Expression of eukaryotic translation initiation factors 4E and 2alpha is increased frequently in bronchioloalveolar but not in squamous cell carcinomas of the lung.

BACKGROUND: When resting cells are stimulated by growth factors, an increase in protein synthesis follows that depends in part on two key eukaryotic translation initiation factors, 4E and 2alpha (eIF-4E and eIF-2alpha, respectively). In the normal cell, expression and activity of both factors are increased transiently, whereas they become elevated constitutively in oncogene-transformed cultured cells, and overexpression of either initiation factor in rodent cells makes them tumorigenic. In this study, the authors investigated an association between the expression of these translation initiation factors and lung carcinogenesis. METHODS: The authors analyzed the expression of the protein synthesis initiation factors eIF-4E and eIF-2alpha by immunohistochemistry in bronchioloalveolar (BA) and squamous cell (SC) carcinomas of the lung. Western blot analysis was performed to validate the specificity of antibodies in detecting their cognate proteins. RESULTS: Both eIF-4E and eIF-2alpha were increased frequently in BA carcinomas, whereas only rarely did SC carcinomas demonstrate elevation of these translation initiation factors. An analysis of cyclin D1 expression did not show a strict correlation with the expression of eIF-4E and eIF-2alpha. CONCLUSIONS: Increased expression of either one or both translation initiation factors may facilitate accelerated growth and division of neoplastic cells in BA carcinoma of the lung. However, the current findings suggest a possibility that increased cell growth and proliferation in SC carcinoma may be achieved through a mechanism independent of increases in eIF-4E and eIF-2alpha expression.

Expression of eukaryotic translation initiation factors 4E and 2alpha correlates with the progression of thyroid carcinoma.

Cell growth and proliferation depend on protein synthesis that is regulated, in part, by two eukaryotic translation initiation factors, eIF-4E and eIF-2alpha. These factors are transiently increased as normal cells respond to growth factors and are constitutively elevated in transformed cells. In cultured cells, eIF-4E facilitates cell cycle progression by increasing the expression of cell cycle promoting proteins including cyclin D1. Our previous study revealed elevated cyclin D1 expression in histologically more aggressive thyroid carcinomas as compared to conventional papillary carcinoma. We hypothesized that the increased cyclin D1 expression might correlate with increased eIF-4E expression. We, therefore studied the expression of eIF-4E by immunohistochemistry in 25 cases of conventional papillary carcinoma (CPC) and 28 cases of aggressive thyroid carcinomas (ATC), the latter included 11 tall cell/columnar cell variant of papillary carcinoma, 5 insular carcinomas, and 12 anaplastic carcinomas. We also analyzed the expression of eIF-2a in the same samples as this factor is usually regulated similarly to eIF-4E in cell culture models. Of the 25 CPC, 13 were eIF-4E positive (11 weakly and 2 strongly), and 19 were eIF-2a positive (14 weakly and 5 strongly). Conversely, of the 28 ATC, 25 were eIF-4E positive (4 weakly and 21 strongly), and 23 were eIF-2alpha positive (4 weakly and 19 strongly). There was a significantly increased expression of both eIF-4E (p < 0.001) and eIF-2alpha (p < 0.001) in ATC compared to CPC, suggesting that these translation initiation factors may play a role in the progression of thyroid cancer.

The role of cell cycle regulatory protein, cyclin D1, in the progression of thyroid cancer.

Cell cycle progression is facilitated by cyclin-dependent kinases that are activated by cyclins including cyclin D1 and inactivated by cyclin-dependent kinase inhibitors (CDKIs) such as p27. Our previous studies have demonstrated decreased p27 expression in both papillary and more aggressive carcinomas of the thyroid compared to thyroid adenoma and almost similar level of cyclin D1 expression between thyroid adenoma and papillary carcinoma. These results indicate that CDKIs may have an important role in the carcinogenesis of the thyroid and that they probably have a limited role in malignant progression of the thyroid cancer. The role of cyclin D1 in malignant progression of thyroid carcinoma has yet to be established. We studied the expression of cyclin D1 by immunohistochemistry in 34 cases of conventional papillary carcinoma (CPC), 10 cases of minimally invasive follicular carcinoma (MIFC), and 32 cases of more aggressive thyroid carcinoma (ATC), which included 11 tall cell variants, one columnar cell variant of papillary carcinoma, seven insular carcinomas, and 13 anaplastic carcinomas. Cyclin D1 staining was classified by staining score as 0, negative; 1+, less than 25%; 2+, 25 to 50%; and 3+, more than 50% tumor cells staining positive. Kruskal-Wallis one-way ANOVA and Wilcoxon Rank Sum/Mann-Whitney U Test was used to assess the difference in the expression of cyclin D1 between the study groups. Twenty-eight out of the 34 CPCs were cyclin D1 positive, 24 (70%) were 1+, 3 (9%) were 2+, and one (3%) were 3+ positive. Seven of 10 MIFCs were cyclin D1 positive, five (71%) were 1+, and the remaining two (29%) were 2+ positive. On the other hand, 28 of 32 ATCs showed cyclin D1 immunostaining. Of these, three (9%) were 1+, five (13%) were 2+, and 20 (63%) were 3+ positive. This study demonstrates a significant overexpression of cyclin D1 in ATC compared CPC (P < .001) and MIFC (P < .005), suggesting that the cyclin D1 expression may play a role in tumor progression and may have prognostic significance in thyroid cancer.

Superior vena cava syndrome secondary to an angiotropic large cell lymphoma.

BACKGROUND: Angiotropic large cell lymphoma (ALCL) is characterized by the intravascular proliferation of malignant lymphoid cells in small and medium-sized blood vessels. In the current study, the authors report an unusual case in which the initial presentation of the ALCL was that of superior vena cava (SVC) syndrome. METHODS: The case is presented, followed by a general review of the literature regarding ALCL. RESULTS: Surgical intervention was required for diagnosis in this case. Successful treatment with chemotherapy followed by involved field radiation ensued with a maintained disease remission at 48 months of follow-up. CONCLUSIONS: Although usually presenting in small blood vessels, ALCL can present initially with large blood vessel involvement and should be considered in the differential diagnosis of this condition, even in the absence of extravascular lymph node involvement. Aggressive treatment with antineoplastic therapy is warranted and may result in long term recurrence free survival.

Expression of the eukaryotic translation initiation factors 4E and 2alpha in non-Hodgkin's lymphomas.

Transition of cells from quiescence to proliferation requires an increase in the rate of protein synthesis, which is regulated in part by two key translation initiation factors, 4E and 2alpha. The expression and activity of both factors are increased transiently when normal resting cells are stimulated to proliferate. They are constitutively elevated in oncogene transformed cultured cells, and overexpression of either initiation factor in rodent cells makes them tumorigenic. In this study we investigate an association between the expression of translation initiation factors and lymphomagenesis. We have analyzed the expression of the protein synthesis initiation factors 4E and 2alpha by immunohistochemistry in reactive lymph nodes and several types of non-Hodgkin's lymphoma representing a wide range of clinical behaviors based on the Revised European-American Lymphoma behavioral classification. The study included 7 benign lymph nodes with follicular hyperplasia, 26 indolent lymphomas (6 marginal zone lymphomas, 7 small lymphocytic lymphomas, and 13 follicular lymphomas, grades 1 and 2), 16 moderately aggressive lymphomas (8 mantle cell lymphomas and 8 follicular lymphomas, grade 3), 24 aggressive lymphomas (14 large-B-cell lymphomas and 10 anaplastic large-cell lymphomas), and 15 highly aggressive lymphomas (7 lymphoblastic lymphomas and 8 Burkitt's lymphomas). Strong expression of initiation factors 4E and 2alpha was demonstrated in the germinal centers of reactive follicles. Minimal or no expression was seen in the mantle zones and surrounding paracortices, indicating that high expression of initiation factors 4E and 2alpha is associated with the active proliferation of lymphocytes. Most cases of aggressive and highly aggressive lymphomas showed strong expression of initiation factors 4E and 2alpha, in contrast to the cases of indolent and moderately aggressive lymphoma, in which their expression was intermediate between the germinal centers and the mantles of reactive follicles. A positive correlation was found between the expression of both initiation factors 4E and 2alpha and the Revised European-American Lymphoma behavior classification (P < 0.05). Thus, constitutively increased expression of initiation factors 4E and 2alpha may play an important role in the development of lymphomas and is correlated with their biological aggressiveness.

Electrical resonance of isolated hair cells does not account for acoustic tuning in the free-standing region of the alligator lizard's cochlea.

The cochlea of the alligator lizard is divided into two morphologically and physiologically distinct regions. In the "tectorial region," hair bundles of hair cells are draped by a tectorial membrane, whereas in the "free-standing region," hair bundles are said to be free-standing because there are no overlying tectorial structures. The acoustic tuning of the free-standing region depends at least in part on mechanical resonances of the hair bundles. In the turtle cochlea, in contrast, acoustic tuning depends in large part upon the electrical properties of the hair cells. We have investigated the electrical properties of hair cells isolated from the free-standing region of the alligator lizard's cochlea. When injected with steps of depolarizing current, these "free-standing hair cells" exhibited electrical resonances that were comparable in frequency and quality to electrical resonances in cochlear hair cells from turtles, chicks, and alligators, and in saccular hair cells from frogs and fish. In the lizard's free-standing hair cells, however, the electrical resonance frequencies (< 300 Hz) were a decade below the cells' acoustic characteristic frequencies (between 1 and 4 kHz), showing that the electrical resonance is not likely to contribute to acoustic tuning. The electrical resonances were not apparent at rest. The cells' resting potentials were significantly more negative than the activation voltage (approximately -40 mV) of the Ca(2+)-dependent K+ current upon which the electrical resonance has been shown to depend in other hair cells. At potentials more negative than -50 mV, an inwardly rectifying K+ conductance dominated. Because we observed no electrical tuning above 300 Hz, our results indirectly support a mechanical origin for acoustic tuning in the free-standing region of the alligator lizard cochlea. These results further show that acoustic tuning cannot be inferred solely from the electrical resonances of isolated hair cells.