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62 tubular, papillary, mixed adenomas and car- cinomas. The larger mixed-pattern neoplasms and small or large tubular neoplasms usual- ly had the least number of cells with SAP. The majority of large papillary adenomas and carcinomas in BALB/c mice exposed to ENU and in untreated A strain mice contain- ed SAP in the nuclei of many neoplastic but only in the cytoplasm of a few neoplastic cells. CCA was found in normal Clara cells of bronchi and bronchioles but not in any hyperplastic or neoplastic lesion of any mouse studied. This study provided immuno- cytochemical evidence that the vast majo- rity of naturally occurring and experimen- tally induced pulmonary neoplasms of mice are alveolar Type II cell adenomas and carcinomas. Oxidative Properties of 12-O-Tetradecanoyl- phorbol-13-Acetate-Stimulated Human Blood Monomorphonuclear Leukocytes and Their Tox- icity Against a Human Lung Carcinoma Cell Line. Gescher, A., Brodie, A.E., Reed, D.J. Can- cer Research Campaign Experimental Chemo- therapy Group, Department of Pharmacy, Uni- versity of Aston, Birmingham B4 7ET, United Kingdom. Cancer Res. 45: 1638-1643, 1985. Human monomorphonuclear leukocytes (M/~s) stimulated with 12-0-tetradecanoylphorbol- 13-acetate (TPA) were found to be toxic towards human A549 lung carcinoma cells which have been desensitized against the direct growth-inhibitory effect of TPA. This toxicity was dependent on the TPA concen- tration and the ratio of MMNs to A549 cells. Using a TPA concentration of 10sup -sup 7 M and an effector: target cell ratio of 30:1, experiments were performed to give clues as to the mechanisms by which TPA- stimulated MMNs cause toxicity. Levels of the endogenous thiol glutathione were re- duced by 37% in MMNs exposed to TPA for 24 h, but the glutathione levels in the A549 target cells were not markedly af- fected by TPA-stimulated MMNs. The superna- tant of incubations of MMNs with TPA con- tained a species which was capable of oxi- dizing the thiol agent 5-thio-2-nitroben- zoic acid. Within 2 h, 9 nmol of this oxi- dant were produced by 10sup 7 MMNs. The oxidant exhibited a half-life of 20 h, and its formation was abolished by adding ca- talase (150 units/ml), azide (i m M), or cyanide (i mM) to the incubations of MMNs with TPA. The addition of superoxide dis- mutase (i00 units/ml) enhanced oxidant for- mation. These results indicate that its generation was dependent on the myeloperox- idase: Hsub 20sub 2: halide system. Large amounts of an oxidizing species with pro- perties identical to those described here have been characterized recently in poly- morphonuclear leukocytes (S.J. Weiss, M.B. Lampert, and S.T. Test. Science (Wash. DC), 222: 626-627, 1983). The toxicity exerted by TPA-sti- mulated MMNs was partially inhibited by super- oxide dismutase and by retinoic acid (30 muM) but not at all by catalase, azide, or cyanide. Therefore, the 5-thio-2-nitrobenzoic acid oxi- dant does not appear to be involved in the pro- cess which led to cytotoxicity by TPA-stimula- ted MMNs in A549 cells. Intermediate Filament and Cross-Linked Envelope Expression in Human Lung Tu~or Cell Lines. Banks-Schlegel, S.P., Gazdar, A.F., Harris, C.C. Laboratory of Human Carcinogenesis, Division of Cancer Etiology, National Cancer Institute, Bethesda, MD 20205, U.S.A. Cancer Res. 45: 1187- 1197, 1985. Human lung tumor cell lines established from the major histological types of lung cancer were examined by immunofluorescent staining techni- ques for their patterns of intermediate filament (keratin, vimentin, and neurofilament triplet protein) expression. All cell lines examined, both small cell lung carcinoma (SOLC) and non- SCLC (squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and mesothelioma) contain- ed keratin, consistent with their epithelial derivation. These lung carcinoma cell lines also expressed vimentin, the characteristic in- termediate filament of mesenchymal cells in vivo. In light of the proposed neuroectodermal origin of SCLC, cell lines were also studied for neuro- filament expression. Two of four SCLC tumor cell lines, as well as non-SCLC cell lines~ showed no reactivity with antibodies to neuro- filament triplet protein. Two of the SCLC cell lines stained weakly with anti-neurofilament antibody. Examination of specific keratin pat- terns in human lung tumor cell lines by selecti- ve immunoprecipitation with keratin antiserum and sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that small-sized kera- tin proteins (M(r) 44,000 to 52,000) were present in cell lines derived from SCLC and non-SCLC types of lung cancer. Tumor cell lines exhibi- ting squamous differentiation by light micro- scopic criteria (i.e., intracellular keratin, intercellular bridging, "pearl" formation, and/ or individual cell keratinization) also dis- played a preponderance on intermediate-sized keratins (M(r) 57,000 and 59,000) and exhibited another feature of terminal keratinocyte diffe- rentiation (cross-linked envelope formation). Mesothelioma cell lines had varying keratin profiles. The presence of keratin proteins in all SCLC cell lines examined argues against a neuroectodermal origin for these tumors and is consistent with the notion that these tumors arise from a common bronchial "Stem cell", si- milar to that from which other types of bron- chogenic carcinomas arise. Human Papillomavirus Type 16 Related DNA in an Anaplastic Carcinoma of the Lung. Stremlau, A., Gissmann, L., Ikenberg, H., et al.

Human papillomavirus type 16 related DNA in an anaplastic carcinoma of the lung

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62

tubular, papillary, mixed adenomas and car- cinomas. The larger mixed-pattern neoplasms

and small or large tubular neoplasms usual- ly had the least number of cells with SAP. The majority of large papillary adenomas and carcinomas in BALB/c mice exposed to ENU and in untreated A strain mice contain- ed SAP in the nuclei of many neoplastic but only in the cytoplasm of a few neoplastic cells. CCA was found in normal Clara cells of bronchi and bronchioles but not in any hyperplastic or neoplastic lesion of any mouse studied. This study provided immuno- cytochemical evidence that the vast majo- rity of naturally occurring and experimen- tally induced pulmonary neoplasms of mice are alveolar Type II cell adenomas and carcinomas.

Oxidative Properties of 12-O-Tetradecanoyl- phorbol-13-Acetate-Stimulated Human Blood Monomorphonuclear Leukocytes and Their Tox- icity Against a Human Lung Carcinoma Cell Line. Gescher, A., Brodie, A.E., Reed, D.J. Can- cer Research Campaign Experimental Chemo- therapy Group, Department of Pharmacy, Uni- versity of Aston, Birmingham B4 7ET, United Kingdom. Cancer Res. 45: 1638-1643, 1985.

Human monomorphonuclear leukocytes (M/~s) stimulated with 12-0-tetradecanoylphorbol- 13-acetate (TPA) were found to be toxic towards human A549 lung carcinoma cells which have been desensitized against the direct growth-inhibitory effect of TPA. This toxicity was dependent on the TPA concen- tration and the ratio of MMNs to A549 cells. Using a TPA concentration of 10sup -sup 7 M and an effector: target cell ratio of 30:1, experiments were performed to give clues as to the mechanisms by which TPA- stimulated MMNs cause toxicity. Levels of the endogenous thiol glutathione were re- duced by 37% in MMNs exposed to TPA for 24 h, but the glutathione levels in the A549 target cells were not markedly af- fected by TPA-stimulated MMNs. The superna- tant of incubations of MMNs with TPA con- tained a species which was capable of oxi- dizing the thiol agent 5-thio-2-nitroben- zoic acid. Within 2 h, 9 nmol of this oxi- dant were produced by 10sup 7 MMNs. The oxidant exhibited a half-life of 20 h, and its formation was abolished by adding ca- talase (150 units/ml), azide (i m M), or cyanide (i mM) to the incubations of MMNs with TPA. The addition of superoxide dis- mutase (i00 units/ml) enhanced oxidant for- mation. These results indicate that its generation was dependent on the myeloperox- idase: Hsub 20sub 2: halide system. Large amounts of an oxidizing species with pro- perties identical to those described here have been characterized recently in poly-

morphonuclear leukocytes (S.J. Weiss, M.B.

Lampert, and S.T. Test. Science (Wash. DC), 222:

626-627, 1983). The toxicity exerted by TPA-sti- mulated MMNs was partially inhibited by super- oxide dismutase and by retinoic acid (30 muM) but not at all by catalase, azide, or cyanide. Therefore, the 5-thio-2-nitrobenzoic acid oxi- dant does not appear to be involved in the pro- cess which led to cytotoxicity by TPA-stimula- ted MMNs in A549 cells.

Intermediate Filament and Cross-Linked Envelope Expression in Human Lung Tu~or Cell Lines. Banks-Schlegel, S.P., Gazdar, A.F., Harris, C.C. Laboratory of Human Carcinogenesis, Division of Cancer Etiology, National Cancer Institute, Bethesda, MD 20205, U.S.A. Cancer Res. 45: 1187- 1197, 1985.

Human lung tumor cell lines established from the major histological types of lung cancer were examined by immunofluorescent staining techni- ques for their patterns of intermediate filament (keratin, vimentin, and neurofilament triplet protein) expression. All cell lines examined, both small cell lung carcinoma (SOLC) and non- SCLC (squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and mesothelioma) contain- ed keratin, consistent with their epithelial derivation. These lung carcinoma cell lines also expressed vimentin, the characteristic in- termediate filament of mesenchymal cells in vivo. In light of the proposed neuroectodermal origin of SCLC, cell lines were also studied for neuro- filament expression. Two of four SCLC tumor cell lines, as well as non-SCLC cell lines~ showed no reactivity with antibodies to neuro- filament triplet protein. Two of the SCLC cell lines stained weakly with anti-neurofilament antibody. Examination of specific keratin pat- terns in human lung tumor cell lines by selecti- ve immunoprecipitation with keratin antiserum and sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that small-sized kera- tin proteins (M(r) 44,000 to 52,000) were present in cell lines derived from SCLC and non-SCLC types of lung cancer. Tumor cell lines exhibi- ting squamous differentiation by light micro- scopic criteria (i.e., intracellular keratin, intercellular bridging, "pearl" formation, and/ or individual cell keratinization) also dis- played a preponderance on intermediate-sized keratins (M(r) 57,000 and 59,000) and exhibited another feature of terminal keratinocyte diffe- rentiation (cross-linked envelope formation). Mesothelioma cell lines had varying keratin profiles. The presence of keratin proteins in all SCLC cell lines examined argues against a neuroectodermal origin for these tumors and is consistent with the notion that these tumors arise from a common bronchial "Stem cell", si- milar to that from which other types of bron- chogenic carcinomas arise.

Human Papillomavirus Type 16 Related DNA in an Anaplastic Carcinoma of the Lung.

Stremlau, A., Gissmann, L., Ikenberg, H., et al.

63

Institut f~r Virusforschung, Deutsches Krebs- forschungszentrum, 6900 Heidelberg, Germany. Cancer 55: 1737-1740, 1985.

Twenty-four biopsy specimens from various histologic types of human carcinomas in the lung were analyzed for the presence of human papillomavirus (HPV) DNA. DNA from the indi- vidual specimens was tested for the presence of homologous sequences to HPV genotypes i, 2, 4, 8, 9, i0, ii, 13, 16 and 18. One ana- plastic carcinoma in the lung contained mul- tiple copies of DNA hybridizing under stringent conditions to HPV 16 DNA. The lat- ter DNA has been found to be frequently associated with human genital cancer (cer- vical, penile, and vilval cancer) and genital Howen's disease. The HPV 16 posi- tive lung tumor originated from a 61-year-old female patient who underwent hysterectomy due to cervical cancer 9 years earlier.

Dimethyl Sulfoxide Induces Expression of H-2 Antigens on Mouse Lung Carcinoma Cells. Bahler, D.W., Lord, E.M. Department of Microbiology and Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, U.S.A.J. Immunol. 134: 2790-2798, 1985.

The addition of dimethyl sulfoxide (DMSO) to cultures of line 1 carcinoma cells can increase the surface expression of H-2K and H-2D antigens at least 100-fold from bare- ly detectable initial levels, as determined by using specific monoclonal antibodies and flow cytometry. H-2 values stabilize approx- imately 1 wk after exposure to maximally inducing concentrations of DMSO (3% vol) at densities found on normal spleen cells. Increased expression of H-2 antigens is not the result of cell selection, it is specific in that expression of an unrelated surface protein decreases, and it is associ- ated with increased synthesis of these an- tigens as measured by incorporation of (sup 3sup, 5S)methionine. Additonal DMSO- induced changes in the growth, cycling, lectin binding, and antigenic properties of line 1 cells are consistent with increa- sed cell maturation. All changes are rever- sed when DMSO is removed. This system may facilitate study of products associated with differentiation that influence tumor cell malignancy.

Selective Cytotoxicity of SMI Monoclonal Antibody Towards Small Cell Carcinoma of the Lung. Bernal, S.D., Mabry, M., Stahel, R.A., et al. Division of Medicine and Medical Onco- logy, Dana-Farber, Cancer Institute and Harvard Medical School, Boston, MA 02115, U.S.A. Cancer Res. 45: 1026-1032, 1985.

A murine monoclonal antibody, SMI, is strongly reactive with the surface membrane

of small cell carcinoma of the lung (i).

SMI antibody is unreactive with most other

cancers and various normal tissues including bone marrow cells. We now find that SMI anti- body is selectively cytotoxic to small cell carcinoma (SCC) in vitro. The antibody is pre- sent in high titers in supernatant fluids or ascites obtained by i.p. injection of SMI hy- bridoma cells into pristaned BALC/c mice. The cytotoxic effect of the antibody is reduced to one-half maximal activity only at dilutions greater than 1:40,000. The efficiency of tumor cell lysis is greater enhanced by repeated treatments with antibody and complement. Using three treatments with antibody and complement, 99.9% of SCC cells are lysed, as determined by the chromium release. Similar efficiency of SCC cell kill was observed by clonogenic assays. SMI antibody produces no significant antibody- dependent lysis of cell lines derived from non- SCC lung carcinomas and leukemia cells. The result from chromium release assay and clono- genic assays also indicate that the effect of SMI antibody and complement on bone marrow cells is minimal and could be accounted for by the effect of complement alone.

A 5p Deletion in Small Cell Lung Carcinoma. Falor, W.H., Ward-Skinner, R., Wegryn, S. Cyto- genetics Laboratory, Akron City Hospital, Akron, OH 44309, U.S.A. Cancer Genet. Cytogenet. 16: 175-177, 1985.

A specific chromosomal abnormality (3p del) was found in direct preparations from three small cell carcinomas of the lung: one prima- ry tumor and two metastatic tumors in media- stinal lymph nodes. This lends support to Whang-Peng et al.'s (3) detection of the dele- tion in tissue cultures.

Urinary Hypoxanthine and Pseudouridine as Indi- cators of T~or Development in Mesothelioma- Transplanted Nude Mice. Buhl, L., Dragsholt, C., Svendsen, P., et al. Department of Pathology, Odense University Hos- pital, Odense, Denmark. Cancer Res. 45: 1159- 1162, 1985.

A human mesothelioma was heterotransplan- ted to nude mice, and the urinary excretions of hypoxanthine, xanthine, pseudourifline, oro- tic acid, 7-methylguanine, and l-methylhypo- xanthine have been followed before and after the tumor transplantation. The compounds were measured by means of isotachophoresis, which has been found a rapid and precise method. The tumor reached maximum size within 30 days, and at this time a significantly increased excre- tion of pseudouridine and hypoxanthine was ob- served. Tumor growth was stopped by chemothe- rapy (vincristine, cyclophosphamide, predniso- lone, and adriamycin), and corresponding to this, a decrease occurred in both pseudouridi- ne and hypoxanthine excretion tO normal values.

I,~nunoreactive Neuron-Specific Enolase, Bombe-

sin, and Chromogranin as Markers for Neuro-