Tumor cell invasiveness correlates with changes in integrin expression and localization

Maschler, Sabine; Wirl, Gerhard; Spring, Herbert; Bredow, Dorothea v; Sordat, Isabelle; Beug, Hartmut; Ernst, Rolf

doi:10.1038/sj.onc.1208423

Cited by 151 publications

(129 citation statements)

References 37 publications

(48 reference statements)

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“…TMPRSS4 also caused enhanced expression of the integrin subunit a5. Integrin expression is often altered in tumors; for example, a5b1 has been centrally implicated in EMT induction and cell motility (Maschler et al, 2005). The increased adhesion to ECM proteins was efficiently inhibited by the integrin antagonist, RGD peptide.…”

Section: Discussionmentioning

confidence: 99%

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

et al. 2007

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TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon and gastric cancer tissues. However, the biological functions of TMPRSS4 in cancer are unknown. Here we show, using reverse transcription-PCR, that TMPRSS4 is highly elevated in lung cancer tissues compared with normal tissues and is also broadly expressed in a variety of human cancer cell lines. Knockdown of TMPRSS4 by small interfering RNA treatment in lung and colon cancer cell lines was associated with reduction of cell invasion and cell-matrix adhesion as well as modulation of cell proliferation. Conversely, the invasiveness, motility and adhesiveness of SW480 colon carcinoma cells were significantly enhanced by TMPRSS4 overexpression. Furthermore, overexpression of TMPRSS4 induced loss of E-cadherin-mediated cell-cell adhesion, concomitant with the induction of SIP1/ZEB2, an Ecadherin transcriptional repressor, and led to epithelialmesenchymal transition events, including morphological changes, actin reorganization and upregulation of mesenchymal markers. TMPRSS4-overexpressing cells also displayed markedly increased metastasis to the liver in nude mice upon intrasplenic injection. Taken together, these studies suggest that TMPRSS4 controls the invasive and metastatic potential of human cancer cells by facilitating an epithelial-mesenchymal transition; TMPRSS4 may be a potential therapeutic target for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

et al. 2007

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“…Some workers have reported that epidermal growth factor, insulin-like growth factor-1, interferon-γ and keratinocyte growth factor, transforming growth factor (TGF)-α tumor necrosis factor (TNF)-α, TGF-β1 and TPA trigger an increase in laminin-332 production by epithelial cells in vitro [52,113,114]. In contrast, others have presented evidence that at least one of the above growth factors (TGF-β) induces a decrease in the expression of laminin-332 [115]. Moreover, TGF-β1 causes dramatic changes in cellular interactions of keratinocytes with laminin-332.…”

Section: Regulation Of Laminin-332 Expression and Potential Role In Cmentioning

confidence: 92%

Laminin-332-Integrin Interaction: A Target For Cancer Therapy?

Tsuruta

Kobayashi²,

Imanishi³

et al. 2008

CMC

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For many years, extracellular matrix (ECM) was considered to function as a tissue support and filler. However, we now know that ECM proteins control many cellular events through their interaction with cell-surface receptors and cytoplasmic signaling pathways. For example, they regulate cell proliferation, cell division, cell adhesion, cell migration, and apoptosis. We focus in this review on a laminin isoform, laminin-332 (formerly termed laminin-5), a major component of the basement membrane (BM) of skin and other epithelial tissues. It is composed of 3 subunits (α3, β3, and γ2) and interacts with at least two integrin receptors expressed by epithelial cells (α3β1 and α6β4 integrin). Mutations in either laminin-332 or integrin α6β4 result in junctional epidermolysis bullosa, a blistering skin disease, while targeting of laminin-332 by autoantibodies in cicatricial pemphigoid leads to dysadhesion of epithelial cells from their underlying connective tissue. Abnormal expression of laminin-332 and its integrin receptors is also a hallmark of certain tumor types and is believed to promote invasion of colon, breast and skin cancer cells. Moreover, there is emerging evidence that laminin-332 and its protease degradation products are not only found at the leading front of several tumors but also likely induce and/or promote tumor cell migration. Thus, in this review, we focus specifically on the role of laminin-332 and its integrin receptors in adhesion, proliferation, and migration/invasion of cancer cells. Finally, we discuss strategies for the development of laminin-332-based antagonists for the treatment of malignant tumors.

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“…Protein concentration was assessed using the BCA kit (Pierce), and the nuclear extracts' quality was first controlled using western blotting for SP1, HP1α, Hdac3 and Gapdh as exemplified in Supplementary Figures. Western blottings were performed as described 49,50 using the primary antibodies listed in Supplementary Table S2. Blots were incubated with horseradish peroxidase-coupled secondary antibodies (GE Healthcare) and developed using Amersham ECL (GE Healthcare) or Luminata (Pierce) and ECL Hyperfilms (GE Healthcare) or a Chemidoc device (Bio-Rad, Madrid, Spain).…”

Section: Methodsmentioning

confidence: 99%

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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Epithelial-to-mesenchymal transition (EMT) is essential for embryonic morphogenesis and wound healing and critical for tumour cell invasion and dissemination. The AP-1 transcription factor Fra-1 has been implicated in tumorigenesis and in tumour-associated EMT in human breast cancer. We observed a significant inverse correlation between Fra-1 mRNA expression and distant-metastasis-free survival in a large cohort of breast cancer patients derived from multiple array data sets. This unique correlation among Fos genes prompted us to assess the evolutionary conservation between Fra-1 functions in EMT of human and mouse cells. Ectopic expression of Fra-1 in fully polarized, non-tumourigenic, mouse mammary epithelial EpH4 cells induced a mesenchymal phenotype, characterized by a loss of epithelial and gain of mesenchymal markers. Proliferation, motility and invasiveness were also increased in the resulting EpFra1 cells, and the cells were tumourigenic and efficiently colonized the lung upon transplantation. Molecular analyses revealed increased expression of Tgfβ1 and the EMT-inducing transcription factors Zeb1, Zeb2 and Slug. Mechanistically, Fra-1 binds to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1. Furthermore, increased activity of a zeb2 promoter reporter was detected in EpFra1 cells and shown to depend on AP-1-binding sites. Inhibiting TGFβ signalling in EpFra1 cells moderately increased the expression of epithelial markers, whereas silencing of zeb1 or zeb2 restored the epithelial phenotype and decreased migration in vitro and tumorigenesis in vivo. Thus Fra-1 induces changes in the expression of genes encoding EMT-related transcription factors leading to the acquisition of mesenchymal, invasive and tumorigenic capacities by epithelial cells. This study defines a novel function of Fra-1/AP-1 in modulating tgfb1, zeb1 and zeb2 expression through direct binding to genomic regulatory regions, which establishes a basis for future in vivo genetic manipulations and preclinical studies using mouse models. Epithelial-to-mesenchymal transition (EMT) is a complex biological programme that occurs in physiological processes during embryonic development and wound healing as well as in pathological conditions, such as organ fibrosis and carcinogenesis. During EMT, cells lose epithelial features and acquire mesenchymal characteristics. The acquisition of a mesenchymal state by malignant cancer cells is associated with decreased cell-cell adhesion, and increased migratory and invasive properties, which are crucial for metastasis. [1][2][3][4][5] The adherens junction (AJ) protein E-cadherin, encoded by cdh1, is a central determinant of the epithelial state and its downregulation is the hallmark of EMT. A number of molecular pathways converging on E-cadherin have been implicated in EMT. Transcription factors (TF) of the Snail, Zeb and Twist families, initially identified as regulators of epithelialmesenchymal plasticity during morphogenesis were shown to orchestrate EMT by...

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Tumor cell invasiveness correlates with changes in integrin expression and localization

Cited by 151 publications

References 37 publications

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial–mesenchymal transition

Laminin-332-Integrin Interaction: A Target For Cancer Therapy?

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

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