AvB6 Integrin Promotes the Invasion of Morphoeic Basal Cell Carcinoma through Stromal Modulation (original) (raw)
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v 6 Integrin Promotes the Invasion of Morphoeic Basal Cell Carcinoma through Stromal Modulation
Cancer Research, 2008
Basal cell carcinoma (BCC) is the most prevalent cancer in the Western world and its incidence is increasing. The pathogenesis of BCC involves deregulated Sonic hedgehog signaling, leading to activation of the Gli transcription factors. Most BCCs have a nodular growth pattern, and are indolent, slowgrowing, and considered ''low-risk'' lesions. In contrast, the ''high-risk'' morphoeic variant, which causes significant morbidity, has an infiltrative growth pattern, and is so-called because of its densely fibrous stroma. As AvB6 is capable of promoting both carcinoma invasion and fibrosis, we examined the expression of this integrin in BCCs and found that the morphoeic type showed significantly higher AvB6 expression than the nodular type (P = 0.0009). In order to examine the function of AvB6, we transfected the transcription factors Gli1 or Gli2 into NTERT, human keratinocytes to generate a BCC model. These cells expressed AvB6 and were invasive, although inhibition of AvB6 had no direct effect on cell invasion. However, the cells showed AvB6-dependent activation of transforming growth factor-B1, which induced transdifferentiation of human fibroblasts into myofibroblasts. Paracrine secretion of hepatocyte growth factor/scatter factor by these myofibroblasts promoted c-Met-dependent tumor invasion in both Transwell and three-dimensional organotypic assays. These experimental in vitro findings were confirmed using human clinical samples in which we showed that the stroma of morphoeic BCC is myofibroblast-rich compared with nodular BCC (P = 0.0036), that myofibroblasts express hepatocyte growth factor/scatter factor, and that morphoeic BCCs are strongly c-Met-positive. These data suggest that AvB6-dependent transforming growth factor-B1 activation induces both the infiltrative growth pattern and fibrotic stroma so characteristic of morphoeic BCC. [Cancer Res 2008;68(9):3295-303]
2008
Basal cell carcinoma (BCC) is the most prevalent cancer in the Western world and its incidence is increasing. The pathogenesis of BCC involves deregulated Sonic hedgehog signaling, leading to activation of the Gli transcription factors. Most BCCs have a nodular growth pattern, and are indolent, slowgrowing, and considered ''low-risk'' lesions. In contrast, the ''high-risk'' morphoeic variant, which causes significant morbidity, has an infiltrative growth pattern, and is so-called because of its densely fibrous stroma. As AvB6 is capable of promoting both carcinoma invasion and fibrosis, we examined the expression of this integrin in BCCs and found that the morphoeic type showed significantly higher AvB6 expression than the nodular type (P = 0.0009). In order to examine the function of AvB6, we transfected the transcription factors Gli1 or Gli2 into NTERT, human keratinocytes to generate a BCC model. These cells expressed AvB6 and were invasive, although inhibition of AvB6 had no direct effect on cell invasion. However, the cells showed AvB6-dependent activation of transforming growth factor-B1, which induced transdifferentiation of human fibroblasts into myofibroblasts. Paracrine secretion of hepatocyte growth factor/scatter factor by these myofibroblasts promoted c-Met-dependent tumor invasion in both Transwell and three-dimensional organotypic assays. These experimental in vitro findings were confirmed using human clinical samples in which we showed that the stroma of morphoeic BCC is myofibroblast-rich compared with nodular BCC (P = 0.0036), that myofibroblasts express hepatocyte growth factor/scatter factor, and that morphoeic BCCs are strongly c-Met-positive. These data suggest that AvB6-dependent transforming growth factor-B1 activation induces both the infiltrative growth pattern and fibrotic stroma so characteristic of morphoeic BCC. [Cancer Res 2008;68(9):3295-303]
Clinical Cancer Research, 2010
The hedgehog (Hh) signaling pathway plays an important role in embryogenesis across multiple species. Its activity is reduced or absent in adult organisms. However, activation of the pathway has been shown to be a factor in the development of a number of human malignancies and inhibition of the pathway is being investigated as a potential treatment for multiple cancers. The most extensively investigated and best characterized is basal cell carcinoma (BCC), which occurs in both an inherited form (basal cell nevus syndrome or Gorlin's syndrome) and a sporadic form. Sporadic BCCs are the most common human malignancy. There is recent data available on the use of a small molecule inhibitor of the pathway in BCC. Clin Cancer Res; 16(13); 3335-9. ©2010 AACR.
Journal of Clinical Medicine
Basal cell carcinoma (BCC) is the most common malignant skin tumor. BCC displays a different behavior compared with other neoplasms, has a slow evolution, and metastasizes very rarely, but sometimes it causes an important local destruction. Chronic ultraviolet exposure along with genetic factors are the most important risk factors involved in BCC development. Mutations in the PTCH1 gene are associated with Gorlin syndrome, an autosomal dominant disorder characterized by the occurrence of multiple BCCs, but are also the most frequent mutations observed in sporadic BCCs. PTCH1 encodes for PTCH1 protein, the most important negative regulator of the Hedgehog (Hh) pathway. There are numerous studies confirming Hh pathway involvement in BCC pathogenesis. Although Hh pathway has been intensively investigated, it remains incompletely elucidated. Recent studies on BCC tumorigenesis have shown that in addition to Hh pathway, there are other signaling pathways involved in BCC development. In t...
Indian Journal of Pharmacology, 2014
The Hedgehog signaling pathway is one of the major regulators of cell growth and differentiation during embryogenesis and early development. It is mostly quiescent in adults but inappropriate mutation or deregulation of the pathway is involved in the development of cancers. Therefore; recently it has been recognized as a novel therapeutic target in cancers. Basal cell carcinomas (BCC) and medulloblastomas are the two most common cancers identified with mutations in components of the hedgehog pathway. The discovery of targeted Hedgehog pathway inhibitors has shown promising results in clinical trials, several of which are still undergoing clinical evaluation. Vismodegib (GDC-0449), an oral hedgehog signaling pathway inhibitor has reached the farthest in clinical development. Initial clinical trials in basal cell carcinoma and medulloblastoma have shown good efficacy and safety and hence were approved by U.S. FDA for use in advanced basal cell carcinomas. This review highlights the molecular basis and the current knowledge of hedgehog pathway activation in different types of human cancers as well as the present and future prospects of the novel drug vismodegib.
Basal cell carcinoma — molecular biology and potential new therapies
Journal of Clinical Investigation, 2012
Basal cell carcinoma (BCC) of the skin, the most common malignancy in individuals of mixed European descent, is increasing in incidence due to an aging population and sun exposure habits. The realization that aberrant activation of Hedgehog signaling is a pathognomonic feature of BCC development has opened the way for exciting progress toward understanding BCC biology and translation of this knowledge to the clinic. Genetic mouse models closely mimicking human BCCs have provided answers about the tumor cell of origin, and inhibition of Hedgehog signaling is emerging as a potentially useful targeted therapy for patients with advanced or multiple BCCs that have hitherto lacked effective treatment.
Oncotarget
Basal Cell Carcinoma (BCC) is one of the most diagnosed cancers worldwide. It develops due to an unrestrained Sonic Hedgehog (SHH) signaling activity in basal cells of the skin. Certain subtypes of BCC are more aggressive than others, although the molecular basis of this phenomenon remains unknown. We have previously reported that Neogenin-1 (NEO1) is a downstream target gene of the SHH/GLI pathway in neural tissue. Given that SHH participates in epidermal homeostasis, here we analyzed the epidermal expression of NEO1 in order to identify whether it plays a role in adult epidermis or BCC. We describe the mRNA and protein expression profile of NEO1 and its ligands (Netrin-1 and RGMA) in human and mouse control epidermis and in a broad range of human BCCs. We identify in human BCC a significant positive correlation in the levels of NEO1 receptor, NTN-1 and RGMA ligands with respect to GLI1, the main target gene of the canonical SHH pathway. Moreover, we show via cyclopamine inhibition of the SHH/GLI pathway of ex vivo cultures that NEO1 likely functions as a downstream target of SHH/GLI signaling in the skin. We also show how Neo1 expression decreases throughout BCC progression in the K14-Cre:Ptch1 lox/ lox mouse model and that aggressive subtypes of human BCC exhibit lower levels of NEO1 than non-aggressive BCC samples. Taken together, these data suggest that NEO1 is a SHH/ GLI target in epidermis. We propose that NEO1 may be important in tumor onset and is then down-regulated in advanced BCC or aggressive subtypes.
Novel Hedgehog pathway targets against basal cell carcinoma
Toxicology and applied pharmacology, 2007
The Hedgehog signaling pathway plays a key role in directing growth and patterning during embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin, and hair. Aberrant activation of the Hedgehog (Hh) pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and a subset of pancreatic, gastrointestinal, and other cancers. This review will provide an overview of what is known about the mechanisms by which activation of Hedgehog signaling leads to the development of BCCs and will review two recent papers suggesting that agents that modulate sterol levels might influence the Hh pathway. Thus, sterols may be a new therapeutic target for the treatment of BCCs, and readily available agents such as statins (HMG-CoA reductase inhibitors) or vitamin D might be helpful in reducing BCC incidence.
Life Science Alliance
Basal cell carcinoma (BCC) is the most common skin cancer and human malignancy. Although most BCCs are easily managed, some are aggressive locally, require Mohs micrographic surgery, or can even metastasize. In the latter, resistance to Sonic Hedgehog inhibitors may occur. Despite their frequent occurrence in clinical practice, their transcriptional landscape remains poorly understood. By analyzing BCC RNA sequencing data according to clinically important features (all BCCs versus normal skin, high-risk versus low-risk BCCs based solely on histopathological subtypes with aggressive features, advanced versus non-advanced BCCs, and vismodegib-resistant versus vismodegib-sensitive tumors), we have identified novel differentially regulated genes and new targetable pathways implicated in BCC tumorigenesis. Pathways as diverse as IL-17, TLR, Akt/PI3K, cadherins, integrins, PDGF, and Wnt/β-catenin are promising therapeutic avenues for local and systemic agents in managing this common malig...