Key differences identified between actinic keratosis and cutaneous squamous cell carcinoma by transcriptome profiling

Lambert, Sally R.; Mladkova, Nikol; Gulati, Abha; Hamoudi, Rifat; Purdie, Karin J.; Cerio, R.; Leigh, Irene M.; Proby, Charlotte M.; Harwood, Catherine A.

doi:10.1038/bjc.2013.760

Cited by 98 publications

(95 citation statements)

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“…Immunostaining identified the tumor cells as well as keratinocytes of the normal epidermis, endothelial cells and other stromal cells as the sources of activin (Fig C–E). This expression pattern is similar to the one observed in human SCCs (Antsiferova et al , ) and consistent with the expression of INHBA in tumor cells of AK and SCC patients isolated by laser capture microdissection (Lambert et al , ).…”

Section: Resultssupporting

confidence: 88%

Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages

et al. 2016

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Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal γδ T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2‐positive monocytes. Gene expression profiling of macrophages from pre‐tumorigenic skin and bioinformatics analysis demonstrated that activin induces a gene expression pattern in skin macrophages that resembles the phenotype of tumor‐associated macrophages in different malignancies, thereby promoting angiogenesis, cell migration and proteolysis. The functional relevance of this finding was demonstrated by antibody‐mediated depletion of macrophages, which strongly suppressed activin‐induced skin tumor formation. These results demonstrate that activin induces skin carcinogenesis via attraction and reprogramming of macrophages and identify novel activin targets involved in tumor formation.

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Section: Resultssupporting

confidence: 88%

Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages

et al. 2016

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“…CST6 is a potent endogenous protein inhibitor of lysosomal proteases and its down-regulation, mainly through epigenetic inactivation, promotes tumor cell invasion, cell proliferation and matrix remodeling (64,67). Increased expression of KRT9, KRT10, FLG and FLG2, which are involved in terminal epidermal differentiation, was reported in cSCC using gene-expression analysis (69). The role of KRT9, KRT10, FLG and FLG2 in pathophysiology of human cSCC is not well understood, however KRT10 has been reported to act as skin epithelial tumor suppressor in vivo, primarily through reducing the activity of serine-threonine protein kinase (AKT) and consequently the expression of cyclin D1 (CCND1) (70).…”

Section: Discussionmentioning

confidence: 97%

In Silico Analysis Validates Proteomic Findings of Formalin-fixed Paraffin Embedded Cutaneous Squamous Cell Carcinoma Tissue

Azimi

Kaufman

Ali

et al. 2016

CGP

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“…Targeted analysis of the CDKN2A locus in 40 samples identified alterations (mutation, copy loss, promoter methylation) in 76% of cases (18). Microarray comparison of 10 actinic keratosis and 30 cSCC samples identified several MAPK pathway genes significantly overexpressed in the malignant samples (19). Similar findings were reported by studies involving larger cohorts of primary cSCCs: targeted sequencing of the known NOTCH1/2, TP53, CDKN2A, and RAS genes on 132 cSCCs that developed sporadically and 39 cSCCs that developed after BRAF-inhibitor treatment (20), and exome sequencing of 39 clinically aggressive cSCC primaries (21).…”

Section: Introductionmentioning

confidence: 99%

Genomic Analysis of Metastatic Cutaneous Squamous Cell Carcinoma

Hanna

Laga

et al. 2015

Clinical Cancer Research

251

279

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Purpose A rare 5% of cutaneous squamous cell carcinomas metastasize, lack FDA-approved therapies, and carry a poor prognosis. Our aim was to identify recurrent genomic alterations in this little-studied population of metastatic cSCCs. Experimental Design We performed targeted sequencing of 504 cancer-associated genes on lymph node metastases in 29 patients with cSCC and identified mutations and somatic copy number alterations associated with metastatic cSCC. We determined significantly mutated, deleted and amplified genes and associated genomic alterations with clinical variables. Results The cSCC genome is heterogeneous with widely varying numbers of genomic alterations and does not appear to be associated with HPV. We found previously identified recurrently altered genes (TP53, CDKN2A, NOTCH1/2) but also a wide spectrum of oncogenic mutations affecting RAS/RTK/PI3K, squamous differentiation, cell cycle, and chromatin remodeling pathway genes. Specific mutations in known oncogenic drivers and pathways were correlated with inferior patient outcomes. Our results suggest potential therapeutic targets in metastatic cSCC including PIK3CA, FGFR3, BRAF, and EGFR, similar to those reported in SCCs of the lung and head and neck, suggesting that clinical trials could be developed to accrue patients with SCCs from multiple sites of origin. Conclusions We have genomically characterized a rare cohort of 29 metastatic cSCCs and identified a diverse array of oncogenic alterations that can guide future studies of this disease.

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Key differences identified between actinic keratosis and cutaneous squamous cell carcinoma by transcriptome profiling

Cited by 98 publications

References 50 publications

Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages

Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages

In Silico Analysis Validates Proteomic Findings of Formalin-fixed Paraffin Embedded Cutaneous Squamous Cell Carcinoma Tissue

Genomic Analysis of Metastatic Cutaneous Squamous Cell Carcinoma

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