The EGF Receptor Provides an Essential Survival Signal for SOS-Dependent Skin Tumor Development

Sibilia, Maria; Fleischmann, Alexander; Behrens, Axel; Stingl, Laura; Carroll, Joseph M.; Watt, Fiona M.; Schlessinger, Joseph; Wagner, Erwin F.

doi:10.1016/s0092-8674(00)00026-x

Cited by 278 publications

(251 citation statements)

References 45 publications

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“…This EGFR signaling pathway provides important survival signals involving PI3-K-dependent activation of AKT, as sustained EGFR activity is able to prolong viability of established melanoma upon inactivation of RAS. Conversely, inactivation by dominant-negative EGFR abolishes tumorigenicity of RAS-driven melanoma cells, consistent with observations in other cell systems (fibroblasts, keratinocytes, and intestinal epithelial cells) that autocrine EGFR signaling is required for transformation by activated RAS (Dlugosz et al 1997;Gangarosa et al 1997;Sibilia et al 2000). Thus, in addition to providing experimental evidence that EGFR activation is biologically relevant, the abovementioned study in the inducible model also points out the possibility that EGFR or its ligands may constitute alternative point(s) of therapeutic intervention in RAS-activated melanoma.…”

Section: Receptor Tyrosine Kinase (Rtks) Activationsupporting

confidence: 84%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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Section: Receptor Tyrosine Kinase (Rtks) Activationsupporting

confidence: 84%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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“…The phenotypes observed in k5Pten flox/flox mice are reminiscent of those of Ha-ras , TGF-α (Vassar and Fuchs, 1991), SOS (Sibilia et al, 2000) and IGF-1 (Bol et al, 1997;DiGiovanni et al, 2000) transgenic mice. However, the onset of skin tumor formation in mice requires EGFR and PKB/Akt signaling in addition to SOS/ Ras/ERK signaling (Sibilia et al, 2000).…”

Section: Role Of Pten In Keratinocytesmentioning

confidence: 98%

“…Activation of the TGFα/EGFR pathway (Dominey et al, 1993;Sibilia et al, 2000;Vassar and Fuchs, 1991), IGF-1 (DiGiovanni et al, 2000;Rho et al, 1996) or v-Ha-ras in the epidermis of transgenic mice leads to skin hyperplasia, hyperkeratosis and tumor formation. Transgenic animals overexpressing IGF-1 also show accelerated hair growth (Bol et al, 1997), and mice lacking IGF-1R exhibit hypoplastic skin (Liu et al, 1993).…”

Section: Role Of Pten In Keratinocytesmentioning

confidence: 99%

Physiological Functions of Pten in Mouse Tissues.

Kishimoto

Hamada

Saunders

et al. 2003

Cell Struct. Funct.

107

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ABSTRACT. PTEN is a tumor suppressor gene mutated in many human sporadic cancers and in hereditary cancer syndromes such as Cowden disease, Bannayan-Zonana syndrome and Lhermitte-Duclos disease. The major substrate of PTEN is PIP3, a second messenger molecule produced following PI3K activation induced by variety of stimuli. PIP3 activates the serine-threonine kinase PKB/Akt which is involved in anti-apoptosis, proliferation and oncogenesis. In mice, heterozygosity for a null mutation of Pten (Pten +/-mice) frequently leads to the development of a variety of cancers and autoimmune disease. Homozygosity for the null mutation (Pten -/-mice) results in early embryonic lethality, precluding the functional analysis of Pten in various organs. To investigate the physiological functions of Pten in viable mice, various tissue-specific Pten mutations have been generated using the Cre-loxP system. This review will summarize the phenotypes of conditional mutant mice lacking Pten function in specific tissues, and discuss how these phenotypes relate to the physiological roles of Pten in various organ systems.

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“…To this end, we crossed Bmal1KO mice with a transgenic line expressing oncogenic Sos, an activator of Ras, under the regulation of the Krt5 promoter (K5-SOS) 35 . In an EGFR mutant-heterozygous background, K5-SOS mice spontaneously developed squamous tumours, primarily in the tail, with 100% penetrance, as previously described 35 . Bmal1KO/K5-SOS mice developed significantly fewer neoplastic lesions at early-, mid-and late-stages of carcinoma development than control mice (Fig.…”

Section: Loss Of Bmal1 Reduces Skin Tumorigenesismentioning

confidence: 99%

The circadian molecular clock creates epidermal stem cell heterogeneity

Janich

Pascual

Merlos‐Suárez

et al. 2011

Nature

282

290

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Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.Epidermal stem cells ensure that skin homeostasis is maintained. Murine epidermal stem cells are located either at the permanent portion of the hair follicle-termed the bulge-and are exclusively responsible for hair cycling [1][2][3][4] ; or at the junction between the epidermis and the hair follicle (isthmus), and feed into the epidermis and sebaceous glands [5][6][7] . In addition, a continuous proliferation of basal interfollicular epidermal cells ensures daily epidermal maintenance 8 .Bulge stem cells undergo bouts of activation followed by periods of dormancy, to establish hair follicle cycling. Robust TGF-b and Bmp signals act as 'activation breaks', rendering bulge cells dormant during the resting phase of the hair cycle (telogen) [9][10][11] . At the onset of the growth phase (anagen), bulge cells respond to Wnt signals by migrating into the lower proliferative hair germ region, where they contribute to follicle growth [12][13][14][15] . Subsequently, at mid-anagen, the bulge undergoes a second round of activation, which replenishes cells lost at the onset of anagen 2,3 . However, the response of bulge stem cells to activating stimuli is a heterogeneous process, as only a subset of them become active during either stage of activation 12,13 . The nature of such niche heterogeneity is currently unknown. Importantly, perturbing the equilibrium between the responsive and non-responsive stem cell states causes tissue malfunction and increases the risk of carcinogenesis [16][17][18][19][20] .Here, we analysed the role of the molecular clock in fine-tuning the function of epidermal stem cells. The mammalian clock machinery anticipates and synchronizes vital functions related to the physiological circadian needs of the organism 21 . The core molecular clock is established by a positive limb, composed of heterodimers of the transcription fa...

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The EGF Receptor Provides an Essential Survival Signal for SOS-Dependent Skin Tumor Development

Cited by 278 publications

References 45 publications

Malignant melanoma: genetics and therapeutics in the genomic era

Malignant melanoma: genetics and therapeutics in the genomic era

Physiological Functions of Pten in Mouse Tissues.

The circadian molecular clock creates epidermal stem cell heterogeneity

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