Reduced Expression of Laminin α3 and α5 Chains in Non‐small Cell Lung Cancers

Akashi, Takumi; Ito, Eisaku; Eishi, Yoshinobu; Koike, Masato; Nakamura, Kyoichi; Burgeson, Robert E.

doi:10.1111/j.1349-7006.2001.tb01094.x

Cited by 24 publications

(15 citation statements)

References 42 publications

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“…43A cells expressed strongly laminin 5 chain mRNA and laminin-511 protein, whereas in cells which had undergone EMT, laminin 5 chain and laminin-511 were diminished or totally lacking. Although well-preserved laminin 5 chain expression has been reported in BMs of, e.g., renal tumors (Lohi et al 1996) and prostate carcinoma (Brar et al 2003), reduced laminin 5 chain expression has been described in oral SCC (Kosmehl et al 1999), non-small cell lung carcinomas (Akashi et al 2001), invasive areas of colorectal carcinomas (Lohi et al 2000), and diVuse-type gastric carcinomas . Therefore, it may be assumed that diVerent carcinomas behave diVerently upon malignant transformation in respect of laminin 5 chain expression.…”

Section: Discussionmentioning

confidence: 98%

Epithelial-mesenchymal transition downregulates laminin α5 chain and upregulates laminin α4 chain in oral squamous carcinoma cells

Takkunen

Ainola

Vainionpää

et al. 2008

Histochem Cell Biol

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Basement membranes maintain the epithelial phenotype and prevent invasion and metastasis. We hypothesized that expression of basement membrane laminins might be regulated by epithelial-mesenchymal transition (EMT), hallmark of cancer progression. As EMT is mediated by transcription factor Snail, we used oral squamous carcinoma cells obtained from a primary tumor (43A), from its EMT-experienced recurrence (43B) and Snail-transfected 43A cells (43A-SNA) displaying full EMT, as a model to study laminins and their receptors. Northern blotting, immunofluorescence, and immunoprecipitation showed a gradual loss of laminin-511 and its receptor Lutheran from 43A to 43B and 43A-SNA cells. In contrast, neoexpression of laminin alpha4 mRNA was found congruent with synthesis of laminin-411. Chromatin immunoprecipitation disclosed direct binding of Snail to regions upstream of laminin alpha5 and alpha4 genes. Immunofluorescence and immunoprecipitation showed a switch from hemidesmosomal integrin alpha(6)beta(4) to alpha(6)beta(1) and neoexpression of alpha(1)beta(1) in 43A-SNA cells, and upregulation of integrin-linked kinase in both 43B and 43A-SNA cells. The cells adhered potently to laminin-511 and fibronectin, whereas adhesion to laminin-411 was minimal. In contrast, laminin-411 inhibited cell adhesion to other extracellular matrix proteins. In conclusion, EMT induces a switch from laminin-511 to laminin-411 expression, which may be directly controlled by Snail. Concomitant changes take place in laminin- and collagen-binding receptors. Laminin-411 reduces adhesion to laminin-511 and fibronectin, suggesting that tumor cells could utilize laminin-411 in their invasive behavior.

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Section: Discussionmentioning

confidence: 98%

Epithelial-mesenchymal transition downregulates laminin α5 chain and upregulates laminin α4 chain in oral squamous carcinoma cells

Takkunen

Ainola

Vainionpää

et al. 2008

Histochem Cell Biol

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“…The reduced expression of laminins and integrins is often associated with disrupted interaction of lung tumor cells with extracellular matrix, which could lead to fragmentation of the basement membrane and subsequent invasion of the surrounding stroma. Impaired expression of both protein types is, indeed, observed in lung cancer (Akashi et al 2001) and serves as a poor prognostic factor (Moriya et al 2001;Vitolo et al 2001).…”

Section: Tumor Vascularization and Metastasismentioning

confidence: 99%

Mouse models for human lung cancer

Meuwissen

Berns²

2005

Genes Dev.

272

243

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In recent years several new mouse models for lung cancer have been described. These include models for both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Tumorigenesis in these conditional mouse tumor models can be initiated in adult mice through Cre-recombinase-induced activation of oncogenic mutations in a subset of the cells. They present a marked improvement over mouse models that depend on carcinogen induction of tumors. These models permit us to study the consecutive steps involved in initiation and progression and allow us to address questions like the cell of origin, and the role of cancer stem cells in the maintenance of these tumors. They now need to be validated as suitable preclinical models for intervention studies in which questions with respect to therapy response and resistance can be addressed.During the last decades lung cancer has become the leading cause of cancer deaths in the world, accounting for even more solid tumor deaths than breast, pancreatic, prostate, and colorectal combined (Landis et al. 1999). More then 170,000 new cases are being diagnosed each year in the United States alone, of whom ∼160,000 will eventually die, representing 28% of all cancer deaths (Jemal et al. 2004). Worldwide more than a million deaths are due to lung cancer. Tobacco smoking is the major causal agent, being responsible for ∼85% of the lung cancer incidence. Other respiratory exposure to occupational or environmental carcinogens, such as asbestos or radon, and yet unknown genetic factors contribute to the remaining 15% . Although smoking cessation before the age of 30 does substantially reduce the risk of lung cancer, this is significantly less for those who stop smoking at 50 or 60 yr (Peto et al. 2000;Doll et al. 2004). Interestingly, nearly 50% of all first diagnosed lung cancers in the United States are from people who stopped smoking at least 5 or more years ago (Peto and Lopez 2001). This indicates that extensive damage to the respiratory tract can persist over many years. Indeed, recent studies (Mao 2002;Pfeifer et al. 2002;Wistuba et al. 2002) showed the presence of multiple genetic lesions, often manifested in clonal patches of cells in respiratory epithelium of current and former smokers.Lung cancer can be divided into two major histopathological groups: non-small-cell lung cancer (NSCLC) (Van Zandwijk et al. 1995) SCLC and NSCLC show major differences in histopathologic characteristics that can be explained by the distinct patterns of genetic lesions found in both tumor classes . Responsiveness to treatment with chemotherapy and/or radiation also differs significantly between NSCLC and SCLC and has a dramatic effect on clinical treatment outcome. The overall 5-yr survival rate for lung cancer is ∼14% (Travis et al. 1995); for SCLC alone it is even worse, ∼5% (Worden and Kalemkerian 2000).Spontaneous lung tumors in mice are similar in morphology, histopathology, and molecular characteristics to human adenocarcinomas. Mouse models for lung cancer can thus serve as a valua...

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“…In our previous study of lung adenocarcinomas, the basement membranes were signifi cantly disrupted or disappeared especially in the desmoplastic areas [15] . Many cytokines have binding capacity to extracellular matrix molecules including basement membrane components [16] .…”

Section: Introductionmentioning

confidence: 99%

Basement Membrane Matrix Modifies Cytokine Interactions between Lung Cancer Cells and Fibroblasts

Akashi

Minami²,

Ishige³

et al. 2005

Pathobiology

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Objective: Proliferation of fibroblasts (desmoplastic reaction) in the lung adenocarcinomas is an important phenomenon that correlates with metastases and poor prognosis. Because basement membranes are often involved in the desmoplastic areas and many cytokines have binding capacity to basement membrane molecules, we hypothesized that basement membrane modify the paracrine effects between cancer cells and fibroblasts via the fibrogenic cytokines and this hypothesis was experimentally investigated. Methods: The effects of conditioned media derived from ten lung carcinoma cell lines and normal airway epithelial cells on DNA synthesis of fetal lung fibroblasts were determined. We focused on fibroblast growth factor 2 (FGF-2) as the candidate paracrine cytokines and examined their diffusion through an experimental basement membrane matrix model, Matrigel™. Results: All the conditioned media promoted DNA synthesis of fetal lung fibroblasts. Detection by ELISA methods and the neutralizing antibodies suggested that FGF-2 was one of the responsible factors for the growth promotion. Diffusion of FGF-2 across the polycarbonate membrane was suppressed by coating with Matrigel. When FGF-2-secreting A549 cells were covered with Matrigel, FGF-2 was stored in Matrigel and its diffusion into the culture media was significantly reduced. Binding of FGF-2 to Matrigel was completely blocked by a basic protein, protamine sulfate. In the presence of protamine sulfate in Matrigel overlaid on A549 cells, diffusion of FGF-2 increased 7-fold as much as that without overlaid Matrigel. Conclusion: These results suggest that the basement membrane acts as a barrier to the diffusion and a reservoir of cytokines secreted by cancer cells, and that the subsequent degradation of the basement membrane by cancer cells could release the stored cytokines and promote growth of fibroblasts.

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Reduced Expression of Laminin α3 and α5 Chains in Non‐small Cell Lung Cancers

Cited by 24 publications

References 42 publications

Epithelial-mesenchymal transition downregulates laminin α5 chain and upregulates laminin α4 chain in oral squamous carcinoma cells

Epithelial-mesenchymal transition downregulates laminin α5 chain and upregulates laminin α4 chain in oral squamous carcinoma cells

Mouse models for human lung cancer

Basement Membrane Matrix Modifies Cytokine Interactions between Lung Cancer Cells and Fibroblasts

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