Proliferation Of Normal Lung Fibroblasts Research Articles

Novel recombinant coxsackievirus B3 with genetically inserted basic peptide elicits robust antitumor activity against lung cancer.

Cancer therapy that utilizes oncolytic virus may offer an exciting alternative, and coxsackievirus B3 (CVB3) is a potent oncolytic virus. This study was to assess the oncolytic activities of novel recombinant CVB3 with genetically inserted basic peptides in lung cancer. Recombinant CVB3 was produced in Vero cells, with or without genetically inserted basic peptides. In vitro and in vivo experiments with nude mouse models bearing human lung carcinoma xenografts were performed to examine the antitumor activities. Cytokines and immune responses to the recombinant CVB3 were determined in cynomolgus monkeys. Recombinant CVB3 with genetically inserted basic peptides was associated with significantly higher pH values within tumors. Mice treated with recombinant CVB3 showed significantly less tumor progression, and recombinant CVB3 with genetically inserted basic peptides appeared to enhance tumor suppression. Recombinant CVB3 was associated with significantly less proliferation of various lung cancer cells without affecting proliferation of normal lung fibroblasts. The cytokine profiles of the cynomolgus monkeys were comparable among control group (normal saline solution) and those given recombinant CVB3 with or without fused basic peptides, with no induction of excessive cytokine or immune responses. In conclusions, recombinant CVB3, especially those with fused basic peptides, possess strong antitumor activities without eliciting excessive immune responses.

The extracellular SEMA domain attenuates intracellular apoptotic signaling of semaphorin 6A in lung cancer cells

Semaphorin 6A (SEMA6A), a membrane-bound protein, is downregulated in lung cancer tissue compared to its adjacent normal tissue. However, the functions of SEMA6A in lung cancer cells are still unclear. In the present study, full length SEMA6A and various truncations were transfected into lung cancer cells to investigate the role of the different domains of SEMA6A in cell proliferation and survival, apoptosis, and in vivo tumor growth. SEMA6A-induced cell signaling was explored using gene silencing, co-immunoprecipitation, and co-culture assays. Our results showed that overexpression of SEMA6A reduced the growth of lung cancer cells in vitro and in vivo, and silencing SEMA6A increased the proliferation of normal lung fibroblasts. Truncated SEMA6A lacking the SEMA domain or the extracellular region induced more apoptosis than full length SEMA6A, and reintroducing the SEMA domain attenuated the apoptosis. Fas-associated protein with death domain (FADD) bound to the cytosolic region of truncated SEMA6A and was involved in SEMA6A-associated cytosol-induced apoptosis. This study suggests a novel function of SEMA6A in inducing apoptosis via FADD binding in lung cancer cells.

Different Effects of Growth Factors on Proliferation and Matrix Production of Normal and Fibrotic Human Lung Fibroblasts

In idiopathic pulmonary fibrosis (IPF), proliferation of fibroblasts and increased matrix deposition result in pulmonary damage and respiratory insufficiency. We cultured human fibroblasts from lung biopsies of healthy adults and of three patients with IPF (histologically usual interstital pneumonitis, UIP) in order to compare proliferation ([(3)H]thymidine incorporation, cell count) and matrix protein expression (immune fluorescence, quantification of fibronectin synthesis using time-resolved immune fluorescence) of normal and UIP fibroblasts in response to various growth factors. The growth factors platelet-derived growth factor-BB (PDGF), epidermal growth factor (EGF), insulin growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), tumor necrosis factor alpha (TNFalpha), Transforming growth factor-beta (TGFbeta(1)), and fibroblast growth factor-2 (FGF-2) stimulate proliferation of normal lung fibroblasts significantly more than proliferation of UIP fibroblasts. Immunofluorescence reveals extensive expression of collagen I, collagen III, and fibronectin induced by serum, TGFbeta(1), and TNFalpha. This expression is more pronounced in UIP fibroblasts than in normal fibroblasts. Quantification of fibronectin synthesis reveals an enhanced fibronectin synthesis by UIP fibroblasts in response to PDGF, EGF, IGF-1, IGF-2, TNFalpha, TGFbeta(1), and FGF-2). Fibroblasts from normal and UIP lungs differ in their response to growth factors: Whereas normal fibroblasts show a predominantly proliferative response, UIP fibroblasts show an enhanced synthetic activity. Different fibroblast responses may contribute to progressive pulmonary fibrosis in patients with UIP.