New roles for integrins in squamous-cell carcinoma

Janes, Sam M.; Watt, Fiona M.

doi:10.1038/nrc1817

Cited by 167 publications

(148 citation statements)

References 60 publications

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“…Regardless of the initiating events and the amount of time needed to progress to metastasis, it is becoming clear that there are genes in which expression seems critical for the generation of a metastatic cell, and that these genes fit into the previously proposed essential alterations and steps toward metastasis (37,38). Among these genes are those that are up-regulated in 3T3.mD52 cells, including Vav3 (29), the antiapoptosis gene CARD10 (39), and integrin-a3 and integrin-a6, two members of the integrin family involved in the inhibition of apoptosis, growth stimulation, adhesion, and metastasis (30)(31)(32). Several genes that may be important in preventing tumor formation and metastasis were downregulated in 3T3.mD52 cells, including caveolin (34), four members of the cadherin gene family (40), specifically cadherins 11 and 2 and protocadherins 7 and 18, as well as the antiangiogenesis gene thrombospondin 2 (35).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to a 24-fold increase in mD52 expression, several genes involved in cancer progression and metastasis showed increased expression in 3T3.mD52 cells (Table 1). Up-regulated genes include the oncogenes Vav3 (29), Myc, and homologue U of Ras, as well as adhesion molecules integrin-a3, integrin-a6 (30)(31)(32), and lamanin-a5 (Lama5; ref. 33).…”

Section: Analysis Of Differential Gene Expression In 3t3md52 Versus mentioning

confidence: 99%

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Induction of Tumorigenesis and Metastasis by the Murine Orthologue of Tumor Protein D52

Lewis

Payton

Whitford

et al. 2007

Molecular Cancer Research

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Expression studies have consistently identified tumor protein D52 (TPD52) overexpression in tumor cells. Murine TPD52 (mD52) shares 86% identity with the human orthologue. To study a possible role for TPD52 in transformation, 3T3 fibroblasts were transfected with the full-length cDNA for mD52. Expression of mD52 was confirmed by reverse transcription-PCR (RT-PCR), real-time PCR, and Western blot analysis compared with 3T3 and vector-transfected 3T3 (3T3.V), and the resultant cell line was designated 3T3.mD52. At 4 weeks, 3T3.mD52 gained a 2-fold increase in growth rate, lost contact inhibition, and exhibited a marked phenotype change. Further characterization revealed an acquired ability for anchorage-independent cell growth. To determine whether 3T3.mD52 had become tumorigenic, naïve, healthy, immunocompetent syngeneic mice were inoculated subcutaneously with varying cell doses. Tumors measuring >1 cm 2 were detected 60 days postinoculation with 3T3.mD52, and a 50% subcutaneous tumor incidence was obtained with as few as 5 Â 10 5 3T3.mD52 cells. Remarkably, when lungs from 3T3.mD52 tumor-bearing mice were analyzed, numerous tumor nodules were observed, ranging from nodules less than 10 to nodules too numerous to count (inoculation with 1 Â 10 5 and 5 Â 10 6 cells, respectively). Further support for the metastatic capacity of 3T3.mD52 was the demonstration that transforming growth factor (TGF)-BR1 (receptor) expression decreased and TGF-B1 secretion increased in 3T3.mD52 compared with 3T3 controls. cDNA microarray analysis showed a gene expression pattern that further supported mD52-induced transformation and metastasis. Together, these data suggest that mD52 expression in 3T3 cells initiated cellular transformation, tumorigenesis, and progression to metastasis. (Mol Cancer Res 2007;5(2):133 -44)

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Differential Gene Expression In 3t3md52 Versus mentioning

confidence: 99%

Induction of Tumorigenesis and Metastasis by the Murine Orthologue of Tumor Protein D52

Lewis

Payton

Whitford

et al. 2007

Molecular Cancer Research

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“…48,49 The finding of deregulated integrin signaling in our study is not surprising as the upregulation of different integrins has been previously demonstrated in cutaneous squamous cell carcinomas. 50,51 …”

Section: Integrin Signalingmentioning

confidence: 99%

Molecular discrimination of cutaneous squamous cell carcinoma from actinic keratosis and normal skin

Hui

Binder

2011

Modern Pathology

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Actinic keratosis is widely believed to be a neoplastic lesion and a precursor to invasive squamous cell carcinoma. However, there has been some debate as to whether actinic keratosis is in fact actually squamous cell carcinoma and should be treated as such. As the clinical management and prognosis of patients is widely held to be different for each of these lesions, our goal was to identify unique gene signatures using DNA microarrays to discriminate among normal skin, actinic keratosis, and squamous cell carcinoma, and examine the molecular pathways of carcinogenesis involved in the progression from normal skin to squamous cell carcinoma. Formalin-fixed and paraffin-embedded blocks of skin: five normal skins (pooled), six actinic keratoses, and six squamous cell carcinomas were retrieved. The RNA was extracted and amplified. The labeled targets were hybridized to the Affymetrix human U133plus2.0 array and the acquisition and initial quantification of array images were performed using the GCOS (Affymetrix). The subsequent data analyses were performed using DNA-Chip Analyzer and Partek Genomic Suite 6.4. Significant differential gene expression (42 fold change, Po0.05) was seen with 382 differentially expressed genes between squamous cell carcinoma and normal skin, 423 differentially expressed genes between actinic keratosis and normal skin, and 9 differentially expressed genes between actinic keratosis and squamous cell carcinoma. The differentially expressed genes offer the possibility of using DNA microarrays as a molecular diagnostic tool to distinguish between normal skin, actinic keratosis, and squamous cell carcinoma. In addition, the differentially expressed genes and their molecular pathways could be potentially used as prognostic markers or targets for future therapeutic innovations.

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“…Even within a single cell type, reciprocal signalling between different cell compartments can profoundly influence tumour initiation and progression. This is evident in the interfollicular epidermis, where suprabasal, differentiating cells can positively or negatively regulate proliferation of stem cells in the underlying basal layer (Owens and Watt, 2003;Janes and Watt, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Integrin expression is normally confined to the basal cell layer; however, in many squamous cell carcinomas (SCCs) integrins are also expressed by suprabasal cells (Owens and Watt, 2003). Transgenic mice in which integrins are expressed above the basal layer under the control of the involucrin promoter can show increased susceptibility to chemical carcinogenesis (Owens and Watt, 2003;Janes and Watt, 2006). Suprabasal b1 integrins signal through Erk MAPK (Owens and Watt, 2003).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation

et al. 2011

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We have previously described InvEE transgenic mice in which non-dividing, differentiating epidermal cells express oncogenically activated MAPK kinase 1 (MEK1). Skin wounding triggers tumour formation in InvEE mice via a mechanism that involves epidermal release of IL-1a and attraction of a pro-tumorigenic inflammatory infiltrate. To look for potential effects on the underlying connective tissue, we screened InvEE and wild-type epidermis for differential expression of cytokines and immune modulators. We identified a single protein, CD26 (dipeptidyl peptidase-4). CD26 serum levels were not increased in InvEE mice. In contrast, CD26 was upregulated in keratinocytes expressing mutant MEK1 and in the epithelial compartment of InvEE tumours, where it accumulated at cell-cell borders. CD26 expression was increased in dermal fibroblasts following skin wounding but was downregulated in tumour stroma. CD26 activity was stimulated by calcium-induced intercellular adhesion in keratinocytes, suggesting that the upregulation of CD26 in InvEE epidermis is due to expansion of the differentiated cell layers. IL-1a treatment of dermal fibroblasts stimulated CD26 activity, and therefore epidermal IL-1a release may contribute to the upregulation of CD26 expression in wounded dermis. Pharmacological blockade of CD26, via Sitagliptin, reduced growth of InvEE tumours, while combined inhibition of IL-1a and CD26 delayed tumour onset and reduced tumour incidence. Our results demonstrate that inappropriate activation of MEK1 in the epidermis leads to changes in dermal fibroblasts that, like the skin inflammatory infiltrate, contribute to tumour formation.

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New roles for integrins in squamous-cell carcinoma

Cited by 167 publications

References 60 publications

Induction of Tumorigenesis and Metastasis by the Murine Orthologue of Tumor Protein D52

Induction of Tumorigenesis and Metastasis by the Murine Orthologue of Tumor Protein D52

Molecular discrimination of cutaneous squamous cell carcinoma from actinic keratosis and normal skin

Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation

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