermethylation in colorectal cancer cells. Restoration of WIF-1 function, Wnt-1 siRNA, or a monoclonal anti-Wnt-1 antibody that we developed attenuates Wnt-1 signaling and induces significant apoptosis in these cells containing downstream mutations and expressing Wnt-1. In addition, this monoclonal anti-Wnt-1 antibody showed synergistic effects with docetaxel in treating these colorectal cancer cells and great efficacy in treating primary colorectal cancer cultures freshly prepared from patients. Therefore, our data support the hypothesis that constitutive Wnt signaling may be required to complement downstream mutations in the evolution of colorectal cancer. Furthermore, our results suggest that blockade of the Wnt signal may have a therapeutic role in the treatment of colorectal cancer.
Apoptosis↗
Unusual thoracic problems in patients with malignancies: case 3. Carcinoid tumor of the thymus.
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Adenocarcinoma, Papillary↗
Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells.
The secreted frizzled-related proteins (SFRPs) function as negative regulators of Wnt signaling and have important implications in tumorigenesis. Frequent promoter hypermethylation of SFRPs has been identified in human cancer. Restoration of SFRP function attenuates Wnt signaling and induces apoptosis in a variety of cancer types. Wnt signaling is known to inhibit apoptosis through activation of beta-catenin/Tcf-mediated transcription. Recently, we identified aberrant Wnt activation as a result of Dishevelled overexpression in malignant mesothelioma. Here, we report that silencing of SFRP4 is correlated with promoter hypermethylation in beta-catenin-deficient mesothelioma cell lines. Reexpression of SFRP4 in these beta-catenin-deficient mesothelioma cell lines blocks Wnt signaling, induces apoptosis, and suppresses growth. Conversely, knocking down SFRP4 by small interfering RNA in cell lines expressing both SFRP4 and beta-catenin stimulates Wnt signaling, promotes cell growth, and inhibits chemodrug-induced apoptosis. Our results suggest that methylation silencing of SFRP4 may play an important role in aberrant Wnt activation in mesothelioma even in the absence of beta-catenin. Our data also suggest that beta-catenin-independent noncanonical pathway(s) may be involved in the apoptotic inhibition caused by activation of Wnt signaling.
Adaptor Proteins, Signal Transducing↗
Changes in radiographic abnormalities in organ donors: associations with lung transplantation.
BACKGROUND: Only 20% of organ donors are considered suitable for lung transplantation. No extensive study exists that has evaluated changes in thoracic radiographic abnormalities in organ donors. The purpose of this study was to determine the impact of radiographic abnormalities on successful transplantation. METHODS: In a retrospective survey of 110 organ donors, chest radiographs (N = 417) taken during the initial 24 hours after admission and just before organ harvest were evaluated for 9 radiographic criteria, radiographic diagnoses and clinical characteristics and their association with lung transplantation. RESULTS: Initial lung densities were present in 37% of lungs; there were bilateral infiltrates in 25% of cases. During evaluation (69.7 +/- 60 hours), 38% of right lungs and 28% of left lungs improved radiographically. Up to 51% of lungs with initial infiltrates resolved completely. Worsening of lung infiltrates was more common in the non-transplant group (p = 0.02); however, improvement in densities was not associated with transplantation (p = 0.6). Multivariate analysis determined that moderate and severe lung densities (OR 7.68, p = 0.01; OR 10.8, p = 0.004) and bilateral infiltrates (OR 4.79, p = 0.02) were independent predictors of rejection for transplantation. With densities removed from the model, the number of abnormal diagnoses on the final films was an independent predictor of rejection for transplantation (OR 3.23, p = 0.003). CONCLUSIONS: More than 33% of proposed organ donors initially have lung infiltrates, with >33% showing improvement or resolution, but this improvement does not impact on procurement. Multiple abnormal radiographic diagnoses also contribute to transplant rejection.
Adult↗
Salmonella infection in an anterior mediastinal mass.
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Abscess↗
Phase III intergroup study of talc poudrage vs talc slurry sclerosis for malignant pleural effusion.
STUDY OBJECTIVE: To demonstrate the efficacy, safety, and appropriate mode of instillation of talc for sclerosis in treatment of malignant pleural effusions (MPEs). DESIGN: A prospective, randomized trial was designed to compare thoracoscopy with talc insufflation (TTI) to thoracostomy and talc slurry (TS) for patients with documented MPE. MEASUREMENTS: The primary end point was 30-day freedom from radiographic MPE recurrence among surviving patients whose lungs initially re-expanded > 90%. Morbidity, mortality, and quality of life were also assessed. RESULTS: Of 501 patients registered, those eligible were randomized to TTI (n = 242) or TS (n = 240). Patient demographics and primary malignancies were similar between study arms. Overall, there was no difference between study arms in the percentage of patients with successful 30-day outcomes (TTI, 78%; TS, 71%). However, the subgroup of patients with primary lung or breast cancer had higher success with TTI than with TS (82% vs 67%). Common morbidity included fever, dyspnea, and pain. Treatment-related mortality occurred in nine TTI patients and seven TS patients. Respiratory complications were more common following TTI than TS (14% vs 6%). Respiratory failure was observed in 4% of TS patients and 8% of TTI patients, accounting for five toxic deaths and six toxic deaths, respectively. Quality-of-life measurement demonstrated less fatigue with TTI than TS. Patient ratings of comfort and safety were also higher for TTI, but there were no differences on perceived value or convenience of the procedures. CONCLUSIONS: Both methods of talc delivery are similar in efficacy; TTI may be better for patients with either a lung or breast primary. The etiology and incidence of respiratory complications from talc need further exploration.
Adult↗