elastin and Carcinoma--Non-Small-Cell-Lung

Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary diseases, has been recently involved in non-small cell lung cancer progression. It can act at several levels (i) intracellularly, cleaving for instance the adaptor molecule insulin receptor substrate-1 (IRS-1) (ii) at the cell surface, hydrolyzing receptors as CD40 (iii) in the extracellular space, generating elastin fragments i.e. morphoelastokines which potently stimulate cancer cell invasiveness and angiogenesis. Since decades, researchers identified natural compounds and/or synthesized agents which antagonize HNE activity that will be described in this review article. Some of these compounds might be of value as therapeutic agents in lung cancer. However, it is now widely accepted that lung tumor invasion and metastasis involve proteolytic cascades. Accordingly, we will here mainly focus our attention to natural substances able to display a dual inhibitory capacity (i.e. lipids and derivatives, phenolics) towards HNE and matrix metalloproteinases (MMPs), particularly MMP-2. To that purpose, we recently synthesize substances named "LipoGalardin" (Moroy G. et al., Biochem. Pharmacol., 2011, 81(5), 626-635) exhibiting such inhibitory bifunctionality. At last, we will propose an original synthetic scheme for designing a potent biheaded HNE/MMP-2 inhibitor.

Topics: alpha 1-Antitrypsin; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; CD40 Antigens; Elastin; Enzyme Inhibitors; Humans; Insulin Receptor Substrate Proteins; Leukocyte Elastase; Lung Neoplasms; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Models, Molecular

Elastin is a signature protein of lungs. Increased elastin turnover driven by altered proteolytic activity is an important part of lung tumorigenesis. Elastin-derived fragments have been shown to be pro-tumorigenic, however, little is known regarding the biomarker potential of such elastin fragments. Here, we present an elastin turnover profile by non-invasively quantifying five specific elastin degradation fragments generated by different proteases.. Elastin fragments were assessed in serum from patients with stage I-IV non-small cell lung cancer (NSCLC) (n = 40) and healthy controls (n = 30) using competitive ELISAs targeting different protease-generated fragments of elastin: ELM12 (generated by matrix metalloproteinase MMP-9 and -12), ELM7 (MMP-7), EL-NE (neutrophil elastase), EL-CG (cathepsin G) and ELP-3 (proteinase 3).. ELM12, ELM7, EL-NE and EL-CG were all significantly elevated in NSCLC patients (n = 40) when compared to healthy controls (n = 30) (ELM12, p = 0.0191; ELM7, p < 0.0001; EL-NE, p < 0.0001; EL-CG, p < 0.0001). ELP-3 showed no significant difference between patients and controls (p = 0.8735). All fragments correlated positively (Spearman, r: 0.69-0.81) when compared pairwise, except ELM12 (Spearman, r: 0.042-0.097). In general, all fragments were detectable across all stages of the disease.. Elastin fragments generated by different proteases are elevated in lung cancer patients compared to healthy controls but differ in their presence. This demonstrates non-invasive biomarker potential of elastin fragments in serum from lung cancer patients and suggests that different pathological mechanisms may be responsible for the elastin turnover, warranting further validation in clinical trials.

Topics: Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Elastin; Female; Follow-Up Studies; Humans; Lung; Lung Neoplasms; Male; Middle Aged; Prognosis

Topics: A549 Cells; Administration, Inhalation; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Chitosan; Curcumin; Doxorubicin; Drug Carriers; Drug Liberation; Elastin; Humans; Hydrogen-Ion Concentration; Lung Neoplasms; Microspheres; Particle Size; Solubility

Non-small cell lung carcinoma (NSCLC) is a highly fibrotic malignancy, which exhibits a prominent desmoplastic stroma. Epithelial-mesenchymal transition (EMT) is one of the main modes of carcinoma invasion. We identified the stromal N-glycoprotein periostin by mass spectrometry of lung adenocarcinoma pleural effusions. Validation on a NSCLC tissue microarray and on tumor whole sections by immunohistochemistry indicated that periostin is strongly upregulated at the invasive front in both tumor epithelia and the surrounding matricellular space. In comparison to collagen, elastin and vimentin, periostin was found to be most closely associated with parameters of tumor progression such as larger size and higher stage, with the squamous cell histotype, and with decreased survival. An association with decreased survival was also found for the cell adhesion molecule L1CAM. In conclusion, enlargement of NSCLC tumors is associated with an increase of desmoplastic stroma and concomitant upregulation of EMT markers at the invasive front. The tumor-stroma interface may be a candidate topographic region for stroma- or EMT-directed therapy.

Topics: Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cell Adhesion Molecules; Collagen; Disease Progression; Disease-Free Survival; Elastin; Epithelial-Mesenchymal Transition; Humans; Lung; Lung Neoplasms; Mass Spectrometry; Neoplasm Invasiveness; Neural Cell Adhesion Molecule L1; Oligonucleotide Array Sequence Analysis; Up-Regulation; Vimentin

In carcinomas, invasive tumor growth is accompanied by desmoplastic stroma reaction and facilitated by epithelial-mesenchymal transition (EMT) of cancer cells. We investigated the prognostic significance of the EMT indicator proteins periostin and vimentin in comparison with versican, a putative indicator of the opposite mechanism mesenchymal-epithelial transition (MET), and to the desmoplasia proteins collagen and elastin in non-small cell lung cancer (NSCLC).. Tumor of 533 patients with surgically resected NSCLC was used for analysis of stromal and epithelial protein expression by immunohistochemistry (EMT-MET proteins) and Elastica van Gieson histochemical staining (collagen and elastin). A semiquantitative sum scoring system was done on three tissue microarrays.. Of the 533 patients, 48% had squamous cell carcinoma, 47% adenocarcinoma, and 5% adenosquamous carcinoma. High expression of periostin in either stroma or tumor epithelia, independently scored by two pathologists, correlated with male gender, higher stage, higher pT category, and larger tumor size, and in only stroma with tumor relapse. High expression of versican in either stroma or epithelia as well as of stromal collagen had fewer but concordant associations with advanced tumor and periostin, respectively. High expression of elastin was oppositely associated with less advanced disease. Associations of high vimentin were inconsistent (all P values < 0.05). High stromal periostin was found to be a prognostic factor for decreased progression-free survival on univariate analysis (P = 0.007).. Because up-regulation is frequently observed in the stromal and epithelial tumor compartment, EMT-MET indicator proteins may be integrated in progression models of NSCLC.

Topics: Age Factors; Aged; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cell Adhesion Molecules; Cell Differentiation; Collagen; Elastin; Epithelial Cells; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lung Neoplasms; Male; Mesoderm; Middle Aged; Prognosis; Sex Factors; Tissue Array Analysis; Versicans; Vimentin