The Impact of Notch Signaling for Carcinogenesis and Progression of Nonmelanoma Skin Cancer: Lessons Learned from Cancer Stem Cells, Tumor Angiogenesis, and Beyond.

Since many decades, nonmelanoma skin cancer (NMSCs) is the most common malignancy worldwide. Basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) are the major types of NMSCs, representing approximately 70% and 25% of these neoplasias, respectively. Because of their continuously rising incidence rates, NMSCs represent a constantly increasing global challenge for healthcare, although they are in most cases nonlethal and curable (e.

Notch Signaling in Prevention And Therapy: Fighting Cancer with a Two-Sided Sword.

The evolutionary conserved Notch pathway that first developed in metazoans and that was first discovered in fruit flies (Drosophila melanogaster) governs fundamental cell fate decisions and many other cellular key processes not only in embryonic development but also during initiation, promotion, and progression of cancer. On a first look, the Notch pathway appears remarkably simple, with its key feature representing a direct connection between an extracellular signal and transcriptional output without the need of a long chain of protein intermediaries as known from many other signaling pathways. However, on a second, closer look, this obvious simplicity exerts surprising complexity.

Crosstalk Between Vitamin D and p53 Signaling in Cancer: An Update.

It has now been convincingly shown that vitamin D and p53 signaling protect against spontaneous or carcinogen-induced malignant transformation of cells. The vitamin D receptor (VDR) and the p53/p63/p73 proteins (the p53 family hereafter) exert their effects as receptors/sensors that turn into transcriptional regulators upon stimulus. While the p53 clan, mostly in the nucleoplasm, responds to a large and still growing number of alterations in cellular homeostasis commonly referred to as stress, the nuclear VDR is transcriptionally activated after binding its naturally occurring biologically active ligand 1,25-dihydroxyvitamin D with high affinity.

A Snapshot of the Molecular Biology of Notch Signaling: Challenges and Promises.

Evolutionary conserved Notch signaling is of high importance for embryogenesis and adult tissues, representing one of the most fascinating pathways that regulate key cell fate decisions and other core processes. This chapter gives a short introduction to the first volume of the book entitled Notch Signaling in Embryology and Cancer, that is intended to provide both basic scientists and clinicians who seek today`s clearest understanding of the molecular mechanisms that mediate Notch signaling with an authoritative day-to-day source. On a first look, Notch signaling, that first developed in metazoans and that was first discovered in a fruit fly, seems fallaciously simple, with its key feature being a direct link between an extracellular signal and transcriptional output without the requirement of an extended chain of protein intermediaries as needed by the majority of other signaling pathways.

Notch Pathway and Inherited Diseases: Challenge and Promise.

The evolutionary highly conserved Notch pathway governs many cellular core processes including cell fate decisions. Although it is characterized by a simple molecular design, Notch signaling, which first developed in metazoans, represents one of the most important pathways that govern embryonic development. Consequently, a broad variety of independent inherited diseases linked to defective Notch signaling has now been identified, including Alagille, Adams-Oliver, and Hajdu-Cheney syndromes, CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), early-onset arteriopathy with cavitating leukodystrophy, lateral meningocele syndrome, and infantile myofibromatosis.

Notch Signaling and Embryonic Development: An Ancient Friend, Revisited.

The evolutionary highly conserved Notch pathway, which first developed during evolution in metazoans and was first discovered in fruit flies (Drosophila melanogaster), governs many core processes including cell fate decisions during embryonic development. A huge mountain of scientific evidence convincingly demonstrates that Notch signaling represents one of the most important pathways that regulate embryogenesis from sponges, roundworms, Drosophila melanogaster, and mice to humans. In this review, we give a brief introduction on how Notch orchestrates the embryonic development of several selected tissues, summarizing some of the most relevant findings in the central nervous system, skin, kidneys, liver, pancreas, inner ear, eye, skeleton, heart, and vascular system.

Notch Signaling and Tissue Patterning in Embryology: An Introduction.

The attention of science first turned to the gene that later earned the name Notch over a century ago, when the American scientist John S. Dexter discovered in his laboratory at Olivet College the characteristic notched-wing phenotype (a nick or notch in the wingtip) in mutant fruit flies Drosophila melanogaster. At present, it is generally accepted that the Notch pathway governs tissue patterning and many key cell fate decisions and other core processes during embryonic development and in adult tissues.

A snapshot of anatomy teaching: Peer-led anatomy boot camps - Priming for success?

Introduction: Pending changes regarding the medical curricula in Germany prompted us, members of the Department of Anatomy at the Medical Faculty of Saarland University, to critically evaluate anatomy teaching with special attention to macroscopic anatomy and the dissection class. Aiming at a thorough assessment we were particularly interested to which extend an optional peer-led tutorial ("anatomy boot camp"), which had preceded the dissection class, impacted the outcome in a series of oral exams of those who had participated.

Methods: We evaluated a student cohort of 307 students in the fall/winter semester 2015/16 at Saarland University, including those enrolled in medicine and dentistry, by implementing a series of questionnaires specifically designed for five mandatory oral exams during the course of the dissection class.

Solarium Use and Risk for Malignant Melanoma: Meta-analysis and Evidence-based Medicine Systematic Review.

Background: There is an ongoing debate whether solarium use (indoor tanning/artificial UV) may increase the risk for primary cutaneous malignant melanoma.

Aim: A systematic literature search was conducted using MEDLINE and ISI Web of Science. Included studies were critically assessed regarding their risk of bias, and methodological shortcomings.

Modulation of macrophage phagocytosis in vitro-A role for cholinergic stimulation?

Acetylcholine is synthetized and released from neural cells, but also by non-neuronal cells such as epithelial cells or keratinocytes. Cholinergic agonists enhance the phagocytosis of zymosan particles in primary peritoneal macrophages. The aim of this study was to investigate the effect of carbachol stimulation on phagocytosis in a macrophage cell line using microspheres.

Targeting the non-neuronal cholinergic system in macrophages for the management of infectious diseases and cancer: challenge and promise.

Macrophages represent key players of the immune system exerting highly effective defense mechanisms against microbial infections and cancer that include phagocytosis and programmed cell removal. Recent findings highlight the relevance of the non-neuronal cholinergic system for the regulation of macrophage function that opens promising new concepts for the treatment of infectious diseases and cancer. This mini review summarizes our present knowledge on this topic and gives an outlook on future developments.

Human Pigmentation, Cutaneous Vitamin D Synthesis and Evolution: Variants of Genes (SNPs) Involved in Skin Pigmentation Are Associated with 25(OH)D Serum Concentration.

Vitamin D deficiency is common and associated with higher risk for and unfavourable outcome of many diseases. Limited data exist on genetic determinants of serum 25(OH)D concentration. In a cohort of the LURIC study (n=2974, median 25(OH)D concentration 15.

Sunlight, vitamin D and malignant melanoma: an update.

Solar radiation represents an essential requirement for life, not only by spending the thermal energy for photosynthesis in plants, which provides our atmosphere with oxygen, but also by facilitating the cutaneous synthesis of vitamin D in vertebrates and many other organisms. It is well known that humans and most vertebrates have to obtain an adequate source of vitamin D, in order to develop and maintain a healthy mineralized skeleton and in order to be protected against cancer and a broad variety of other diseases. On the other hand, solar UV radiation can be assumed to be the most relevant environmental carcinogen causing melanoma and nonmelanoma skin cancer with increasing incidences.

Tumor suppression in skin and other tissues via cross-talk between vitamin D- and p53-signaling.

P53 and its family members have been implicated in the direct regulation of the vitamin D receptor (VDR). Vitamin D- and p53-signaling pathways have a significant impact on spontaneous or carcinogen-induced malignant transformation of cells, with VDR and p53 representing important tumor suppressors. VDR and the p53/p63/p73 proteins all function typically as receptors or sensors that turn into transcriptional regulators upon stimulus, with the main difference being that the nuclear VDR is activated as a transcription factor after binding its naturally occurring ligand 1,25-dihydroxyvitamin D with high affinity while the p53 family of transcription factors, mostly in the nucleoplasm, responds to a large number of alterations in cell homeostasis commonly referred to as stress.

The relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of non-melanoma skin cancer (NMSC): Present concepts and future perspectives.

Solar UV (UV)-B-radiation exerts both beneficial and adverse effects on human health. On the one hand, it is the most important environmental risk factor for the development of non-melanoma skin cancer [NMSC; most importantly basal (BCC) and squamous (SCC) cell carcinomas], that represent the most common malignancies in Caucasian populations. On the other hand, the human body's requirements of vitamin D are mainly achieved by UV-B-induced cutaneous photosynthesis.

No evidence for induction of key components of the Notch signaling pathway (Notch-1, Jagged-1) by treatment with UV-B, 1,25(OH)(2)D(3), and/or epigenetic drugs (TSA, 5-Aza) in human keratinocytes in vitro.

Notch signaling is of high importance for growth and survival of various cell types. We now analyzed the protein expression of two key components of the Notch signaling pathway (Notch-1, Jagged-1) in spontaneously immortalized (HaCaT) and in malignant (SCL-1) human keratinocytes, using western analysis. We found that Notch-1 and its corresponding ligand Jagged-1 are expressed in both cell lines, with no marked change following UV-B treatment.

Hope and challenge: the importance of ultraviolet (UV) radiation for cutaneous vitamin D synthesis and skin cancer.

Abstract Solar ultraviolet (UV)-radiation is the most important environmental risk factor for the development of non-melanoma skin cancer (most importantly basal and squamous cell carcinomas), that represent the most common malignancies in Caucasian populations. To prevent these malignancies, public health campaigns were developed to improve the awareness of the general population of the role of UV-radiation. The requirements of vitamin D is mainly achieved by UV-B-induced cutaneous photosynthesis, and the vitamin D-mediated positive effects of UV-radiation were not always adequately considered in these campaigns; a strict "no sun policy" might lead to vitamin D-deficiency.

Notch-signaling and nonmelanoma skin cancer: an ancient friend, revisited.

In humans and other species, Notch-signaling is of critical importance for carcinogenesis in several organs, including the skin. Interestingly, Notch-signaling appears to exert opposite roles in skin carcinogenesis as compared to carcinogenesis in other tissues. While the Notch1 receptor (Notch1) acts as a proto-oncogene in most tissues, it has been shown that Notch1 deletion in epidermal keratinocytes causes skin carcinogenesis.

Signature of VDR miRNAs and epigenetic modulation of vitamin D signaling in melanoma cell lines.

Background: Melanoma cells express the nuclear vitamin D receptor (VDR), indicating that malignant melanoma represents a promising target for treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) or its analogs. We previously showed that some melanoma cell lines are resistant to the antiproliferative effects of 1,25(OH)(2)D(3) and that 1,25(OH)(2)D(3)-sensitivity can, at least in part, be restored by co-treatment with the histone deacetylase inhibitor (HDACI) Trichostatin A (TSA) or with the DNA methyltransferase inhibitor (DNMTI), 5-azacytidine (5-Aza). This study aimed at gaining further insights into the molecular mechanisms that underlie the epigenetic modulation of 1,25(OH)(2)D(3)-sensitivity in melanoma cells.

Association of genetic variants of the vitamin D receptor (VDR) with cutaneous squamous cell carcinomas (SCC) and basal cell carcinomas (BCC): a pilot study in a German population.

Background: Vitamin D receptor (VDR) polymorphisms have important implications for vitamin D signalling and are associated with various malignancies.

Patients And Methods: In a German population, the frequency of several VDR polymorphisms (Apa1, Taq1, Bgl1) in basal cell carcinomas (BCCs, n=90) and cutaneous squamous cell carcinomas (SCCs, n=100) as compared to healthy controls (n=51) was analyzed.

Results: Impressive variations in the frequency of some VDR genotypes were found when comparing skin of cancer patients and controls.

Notch- and vitamin D signaling in 1,25(OH)2D3-resistant glioblastoma multiforme (GBM) cell lines.

Recently, an important role of Notch activation for Ras-induced transformation of glial cells and for glioma growth and survival has been demonstrated. It was concluded that activation of Notch-signaling may represent a new target for glioblastoma multiforme (GBM) therapy. We now analyzed five GBM cell lines (Tx3095, Tx3868, U87, U118, U373) for key components of Notch-signaling pathways (Notch-1, Notch-2, Notch-3, Notch-4, Delta-like 1, Delta-like 3, Delta-like 4, Jagged-1, Jagged-2) using conventional RT-PCR.