Impaired Notch Signaling Promotes De novo Squamous Cell Carcinoma Formation

Abstract

Signaling through Notch receptors in the skin has been implicated in the differentiation, proliferation, and survival of keratinocytes, as well as in the pathogenesis of basal cell carcinoma (BCC). To determine the composite function of Notch receptor-mediated signaling in the skin and overcome potential redundancies between receptors, conditional transgenic mice were generated that express the pan-Notch inhibitor, dominant-negative Mastermind Like 1 (DNMAML1), to repress all canonical [CBF-1/Suppressor of hairless/L AG-1 (CSL)-dependent] Notch signaling exclusively in the epidermis. Here, we report that DNMAML1 mice display hyperplastic epidermis and spontaneously develop cutaneous squamous cell carcinoma (SCC) as well as dysplastic precursor lesions, actinic keratoses. Mice expressing epidermal DNMAML1 display enhanced accumulation of nuclear B-catenin and cyclin D1 in suprabasilar keratinocytes and in lesional cells from SCCs, which was also observed in human cutaneous SCC. These results suggest a model wherein CSL-dependent Notch signaling confers protection against cutaneous SCC. The demonstration that inhibition of canonical Notch signaling in mice leads to spontaneous formation of SCC and recapitulates the disease in humans yields fundamental insights into the pathogenesis of SCC and provides a unique in vivo animal model to examine the pathobiology of cutaneous SCC and for evaluating novel therapies. (Cancer Res 2006; 66(15): 7438-44)

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…In the epidermis of induced Notch1 ‐/‐ mice, significantly high levels of free (unphosphorylated) beta‐catenin were observed 30. Loss of Notch1 signaling seems to activate beta‐catenin signaling in human CSCC 28, which can be repressed by the introduction of a dominant active form of NOTCH130. In particular, p21 (a downstream mediator of Notch1‐induced growth arrest as we described above) also contributes to the downregulation of Wnt signaling, which likely account for the decreased levels of beta‐catenin activation by activated NOTCH134.…”

“…Consistently, conditional transgenic mice were generated by expressing a dominant negative MAML1 protein to inhibit Notch signaling in the epidermis. These mice exhibited epidermal hyperplasia and developed spontaneous CSCC 28. Furthermore, the keratinocyte‐specific ablation of NOTCH1 induced significant proliferation of the basal epidermal layer and deregulated expressions of multiple differentiation markers, indicating disrupted balance between growth and differentiation 29.…”

“…2). The disruption of canonical Notch/CSL/MAML‐mediated signaling pathways in transgenic mice by expressing epidermal DNMAML1 (a pan‐Notch inhibitor) resulted in hyperplastic epidermis and spontaneously developed CSCC 28. In mouse keratinocytes, cyclin‐dependent kinase inhibitor p21 was identified as a downstream positive target of NOTCH1, where activated NOTCH1 induces p21 expression to suppress growth in a CSL‐dependent manner 29, 30.…”

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

“…Building on these findings, Parmacek and colleagues demonstrated that dominant negative repression of Notch signaling in mouse skin renders the animials susecptible to developing cSCC, with nuclear β-catenin accumulation and increased cyclinD1 expression, the latter of which is a common target of β-catenin signaling that drives tumour proliferation (Proweller, et al 2006). p63 (a member of the p53 tumour suppressor gene family) has been found to be an upstream regulator of both the WNT/β-catenin and Notch signaling pathways modulating proliferation in immortalised human keratinocytes (Wu, et al 2012).…”

Cancer stem cells as targets for cancer therapy: selected cancers as examples

“…This imbalance is strongly connected to Notch deficiency and Notch1 and Notch2 expression are reduced in BCC [128]. Animal experiments showed that deletion of the Notch gene can lead to BCC in mice [123,140,167] and UV-light exposure triggered malignant basal cell transformation, especially in Notch1-defient skin areas [128]. BCC has an extremely low metastatic potential and is therefore considered a "semi-malignant" tumor.…”