Low incidence of ras oncogene activation in human squamous cell carcinomas

Rumsby, Gillian; Carter, R. L.; Gusterson, Barry A.

doi:10.1038/bjc.1990.80

Cited by 87 publications

(49 citation statements)

References 24 publications

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“…Recent data suggests that aberrant activation of MAPK pathways may play an important role in diverting the TGF-b response towards a pro-oncogenic outcome, and that TGF-b and activated Ras may cooperate to promote invasive, metastatic disease (Park et al, 2000). However, Ras mutations are uncommon in SCC in the western world (Rumsby et al, 1990;Yeudall et al, 1993). Moreover, although the parental cell line H357, used in this study, harbours two point mutations in the c-Ha-ras gene (Yeudall et al, 1993) it retains its sensitivity to the growth inhibitory effects of TGF-b1 (Paterson et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Binding of TGF-β1 latency-associated peptide (LAP) to αvβ6 integrin modulates behaviour of squamous carcinoma cells

et al. 2002

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The integrin avb6 is not detectable on normal keratinocytes in vivo but expression is increased significantly in oral squamous cell carcinoma where this heterodimer has been shown to play a role in cell migration, invasion and protease expression. Although regarded initially as a fibronectin receptor, avb6 may bind to arginine-glycine-aspartic acid sequences in other matrix molecules including tenascin and vitronectin. Interestingly, avb6 has also been shown to have high affinity for the TGF-b1 latency associated peptide and to participate in the activation of the TGF-b1 latent complex. Since TGF-b1 is present in squamous carcinomas, it is possible that latency associated peptide may modulate malignant keratinocyte behaviour independently from the classical TGF-b signalling pathways through its interaction with integrins. We show here that when latency associated peptide is immobilised onto a surface, it acts as an avb6-specific ligand for oral squamous carcinoma cells promoting adhesion and haptotactic migration in addition to avb6-dependent increase in pro-MMP-9 expression. In contrast, even very low concentrations of soluble latency associated peptide (0.1 mg ml 71) inhibited avb6-dependent adhesion, migration and invasion. Thus avb6-dependent processes of oral squamous cell carcinoma, is likely to be modulated, not only by the local concentration of latency associated peptide in the stroma, but also whether it is immobilised in the matrix or released as a soluble protein.

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Section: Discussionmentioning

confidence: 99%

Binding of TGF-β1 latency-associated peptide (LAP) to αvβ6 integrin modulates behaviour of squamous carcinoma cells

et al. 2002

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“…Although only a minor fraction of human SCC harbor Ras mutations (26,27), it is interesting to note that recent data suggest that human SCC may show a block in NF-B signaling based on nuclear exclusion of the RelA NF-B subunit (ref. 4 and M.v.H., unpublished results).…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-κB inhibition

Lind

Rozell²,

Wallin³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

107

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T he Rel͞NF-B transcription factors have a central role in several cellular processes, including proliferation, cell adhesion, apoptosis, and regulation of the immune response (1). Under nonstimulating conditions, NF-B is retained in the cytoplasm in an inactive form because of its interaction with the inhibitory proteins I Bs. In response to an activating stimulus, I B is phosphorylated by an I B kinase (IKK) complex, which targets it for degradation by the proteasome, releasing NF-B, which translocates to the nucleus, where it regulates the transcription of target genes.Evidence gathered from studies during recent years have shown that NF-B has a growth inhibitory function in the skin. Initial studies showed that overexpression of the NF-B subunits p50 or p65 in the basal layer of the murine epidermis by using a keratin 14 (K14) promoter leads to hypoplasia of the epidermis, whereas expression of a superrepressor form of the inhibitor of NF-B type ␣ (I B␣) results in hyperplasia (2). Although K14-I B␣ mice die shortly after birth (day 7), we have shown that mice with keratin 5 (K5)-directed expression of I B␣ (K5-I B␣) to the basal layer of the epidermis survive to adulthood (3). Not only do these mice develop hyperplasia of the epidermis, but the skin phenotype of K5-I B␣ mice is also characterized by an intense neutrophil-dominated inflammation of the skin and an early development of squamous cell carcinomas (SCC).Recent data suggest that human sporadic SCC may show a block in NF-B signaling based on nuclear exclusion of the RelA NF-B subunit (ref. 4 and M.v.H., unpublished results). Furthermore, it was recently shown that coexpression of a superrepressor form of I B␣ and Ha-Ras results in neoplasia resembling invasive SCC in human keratinocytes transplanted to severe combined immunodeficient (scid͞scid) mice, supporting the relevance of a NF-B block in the induction of human SCC (4).Inflammation of the skin with neutrophil infiltration and hyperproliferation is also seen in female heterozygous Ikk␥-deficient mice, which develop a condition similar to the human X-linked disorder Incontinentia Pigmenti (IP) (5, 6). IKK␥ is the regulatory subunit of the IKK complex, which, in addition, contains the two catalytic subunits IKK␣ (IKK1) and IKK␤ (IKK2) (1). It is now well established that human IP results from loss-of-function mutations in the IKK␥ gene (7). Interestingly, subungual keratoacanthoma-like tumors and cases of SCC have been reported as late manifestations of IP (8-11).The catalytic IKK␤ subunit is necessary for activation of NF-B in response to proinflammatory stimuli (1). Skin-specific deletion of the IKK␤ gene, K14-Cre͞Ikk2 FL/FL , was recently shown to result in an inflammatory phenotype with concomitant hyperproliferation of the epidermis (12), very similar to what is seen in the K5-I B␣ mice. Because the K14-Cre͞Ikk2 FL/FL mice die between day 7 and day 9 after birth, it is currently not known whether they, similar to K5-I B␣ mice, are prone to develop SCC.Besides inf lammation and hyperprolifera...

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“…This is in contrast to the very high frequency of Ha-ras mutations in tumors induced in mouse skin by DMBA/ TPA. However, several studies indicate that Ha-ras mutations are a rare event in human SCCs and UVinduced murine tumors (Campbell et al, 1993;Rumsby et al, 1990;Sutter et al, 1993;van der Schroeff et al, 1990) demonstrating the existence of alternative initiating genetic alterations.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Rel/Nuclear Factor-κB signaling in skin results in defective DNA damage-induced cell cycle arrest and Ha-ras- and p53-independent tumor development

Hogerlinden

Auer²,

Toftgárd

2002

Oncogene

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In recent years a growth inhibitory role in skin for the Rel/NF-kB transcription factors has been established, and the block of Rel/NF-kB signaling results in rapid development of spontaneous skin cancer. The molecular mechanism underlying tumor development is however unknown. In the present study, we show that inhibition of NF-kB signaling in mouse skin by targeted expression of degradation resistant IkB-a generates transgenic keratinocytes unable to arrest the cell cycle in response to DNA damage induced by g-radiation. The results indicate that transgenic keratinocytes have a defect at the G1-S checkpoint whereas the G2-M checkpoint response was found to be intact. However, transgenic keratinocytes still respond by induction of the cyclin dependent kinase inhibitor p21 Cip1/Waf after exposure to g-radiation. In the spontaneous skin tumors that develop in transgenic mice no mutations were found in the Haras or p53 gene, suggesting that inhibition of NF-kB signaling in skin can induce cancer development independently of initiating mutations in the Ha-ras gene or additional mutations in the p53 gene. These findings demonstrate an involvement of NF-kB signaling in the DNA damage response and cell cycle checkpoint control in the skin.

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Low incidence of ras oncogene activation in human squamous cell carcinomas

Cited by 87 publications

References 24 publications

Binding of TGF-β1 latency-associated peptide (LAP) to αvβ6 integrin modulates behaviour of squamous carcinoma cells

Binding of TGF-β1 latency-associated peptide (LAP) to αvβ6 integrin modulates behaviour of squamous carcinoma cells

Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-κB inhibition

Inhibition of Rel/Nuclear Factor-κB signaling in skin results in defective DNA damage-induced cell cycle arrest and Ha-ras- and p53-independent tumor development

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