Deregulated Activity of Akt in Epithelial Basal Cells Induces Spontaneous Tumors and Heightened Sensitivity to Skin Carcinogenesis

Segrelles, Carmen; Lu, Jerry; Hammann, Brian; Santos, Mirentxu; Moral, Marta; Cascallana, José Luis; Lara, M. Fernanda; Rho, Okkyung; Carbajal, Steve; Traag, Jeanine; Beltrán, Linda; Martínez-Cruz, Ana Belén; García‐Escudero, Ramón; Lorz, Corina; Ruíz, Sergio; Bravo, Ana; Paramio, Jesús M.; DiGiovanni, John

doi:10.1158/0008-5472.can-07-2564

Cited by 86 publications

(134 citation statements)

References 36 publications

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“…Akt activity is sufficient to induce skin tumors in vivo (47)(48)(49)(50)(51), and Akt activity is increased during SCC progression initiated by chemical carcinogenesis (54). Akt pathway activation was detected by p-Akt in the suprabasal cells of epithelial cysts and was found in remnant follicular structures within SCCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Defining the origins of Ras/p53-mediated squamous cell carcinoma

White

Tran

Khuu

et al. 2011

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

170

158

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The precise identity of cancer cells of origin and the molecular events of tumor initiation in epidermal squamous cell carcinoma (SCC) are unknown. Here we show that malignancy potential is related to the developmental capacity of the initiating cancer cell in a genetically defined, intact, and inducible in vivo model. Specifically, these data demonstrate that SCCs can originate from inside the hair follicle stem cell (SC) niche or from immediate progenitors, whereas more developmentally restricted progeny, the transit amplifying (TA) cells, are unable to generate even benign tumors in the same genetic context. Using a temporal model of tumorigenesis in situ, we highlight the phenotypes of cancer progression from the hair follicle SC niche, including hyperplasia, epithelial to mesenchymal transition, and SCC formation. Furthermore, we provide insights into the inability of hair follicle TA cells to respond to tumorigenic stimuli. mouse models of cancer | tumor initiating cells | epidermal stem cells S quamous cell carcinoma (SCC), a common type of nonmelanoma skin cancer, harbors significant risk of metastasis that can eventually lead to death (1). Permanent treatment and prevention of SCC requires an improved understanding of the unique cell types capable of initiating these malignancies and the mechanisms that underlie their transformation. Mutations in the Ras gene family are found in 30% of all human cancers and are often found in human cases of SCC (2-4). Numerous animal studies have extended the understanding of SCC by demonstrating a causative role for the Ras family in the development of SCC. In these mouse models, Ras signaling has been shown to be sufficient to drive epidermal tumorigenesis through either overexpression or targeted expression of an oncogenic form of Hras or Kras. These studies have targeted broad epidermal cell populations that include stem cells (SCs), as well as cells of the outer root sheath (ORS) and interfollicular epidermis (IFE) (4-9). Among these, a landmark article indicated that the SCC cells of origin reside in the hair follicle rather than the IFE (5). However, the keratin promoter used to drive oncogenic Ras expression did not allow for a direct determination of the cancer cell of origin amongst the different cell types in the hair follicle. The candidates for an SCC cell of origin therefore remained follicular SCs, ORS cells, transit amplifying (TA) cells in the matrix, and the differentiated cells of the inner root sheath (IRS) and hair shaft. In addition, other studies have shown that lineagerestricted or differentiated cells of the IFE are sufficient to serve as cancer cells of origin when subjected to supraphysiological levels of Ras activity at sites of mechanical stress (10). These high levels of Ras expression, however, are not normally found in human cases of SCC (10, 11). Between follicular SCs and TA cells, it is not clear whether one or both are capable of initiating tumorigenesis. Thus, we sought to directly compare the malignancy potential between follicular ...

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Section: Resultsmentioning

confidence: 99%

Defining the origins of Ras/p53-mediated squamous cell carcinoma

White

Tran

Khuu

et al. 2011

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

170

158

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“…AKT signaling is also an essential mediator of epidermal morphogenesis and contributes to epidermal homeostasis by modulating keratinocyte proliferation and apoptosis. Transgenic mice with overexpressed Akt targeted to the epidermal basal cell layer develop spontaneous epithelial tumors in multiple organs with age and are also susceptible to skin carcinogenesis (42).…”

Section: Discussionmentioning

confidence: 99%

XPC silencing in normal human keratinocytes triggers metabolic alterations that drive the formation of squamous cell carcinomas

Rezvani

Kim²,

Rossignol³

et al. 2011

J. Clin. Invest.

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DNA damage is a well-known initiator of tumorigenesis. Studies have shown that most cancer cells rely on aerobic glycolysis for their bioenergetics. We sought to identify a molecular link between genomic mutations and metabolic alterations in neoplastic transformation. We took advantage of the intrinsic genomic instability arising in xeroderma pigmentosum C (XPC). The XPC protein plays a key role in recognizing DNA damage in nucleotide excision repair, and patients with XPC deficiency have increased incidence of skin cancer and other malignancies. In cultured human keratinocytes, we showed that lentivirus-mediated knockdown of XPC reduced mitochondrial oxidative phosphorylation and increased glycolysis, recapitulating cancer cell metabolism. Accumulation of unrepaired DNA following XPC silencing increased DNA-dependent protein kinase activity, which subsequently activated AKT1 and NADPH oxidase-1 (NOX1), resulting in ROS production and accumulation of specific deletions in mitochondrial DNA (mtDNA) over time. Subcutaneous injection of XPC-deficient keratinocytes into immunodeficient mice led to squamous cell carcinoma formation, demonstrating the tumorigenic potential of transduced cells. Conversely, simultaneous knockdown of either NOX1 or AKT1 blocked the neoplastic transformation induced by XPC silencing. Our results demonstrate that genomic instability resulting from XPC silencing results in activation of AKT1 and subsequently NOX1 to induce ROS generation, mtDNA deletions, and neoplastic transformation in human keratinocytes. IntroductionEarly studies of the metabolic changes that accompany the development of cancer led Otto Warburg to propose that a respiratory deficiency might drive neoplastic transformation (1), prompting many investigators to analyze the metabolism of tumor cells. These analyses revealed that a large number of cancer cell lines have a higher rate of glycolysis, an increased rate of glucose transport, increased pentose phosphate pathway (PPP) activity, decreased numbers of mitochondria, and a reduction in mitochondrial oxidative phosphorylation (OXPHOS) proteins and activities (2-4). These alterations in cancer cell energy metabolism could be related to somatic mutations in mitochondrial DNA (mtDNA); oxidative stress as a result of increased ROS level; adaptation to tissue hypoxia (4-7); the activation of oncogenes and/or inactivation of tumor suppressors (TP53,; as well as deregulation of PI3K/AKT, which influences the glycolytic flux through regulation of different factors (8).However, the etiologic relationship among genomic mutations, the Warburg effect, and increased ROS levels in tumor induction remains unclear (3,5,9). Furthermore, there is no clear mechanism(s) linking genomic mutations and modified cellular bioenergetics. To understand the relationships between these factors, we speculated that cells with heightened predisposition to malignant transformation, or cells with the capacity to accumu-

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“…Skin sections (4 m) were stained with H&E or processed for immunohistochemistry. Immunohistochemistry was performed using standard protocols on deparaffinized sections as described previously (36). The slides were microwaved with citrate buffer after deparaffinization to enhance the staining.…”

Section: Methodsmentioning

confidence: 99%

“…The mean Ϯ S.D. percentage of proliferating over total basal cells (Ͼ200) was then estimated as reported previously (36).…”

Section: Methodsmentioning

confidence: 99%

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Contreras‐Jurado

García-Serrano

Gómez-Ferrerı́a

et al. 2011

Journal of Biological Chemistry

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The actions of thyroid hormones are mediated by binding to nuclear receptors, TR␣ 4 and TR␤, that act as ligand-dependent transcription factors by association, generally as heterodimers with retinoid X receptors, with thyroid hormone response elements located in regulatory regions of target genes (1). TRs can also modulate expression of genes that do not contain a hormone response element by modulating the activity of other transcription factors and signaling pathways (2), including activator protein-1 (AP-1)-, cyclic AMP-response element-, and nuclear factor-B (NF-B)-dependent pathways (3-7).Studies with knock-out (KO) mice for TRs obtained by homologous recombination have indicated that KO mice for ␣1 and ␤ TR isoforms have different phenotypes (8 -10) and that the double KO mice, surprisingly, survive (11), indicating that these receptors are not required for viability. Although these animals show extreme resistance to thyroid hormones, they exhibit a milder phenotype than hypothyroid mice, indicating divergent consequences for hormone versus receptor deficiency for some actions.Although the skin is a target tissue for thyroid hormone action, no studies on the skin phenotype in TR KO mice have been reported. TR␣ and TR␤ mRNAs are present in the skin (12-15), and these receptors can regulate either positively or negatively the expression of selected keratins in cultured cells (16 -19). Clinical evidence (19 -27) as well as studies in hypothyroid mice and rats (28 -30) also suggest that thyroid hormones could be involved in epidermal proliferation and differentiation, hair growth, and wound healing besides affecting the function of dermal fibroblasts. A question emerging from these studies is how to distinguish between effects due to altered thyroid hormone levels and effects due to expression of specific TR isoforms.The TR KO mice represent an excellent model for the analysis of the role of these receptors in the skin and its response to hyperproliferative stimuli. Topical application of 12-O-tetradecanolyphorbol-13-acetate (TPA) to mouse skin is a well known model for induction of skin hyperproliferation and also promotes a strong inflammatory reaction that activates multiple immunostimulatory pathways. The skin response to TPA is associated with activation of several intracellular pathways (e.g. mitogen-activated protein kinases (MAPKs), AKT, NF-B, STAT3, and AP-1) as well as an increase in the content of chemical mediators, such as cytokines, chemokines, vasoactive peptides, prostaglandins, leukotrienes, and nitric oxide among others (31)(32)(33)(34).In this work, we have investigated skin proliferation and inflammation, before and after TPA application, in mice lacking TR␣1, TR␤, or both genes, comparing these responses with those of hypothyroid animals to distinguish the specific contributions of receptor expression and activation. We found that TRs and thyroid hormones are required for skin homeostasis after TPA treatment and that both receptor genes contribute to

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Deregulated Activity of Akt in Epithelial Basal Cells Induces Spontaneous Tumors and Heightened Sensitivity to Skin Carcinogenesis

Cited by 86 publications

References 36 publications

Defining the origins of Ras/p53-mediated squamous cell carcinoma

Defining the origins of Ras/p53-mediated squamous cell carcinoma

XPC silencing in normal human keratinocytes triggers metabolic alterations that drive the formation of squamous cell carcinomas

The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

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