The α6β4 integrin and epithelial cell migration

Mercurio, Arthur M.; Rabinovitz, Isaac; Shaw, Leslie M.

doi:10.1016/s0955-0674(00)00249-0

Cited by 262 publications

(226 citation statements)

References 41 publications

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“…As mentioned above, EGF promotes the activation of distinct signaling pathways in cancer cells, including PI3K, 7 which finally leads to cell migration and invasion. To evaluate whether PI3K activation is involved in Matrigel invasion of PC3-Neo cells, invasion assays were performed in the absence or presence of the PI3K inhibitor LY294002 (80 M).…”

Section: Egf-induced Activation Of Pi3k Is Reduced In Pc3-ar Cellsmentioning

confidence: 93%

“…A key role is played by the EGF receptor (EGFR), which, following interaction with the integrin ␣6␤4, promotes cell migration through activation of PI3K and other downstream pathways. 7,8 In a previous study, we demonstrated that the expression of androgen receptor in PC3 cells by transfection with a full-length human androgen receptor expression vector (PC3-AR) determined a decrease in the expression of the integrin ␣6␤4 and in the ability of these cells to invade Matrigel in response to EGF. 6 The treatment with the synthetic androgen R1881 determined a further decrease of the invasion ability of these cells, without however modifying the surface expression of ␣6␤4 6 and prospecting an effect of the androgen on EGF-mediated signaling related to invasion.…”

mentioning

confidence: 98%

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EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

Bonaccorsi

Carloni

Muratori

et al. 2004

Intl Journal of Cancer

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We previously demonstrated that expression of androgen receptor (AR) by transfection of the androgen-independent prostate cancer cell line PC3 decreases invasion and adhesion of these cells (PC3-AR) through modulation of ␣6␤4 integrin expression. The treatment with androgens further reduced invasion of the cells without modifying ␣6␤4 expression, suggesting an interference with the invasion process by androgens. Here, we investigated EGF-mediated signal transduction processes that lead to invasion in PC3-AR cells. We show that EGF-induced EGFR autotransphosphorylation is reduced in PC3-AR cells compared to PC3 cells transfected only with the vector (PC3-Neo). EGF-stimulated PI3K activity, a key signaling pathway for invasion of these cells, and EGF-PI3K interaction are also decreased in PC3 Key words: prostate cancer; epidermal growth factor receptor; androgen receptor; PI3K; invasionProstate Cancer (PC) is one of the most common cancer and the second leading cause of death in American men. 1 Since prostate cancer cell growth is enhanced by androgens, in the advanced stages of the disease, androgen ablation therapy represents a valuable tool for the treatment of these patients. However the development in most patients after few years of treatment of androgenindependent clones, characterized by higher invasiveness and metastatic properties, has focused attention on the molecular mechanisms that lead to loss of androgen-dependence as well as on the pathways that are regulated by androgens in these cells besides proliferation. Indeed, although androgens are the major stimulus for proliferation of prostate cancer cells, maintenance of androgensensitivity appears to keep a more differentiated and less malignant phenotype of these cells. The ability to produce tumors in nude mice, for instance, is higher in androgen-insensitive cell lines (such as PC3 and DU145) with respect to androgen sensitive (LNCaP). 2 In this light, the role of androgens in the regulation of the pathways involved in invasion and metastasis represents a major task in studies on prostate cancer biology. 3 As a result, some androgen-regulated genes involved in signaling pathways that lead to invasion have been recently identified 4 -6 and their role in decreasing invasion ability of androgen-sensitive prostate cancer cells indicated. Migration and invasion of cancer cells is regulated by multiple pathways that employ various growth factor and their receptors, integrins and cytoskeletal elements. A key role is played by the EGF receptor (EGFR), which, following interaction with the integrin ␣6␤4, promotes cell migration through activation of PI3K and other downstream pathways. 7,8 In a previous study, we demonstrated that the expression of androgen receptor in PC3 cells by transfection with a full-length human androgen receptor expression vector (PC3-AR) determined a decrease in the expression of the integrin ␣6␤4 and in the ability of these cells to invade Matrigel in response to EGF. 6 The treatment with the synthetic androgen R1881 determined a ...

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Section: Egf-induced Activation Of Pi3k Is Reduced In Pc3-ar Cellsmentioning

confidence: 93%

mentioning

confidence: 98%

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

Bonaccorsi

Carloni

Muratori

et al. 2004

Intl Journal of Cancer

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“…Although the roles of α6-integrins in cancer cell metastasis and cell survival have been explored extensively, an understanding of the roles of the α6-integrin subunit in angiogenesis per se is relatively limited [10,40,41]. Since the global deletion of α6-integrin results in a lethal phenotype [15], we developed the first mouse model where α6-integrin was deleted specifically in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…α6β1-and α6β4-integrin laminin-receptors have been shown to play important roles in tumourigenesis and the expression of α6β4-integrin is linked to the progression of numerous carcinomas [8][9][10][11][12]. However, the requirement for these integrins in tumour angiogenesis is less well understood.…”

Section: Introductionmentioning

confidence: 99%

Genetic ablation of the alpha 6‐integrin subunit in Tie1Cre mice enhances tumour angiogenesis

Germain

Arcangelis

Robinson

et al. 2009

The Journal of Pathology

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Laminins are expressed highly in blood vessel basement membranes and have been implicated in angiogenesis. α6β1-and α6β4-integrins are major receptors for laminins in endothelial cells, but the precise role of endothelial α6-integrin in tumour angiogenesis is not clear. We show that blood vessels in human invasive ductal carcinoma of the breast have decreased expression of the α6-integrin-subunit when compared with normal breast tissue. These data suggest that a decrease in α6-integrin-subunit expression in endothelial cells is associated with tumour angiogenesis. To test whether the loss of the endothelial α6-integrin subunit affects tumour growth and angiogenesis, we generated α6fl/fl-Tie1Cre+ mice and showed that endothelial deletion of α6-integrin is sufficient to enhance tumour size and tumour angiogenesis in both murine B16F0 melanoma and Lewis cell lung carcinoma. Mechanistically, endothelial α6-integrin deficiency elevated significantly VEGF-mediated angiogenesis both in vivo and ex vivo. In particular, α6-integrin-deficient endothelial cells displayed increased levels of VEGF-receptor 2 (VEGFR2) and VEGF-mediated downstream ERK1/2 activation. By developing the first endothelial-specific α6-knockout mice, we show that the expression of the α6-integrin subunit in endothelial cells acts as a negative regulator of angiogenesis both in vivo and ex vivo.

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“…The adhesion of normal epithelial cells to the ECM, in particular laminin 5, through the formation of hemidesmosomal complexes with the α6β4 integrin, is known to be a critical component for continued cell growth, survival, and genome stability [14][15][16][17][18][19][20]. Laminin 5 is downregulated or lost in several squamous and epithelial carcinomas including the prostate [10,[21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Integrin‐dependent amplification of the G2 arrest induced by ionizing radiation

2005

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The progressive loss of laminin 5 and the α6β4 integrin is a characteristic of the transition of prostatic intraepithelial neoplasia (PIN) to invasive human prostate cancer. Our objective was to determine if the loss of the interaction with laminin 5 would influence the ability of human epithelial cells to respond to DNA damage. Three cellular damage responses to ionizing radiation (IR) were analyzed including G2 progression, cdc2 phosphorylation, and cell survival. The adhesion of normal human prostate epithelial cells to laminin 5 amplified the G2 arrest induced by IR, and depends on a known cell binding domain of laminin 5. The alteration of G2 arrest was confirmed by an inhibition of phospho-cdc2 nuclear translocation. In contrast, a prostate epithelial cancer cell line blocked in G2 independent of adhesion to laminin 5. The survival of these cell lines in response to IR was unaffected by adhesion to laminin 5. These results suggest that cell adhesion to laminin 5 in normal cells will amplify the IR induced G2 cell cycle progression block without altering cell survival. The loss of laminin 5 and the α6β4 integrin in PIN lesions may contribute to the selection and progression of genetically unstable cell types via attenuation of a DNA damage induced G2 arrest.

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The α6β4 integrin and epithelial cell migration

Cited by 262 publications

References 41 publications

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

Genetic ablation of the alpha 6‐integrin subunit in Tie1Cre mice enhances tumour angiogenesis

Integrin‐dependent amplification of the G2 arrest induced by ionizing radiation

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