transforming-growth-factor-beta and Carcinoma--Large-Cell

Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and a dismal prognosis. To identify and functionally characterize genes involved in the mechanisms of osseous metastasis, we developed a murine lung cancer model. Comparative transcriptomic analysis identified genes encoding signaling molecules (such as TCF4 and PRKD3) and cell anchorage-related proteins (MCAM and SUSD5), some of which were basally modulated by transforming growth factor-beta (TGF-beta) in tumor cells and in conditions mimicking tumor-stromal interactions. Triple gene combinations induced not only high osteoclastogenic activity but also a marked enhancement of global metalloproteolytic activities in vitro. These effects were strongly associated with robust bone colonization in vivo, whereas this gene subset was ineffective in promoting local tumor growth and cell homing activity to bone. Interestingly, global inhibition of metalloproteolytic activities and simultaneous TGF-beta blockade in vivo led to increased survival and a remarkable attenuation of bone tumor burden and osteolytic metastasis. Thus, this metastatic gene signature mediates bone matrix degradation by a dual mechanism of induction of TGF-beta-dependent osteoclastogenic bone resorption and enhancement of stroma-dependent metalloproteolytic activities. Our findings suggest the cooperative contribution of host-derived and cell autonomous effects directed by a small subset of genes in mediating aggressive osseous colonization.

Topics: Animals; Bone Neoplasms; Bone Resorption; Carcinoma, Large Cell; Carcinoma, Squamous Cell; Cell Line, Tumor; Extracellular Matrix; Gene Expression Profiling; Humans; Lung Neoplasms; Matrix Metalloproteinases; Mice; Mice, Nude; Osteoclasts; Stromal Cells; Transforming Growth Factor beta

Betaig-h3 as a secreted protein induced by transforming growth factor-beta has been suggested to modulate cell adhesion and tumor formation. Although we have previously shown that downregulation of Betaig-h3 gene is involved in the cellular transformation of human bronchial epithelial cells induced by radiation, its regulation in primary human lung cancers is not clearly understood. In this study, Betaig-h3 expression was studied in 130 primary human lung carcinomas by immunohistochemistry. Betaig-h3 protein was absent or reduced by more than two-fold in 45 of 130 primary lung carcinomas relative to normal lung tissues examined. Recovery of Betaig-h3 expression in H522 lung cancer cells lacking endogenous Betaig-h3 protein significantly suppressed their in vitro cellular growth and in vivo tumorigenicity. In addition, parental H522 cancer cells are resistant to the etoposide induced apoptosis compared with normal human bronchial epithelial cells. However, recovery of Betaig-h3 expression in H522 cancer cells results in significantly higher sensitivity to apoptotic induction than parental tumor cells. IGFBP3 is upregulated in Betaigh3-transfected H522 cells that may mediate the apoptotic sensitivity and antitumor function of Betaig-h3 gene. These observations demonstrate that downregulation of Betaig-h3 gene is a frequent event and related to the tumor progression in human lung cancer.

Topics: Adenocarcinoma; Animals; Apoptosis; Carcinogenicity Tests; Carcinoma, Large Cell; Extracellular Matrix Proteins; Gene Expression Regulation, Neoplastic; Humans; Insulin-Like Growth Factor Binding Protein 3; Lung Neoplasms; Mice; Mice, Nude; Phenotype; Transfection; Transforming Growth Factor beta; Up-Regulation

Transforming growth factor-beta1 (TGF-beta1) functions as a suppressor of tumor initiation by inhibiting cellular proliferation or by promoting cellular differentiation or apoptosis in the early phase of cancer development. Variations in the DNA sequence in the TGF-beta1 gene may lead to altered TGF-beta1 production and/or activity, and so this can modulate an individual's susceptibility to lung cancer. To test this hypothesis, we investigated the association of the TGF-beta1 -509C > T and 869T > C (L10P) polymorphisms and their haplotypes with the risk of lung cancer in a Korean population.. The TGF-beta1 genotypes were determined in 432 lung cancer patients and in 432 healthy control subjects who were frequency-matched for age and gender. The TGF-beta1 haplotypes were predicted using a Bayesian algorithm in the Phase program.. Individuals with at least one -509T allele were at a significantly decreased risk of adenocarcinoma (AC) and small cell carcinoma (SM), as compared with carriers with the -509CC genotype [adjusted odds ratio (OR), 0.63; 95% confidence interval (CI), 0.42-0.96; P = 0.04; and adjusted OR, 0.45; 95% CI, 0.27-0.76; P = 0.002; respectively]. For the 869T > C polymorphism, the combined TC + CC genotype was associated with a significantly decreased risk of SM compared with the TT genotype (adjusted OR, 0.52; 95% CI, 0.31-0.88; P = 0.01). Consistent with the results of the genotyping analyses, the -509T/869C haplotype was associated with a significantly decreased risk of AC and SM as compared with the -509C/869T haplotype (adjusted OR, 0.75; 95% CI, 0.57-0.98; P = 0.04; and adjusted OR, 0.67; 95% CI, 0.47-0.96; P = 0.02; respectively).. The TGF-beta1 -509C > T and 869T > C polymorphisms and their haplotypes may contribute to genetic susceptibility to AC and SM of the lung.

Topics: Adenocarcinoma; Carcinoma, Large Cell; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Case-Control Studies; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Lung Neoplasms; Male; Middle Aged; Polymorphism, Genetic; Risk Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

Plasma transforming growth factor-beta1 (TGFbeta1) levels are increased in many malignancies at the time of diagnosis, including all forms of lung carcinoma. Therefore, the potential use of TGFbeta1 as a plasma marker to predict the long term outcome of lung carcinoma patients treated with radiotherapy (RT) was evaluated.. Plasma samples for 59 newly diagnosed lung carcinoma patients were assayed for TGFbeta1 before RT (pre RT), at the end of RT (end RT), and during follow-up after RT. TGFbeta1 was extracted from plasma using an acid-ethanol method. An enzyme-linked immunoadsorbent assay was used to quantify the plasma TGFbeta1 levels. The normal value for this assay is < or =7.5 ng/mL. Disease status at last follow-up was without knowledge of TGFbeta1 levels. Comparisons within groups and between groups were estimated using analysis of variance and the Student t test for unpaired data, respectively.. The 59 patients were divided into 2 groups according to their disease status at last follow-up: those with no evidence of disease (NED) (n = 13) and those with disease (WD) (n = 46). The median follow up was 26.8 months and 12.4 months, respectively, for the NED and WD groups. No significant differences were found in the clinical characteristics between the two groups. The plasma TGFbeta1 level before RT was significantly higher in the WD group (mean +/- standard error of the mean [SEM] = 12.5+/-1.7 ng/mL; median = 8.6 ng/mL) compared with the NED group (mean +/- SEM = 6.0+/-1.0 ng/mL; median = 6.0 ng/mL) (P = 0.037). At the time of last follow-up, WD patients had a significantly higher plasma TGFbeta1 level (mean +/- SEM = 11.6+/-1.3 ng/mL; median = 9.6 ng/mL) compared with NED patients (mean +/- SEM = 3.7+/-0.5 ng/mL; median = 3.6 ng/mL) (P = 0.002).. These data demonstrate that plasma TGFbeta1 may be a useful tumor marker in patients with lung carcinoma.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Case-Control Studies; Disease-Free Survival; Female; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Prognosis; Transforming Growth Factor beta