transforming-growth-factor-beta and Adenocarcinoma--Bronchiolo-Alveolar

The histologic distinction between bronchioloalveolar carcinoma and other adenocarcinomas is tissue invasion. The clinical importance of lung adenocarcinoma invasion is supported by several recent studies indicating that the risk of death in nonmucinous bronchioloalveolar carcinoma is significantly lower than that of pure invasive tumors and in tumors with greater than 0.5 cm of fibrosis or linear invasion. Using microarray gene expression profiling of human tumors, dysregulation of transforming growth factor-beta signaling was identified as an important mediator of tumor invasion. Subsequent studies showed that the CC chemokine regulated on activation, normal T cell expressed, and presumably secreted was up-regulated in invasive tumors and was required for invasion in cells with repressed levels of the transforming growth factor-beta type II receptor. Taken together, these studies illustrate how information gained from global expression profiling of tumors can be used to identify key pathways and genes mediating tumor growth, invasion, and metastasis.

Topics: Adenocarcinoma, Bronchiolo-Alveolar; Chemokine CCL5; Gene Expression Profiling; Genomics; Humans; Lung Neoplasms; Microarray Analysis; Neoplasm Invasiveness; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; Signal Transduction; Transforming Growth Factor beta

Transforming growth factor beta (TGF-β) is a typical immuno-inhibitory cytokine and highly secreted by lung cancer cells. It was supposed that its immunosuppressive effects to NK cell might be related with the altered expression of activating and inhibitory molecules in lung cancer cells. In this study, we examined the expression of NKG2DLs, PD-L1 and PD-L2 in lung cancer cells after treatment of TGF-β and a TGF-β inhibitor, Galunisertib (LY2157299).. TGF-β reduced the level of surface proteins of five NKG2DLs without altered transcription levels in lung cancer cells. Galunisertib reversed the effect of TGF-β on the expression of NKG2DLs. Since MMP inhibitors, MMPi III and MMP2 inhibitor I, restored the reduced expression of NKG2DLs after treatment of TGF-β, it was thought that TGF-β induced the expression of MMP2 which facilitated the shedding of the NKG2DLs in cancer cells. However, the expression of PD-L1, L2 were not changed by treatment with TGF-β or Galunisertib.. Therefore, inhibition of TGF-β might reverse the immunosuppressive status on immune cells and restore NK cell mediated anticancer immune responses by upregulation of NKG2DLs in cancer cells.

Topics: A549 Cells; Adenocarcinoma, Bronchiolo-Alveolar; Cytotoxicity, Immunologic; Down-Regulation; GPI-Linked Proteins; Humans; Immune Tolerance; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Killer Cells, Natural; Lung Neoplasms; Pyrazoles; Quinolines; Transforming Growth Factor beta; Tumor Escape

Acquisition of mesenchymal phenotype by epithelial cells by means of epithelial-mesenchymal transition (EMT) is considered as an early event in the multistep process of tumor metastasis. Therefore, inhibition of EMT might be a rational strategy to prevent metastasis.. Using the global gene expression profile from a cell culture model of transforming growth factor-β (TGF-β)-induced EMT, we identified potential EMT inhibitors. We used a publicly available database (www.broad.mit.edu/cmap) comprising gene expression profiles obtained from multiple different cell lines in response to various drugs to derive negative correlations to EMT gene expression profile using Connectivity Map, a pattern matching tool.. Experimental validation of the identified compounds showed rapamycin as a novel inhibitor of TGF-β signaling along with 17-AAG, a known modulator of TGF-β pathway. Both of these compounds completely blocked EMT and the associated migratory and invasive phenotype. The other identified compound, LY294002, demonstrated a selective inhibition of mesenchymal markers, cell migration and invasion, without affecting the loss of E-cadherin expression or Smad phosphorylation.. Our data reveal that rapamycin is a novel modulator of TGF-β signaling, and along with 17-AAG and LY294002, could be used as therapeutic agent for inhibiting EMT. This study demonstrates the potential of a systems approach in identifying novel modulators of a complex biological process.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Benzoquinones; Biomarkers, Tumor; Blotting, Western; Cadherins; Cell Movement; Chromones; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Gene Expression Profiling; HSP90 Heat-Shock Proteins; Humans; Immunosuppressive Agents; Lactams, Macrocyclic; Lung Neoplasms; Morpholines; Oligonucleotide Array Sequence Analysis; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction; Sirolimus; Smad Proteins; Transcription, Genetic; Transforming Growth Factor beta; Tumor Cells, Cultured

The antitumor efficiency of secondary lymphoid organ chemokine (SLC), a CC chemokine that chemoattracts both dendritic cells (DCs) and T lymphocytes,was evaluated in SV40 large T-antigen transgenic mice that develop bilateral multifocal pulmonary adenocarcinomas. Injection of recombinant SLC in the axillary lymph node region led to a marked reduction in tumor burden with extensive lymphocytic and DC infiltration of the tumors and enhanced survival. SLC injection led to significant increases in CD4 and CD8 lymphocytes as well as DC at the tumor sites, lymph nodes, and spleen. The cellular infiltrates were accompanied by the enhanced elaboration of Type 1 cytokines and the antiangiogenic chemokines IFN-gamma inducible protein 10, and monokine induced by IFN-gamma (MIG). In contrast, lymph node and tumor site production of the immunosuppressive cytokine transforming growth factor beta was decreased in response to SLC treatment. In vitro, after stimulation with irradiated autologous tumor, splenocytes from SLC-treated mice secreted significantly more IFN-gamma and granulocyte macrophage colony-stimulating factor, but reduced levels of interleukin 10. Significant reduction in tumor burden in a model in which tumors develop in an organ-specific manner provides a strong rationale for additional evaluation of SLC in regulation of tumor immunity and its use in lung cancer immunotherapy.

Topics: Adenocarcinoma, Bronchiolo-Alveolar; Angiogenesis Inhibitors; Animals; Antigens, Polyomavirus Transforming; Chemokine CCL21; Chemokines; Chemokines, CC; Cytokines; Dendritic Cells; Disease Models, Animal; Endothelial Growth Factors; Lung Neoplasms; Lymph Nodes; Lymphokines; Mice; Mice, Transgenic; Neovascularization, Pathologic; Recombinant Proteins; Spleen; T-Lymphocytes; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The distribution of the three isoforms of transforming growth factor (TGF)-beta (TGF-beta 1, -beta 2, and -beta 3) as well as their signaling receptor, TGF-beta type I receptor (T beta R-I), in bronchiolo-alveolar cell hyperplasia (BAH) and bronchiolo-alveolar carcinoma (BAC) was examined by immunohistochemistry using specific antibodies. The results showed that the expression of one or more TGF-beta subtypes occurred in a large proportion of BAC and BAH tissues. The expression of TGF-beta 1 and TGF-beta 3 was increased in tumor cells compared with hyperplastic cells. BAC with expression of two or three ligands was associated with a higher incidence of lymph node metastasis. These results suggest that hyperplastic cells and cancer cells derived from bronchiolo-alveolar cell can synthesize and secrete TGF-beta isoforms and its receptor T beta R-I which may contribute to the progression of BAC in part.

Topics: Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Bronchi; Female; Humans; Hyperplasia; Lung Neoplasms; Male; Middle Aged; Pulmonary Alveoli; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta