Epithelial to mesenchymal transition markers are associated with an increased metastatic risk in primary cutaneous squamous cell carcinomas but are attenuated in lymph node metastases

Toll, Agustí; Masferrer, Emili; Hernández-Ruiz, M.E.; Ferrándiz-Pulido, Carla; Yébenes, Mireia; Jaka, Ane; Tuneu, Anna; Jucglà, Anna; Gimeno, Javier; Baró, Teresa; Casado, Beatriz; Gandarillas, Alberto; Costa, Irmgard; Mojal, Sergi; Peña, Raúl; Herreros, Antonio Garcı́a de; García-Patos, Vicenç; Pujol, Ramón M.; Hernández-Muñoz, Inmaculada

doi:10.1016/j.jdermsci.2013.07.001

Cited by 66 publications

(88 citation statements)

References 45 publications

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“…Several factors have been associated with an increased risk of metastasis, such as immunosuppression, tumour thickness ([4 mm), desmoplasia, horizontal size greater than 2 cm, poor differentiation, localization of the primary tumour to specific sites such as the ear and lips, or increased proliferation ratio of tumour cells [10,36,37]. Tumour relapse is also an independent parameter that predicts cSCC metastasis [10,43,44]; however, there is still a lack of reliable biomarkers that categorize individuals with higher risk of developing cancer relapse and/or metastasis. Such biomarkers would allow the identification of patients that would benefit from the implementation of more accurate follow-up schedules, imaging procedures and/or lymph node biopsy protocols.…”

Section: Introductionmentioning

confidence: 99%

Active nuclear IKK correlates with metastatic risk in cutaneous squamous cell carcinoma

et al. 2015

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About 5% of all cutaneous squamous cell carcinomas (cSCCs) metastasize, which is the principal cause of death by this type of cancer. However, to date there are no reliable biomarkers that categorize those SCC patients that will progress to metastasis. Nuclear active IKKα diminishes Maspin levels in prostate cancer facilitating its metastatic potential. In this paper, we describe the immunohistochemical analysis of active IKK and Maspin in 56 metastasizing and 51 non-metastasizing primary cSCC to measure their association with cancer behaviour. We also determined the effect of inhibiting IKK activity in SCC cell growth and migration in vitro. We found that high levels of nuclear active IKK in the primary tumour are predictive of cSCC metastatic capacity, in particular when combined with poor tumour differentiation and a history of tumour recurrence. Active IKK inversely correlated with Maspin levels in cSCC tumours, and samples negative for Maspin are exclusively found in the metastatic group. Mechanistically, IKK activity regulates cellular motility and SCC cell survival. Our results indicate that nuclear active IKK is a robust biomarker to predict cSCC outcome, and suggest the possibility of targeting IKK activity as a future therapy for treating metastatic cSCC.

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Section: Introductionmentioning

confidence: 99%

Active nuclear IKK correlates with metastatic risk in cutaneous squamous cell carcinoma

et al. 2015

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“…Comparisons of the expression of EMT markers in the primary tumor and corresponding lymph node metastases have been performed for several cancer types (35,36,37). These studies demonstrated that the expression of EMT markers in mature metastatic lymph nodes was lower compared to that in the primary lesions; therefore it was hypothesized that mesenchymal-to-epithelial transition (MET), the reverse phenomenon of EMT, may occur at secondary metastatic sites before the metastasized cells develop into clinically significant metastatic lesions.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of zinc-finger E-box binding homeobox 1 mRNA levels in peritoneal washing for gastric cancer

Yabusaki

Yamada

Murai

et al. 2014

Molecular and Clinical Oncology

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Abstract. Zinc-finger E-box binding homeobox 1 (ZEB1) is an important regulator of epithelial-to-mesenchymal transition and is associated with various types of metastasis. Gastric cancer patients often develop peritoneal carcinomatosis, of which the detection of free cancer cells in the peritoneal washes is an important predictor. We analyzed the correlation of ZEB1 mRNA levels in the peritoneal washing (pZEB1) with clinicopathological variables and survival in 107 gastric cancer patients who underwent surgery and peritoneal washing cytology. Reverse transcription-polymerase chain reaction was performed to quantify pZEB1. The patients were classified into the pZEB1High (n=27) and the pZEB1 Low (n=80) groups based on their pZEB1 expression. pZEB1 was statistically correlated with pathological T stage (P= 0.03) and vascular involvement (P= 0.03). At 5 years, the disease-specific survival was 36.4% for the pZEB1High group and 64.7% for the pZEB1 Low group (P= 0.02), whereas the disease-free survival rate was 46.9% for the pZEB1 High group and 83.0% for the pZEB1 Low group (P= 0.03). When subclassified into 4 categories based on washing cytology and pZEB1, survival was significantly lower in the pZEB1 High compared to the pZEB1 Low group (cytology-negative group, P= 0.01; cytology-positive group, P= 0.13). Therefore, pZEB1 may add valuable information to conventional peritoneal washing cytology as a prognostic determinant in gastric cancer.

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“…There is significant crosstalk between the individual WNT signaling pathways (which is often antagonistic), leading researchers to view WNT pathways as a network of integrated signals, called the WNT signaling network (Kestler and Kuhl 2008;van Amerongen and Nusse 2009).…”

Section: Wnt Signaling In Cancermentioning

confidence: 99%

“…In addition, elevated nuclear β-catenin has been identified in lymphatic metastases of human cSCC, suggesting it may also be associated with advanced stage disease (Toll, et al 2013). Collectively these 'omic' and immunohistochemical studies have identified potentially altered WNT signaling activity in cSCC (in particular the WNT/β-catenin pathway), but what causes it and what effect this signaling has on the behaviour of cSCC cells is still under investigation.…”

Section: Wnt Signaling In Csccmentioning

confidence: 99%

“…Epithelial-to-mesenchymal transition (EMT) events have been suggested as another mechanism that can lead to the accumulation of nuclear β-catenin in cSCC, through loss of E-cadherin-β-catenin binding to facilitate increased β-catenin signaling (Margulis, et al 2005), which is linked with metastatic spread in human cSCC (Toll, et al 2013). More recently, the receptor tyrosine-kinase, Axl, which is over-expressed in cSCC biopsies (Green, et al 2006), was shown to promote expression of EMT markers, nuclear β-catenin and stem-like properties that conferred increased sphere formation, tumor initiation, and drug resistance in human cSCC cells (Cichon, et al 2014).…”

Section: Wnt Signaling In Csccmentioning

confidence: 99%

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WNT Signaling in Cutaneous Squamous Cell Carcinoma: A Future Treatment Strategy?

Sherwood

Leigh

2016

Journal of Investigative Dermatology

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The molecular mechanisms underlying cutaneous squamous cell carcinoma are less well established than other common skin cancers, but recent evidence has highlighted a potentially critical role for WNT signaling in both the development and progression of cSCC.WNT pathways are aberrantly regulated in multiple tumour types (albeit in a context-dependent manner) and this has stimulated the development of WNT inhibitory compounds for cancer treatment. In this review, we examine existing evidence for a role of WNT signaling in cSCC and discuss if WNT inhibition represents a realistic therapeutic strategy for the future.2

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Epithelial to mesenchymal transition markers are associated with an increased metastatic risk in primary cutaneous squamous cell carcinomas but are attenuated in lymph node metastases

Cited by 66 publications

References 45 publications

Active nuclear IKK correlates with metastatic risk in cutaneous squamous cell carcinoma

Active nuclear IKK correlates with metastatic risk in cutaneous squamous cell carcinoma

Clinical significance of zinc-finger E-box binding homeobox 1 mRNA levels in peritoneal washing for gastric cancer

WNT Signaling in Cutaneous Squamous Cell Carcinoma: A Future Treatment Strategy?

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