scholarly journals Hedgehog Signaling in Colorectal Cancer: All in the Stroma?

2021 ◽  
Vol 22 (3) ◽  
pp. 1025
Author(s):  
Natalie Geyer ◽  
Marco Gerling
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressors ◽  
Hedgehog Signaling ◽  
Current Knowledge ◽  
Intestinal Development ◽  
Immunomodulatory Effects ◽  
Gli Transcription Factors ◽  
Hh Signaling ◽  
Potential Impact

Hedgehog (Hh) signaling regulates intestinal development and homeostasis. The role of Hh signaling in cancer has been studied for many years; however, its role in colorectal cancer (CRC) remains controversial. It has become increasingly clear that the “canonical” Hh pathway, in which ligand binding to the receptor PTCH1 initiates a signaling cascade that culminates in the activation of the GLI transcription factors, is mainly organized in a paracrine manner, both in the healthy colon and in CRC. Such canonical Hh signals largely act as tumor suppressors. In addition, stromal Hh signaling has complex immunomodulatory effects in the intestine with a potential impact on carcinogenesis. In contrast, non-canonical Hh activation may have tumor-promoting roles in a subset of CRC tumor cells. In this review, we attempt to summarize the current knowledge of the Hh pathway in CRC, with a focus on the tumor-suppressive role of canonical Hh signaling in the stroma. Despite discouraging results from clinical trials using Hh inhibitors in CRC and other solid cancers, we argue that a more granular understanding of Hh signaling might allow the exploitation of this key morphogenic pathway for cancer therapy in the future.

scholarly journals Role of Hedgehog Signaling in Vasculature Development, Differentiation, and Maintenance

2019 ◽  
Vol 20 (12) ◽  
pp. 3076 ◽  
Author(s):  
Candice Chapouly ◽  
Sarah Guimbal ◽  
Pierre-Louis Hollier ◽  
Marie-Ange Renault
Keyword(s):  
Hedgehog Signaling ◽  
Current Knowledge ◽  
Vascular Biology ◽  
Cerebrovascular Diseases ◽  
Future Research ◽  
Cellular Mechanisms ◽  
Vascular Integrity ◽  
Hh Signaling ◽  
Vessel Integrity

The role of Hedgehog (Hh) signaling in vascular biology has first been highlighted in embryos by Pepicelli et al. in 1998 and Rowitch et al. in 1999. Since then, the proangiogenic role of the Hh ligands has been confirmed in adults, especially under pathologic conditions. More recently, the Hh signaling has been proposed to improve vascular integrity especially at the blood–brain barrier (BBB). However, molecular and cellular mechanisms underlying the role of the Hh signaling in vascular biology remain poorly understood and conflicting results have been reported. As a matter of fact, in several settings, it is currently not clear whether Hh ligands promote vessel integrity and quiescence or destabilize vessels to promote angiogenesis. The present review relates the current knowledge regarding the role of the Hh signaling in vasculature development, maturation and maintenance, discusses the underlying proposed mechanisms and highlights controversial data which may serve as a guideline for future research. Most importantly, fully understanding such mechanisms is critical for the development of safe and efficient therapies to target the Hh signaling in both cancer and cardiovascular/cerebrovascular diseases.

scholarly journals Roles of the Hedgehog Signaling Pathway in Skin Development, Homeostasis and Cancer

2017 ◽  
Author(s):  
Yoshinori Abe ◽  
Nobuyuki Tanaka
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Signaling Pathway ◽  
Basal Cell ◽  
Hedgehog Signaling ◽  
Current Knowledge ◽  
Skin Development ◽  
Morphogenetic Protein ◽  
Hh Signaling

The epidermis is the outermost layer of skin and provides a protective barrier against environmental insults. It is a rapidly renewing tissue undergoing constant regeneration, maintained by several types of stem cells. Hedgehog (HH) ligands activate one of the fundamental signaling pathways that contribute to epidermal development, homeostasis and repair. The HH pathway interacts with other signal transduction pathways such as those activated by Wnt and bone morphogenetic protein. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important to elucidate fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in skin development, homeostasis and basal cell carcinoma formation, providing an update of current knowledge in this field.

Role of Regulatory Oncogenic or Tumor Suppressor miRNAs of PI3K/AKT Signaling Axis in the Pathogenesis of Colorectal Cancer

2019 ◽  
Vol 24 (39) ◽  
pp. 4605-4610 ◽  
Author(s):  
Atena Soleimani ◽  
Farzad Rahmani ◽  
Gordon A. Ferns ◽  
Mikhail Ryzhikov ◽  
Amir Avan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Current Knowledge ◽  
Akt Signaling ◽  
Tumor Tissues ◽  
Radio Therapy ◽  
Signaling Axis ◽  
Cancer Tumor ◽  
Novel Biomarkers

Colorectal cancer (CRC) is the leading cause of cancer death worldwide and its incidence is increasing. In most patients with CRC, the PI3K/AKT signaling axis is over-activated. Regulatory oncogenic or tumor suppressor microRNAs (miRNAs) for PI3K/AKT signaling regulate cell proliferation, migration, invasion, angiogenesis, as well as resistance to chemo-/radio-therapy in colorectal cancer tumor tissues. Thus, regulatory miRNAs of PI3K/AKT/mTOR signaling represent novel biomarkers for new patient diagnosis and obtaining clinically invaluable information from post-treatment CRC patients for improving therapeutic strategies. This review summarizes the current knowledge of miRNAs’ regulatory roles of PI3K/AKT signaling in CRC pathogenesis.

Role of knot (kn) in Wing Patterning in Drosophila

Genetics ◽  
1997 ◽  
Vol 147 (3) ◽  
pp. 1203-1212 ◽  
Author(s):  
Katerina Nestoras ◽  
Helena Lee ◽  
Jym Mohler
Keyword(s):  
Hedgehog Signaling ◽  
Imaginal Disc ◽  
Hedgehog Signaling Pathway ◽  
Posterior Compartment ◽  
Drosophila Wing ◽  
Compartment Boundary ◽  
Hh Signaling ◽  
Embryonic Segmentation ◽  
Anterior Posterior

We have undertaken a genetic analysis of new strong alleles of knot (kn). The original kn1 mutation causes an alteration of wing patterning similar to that associated with mutations of fused (fu), an apparent fusion of veins 3 and 4 in the wing. However, unlike fu, strong kn mutations do not affect embryonic segmentation and indicate that kn is not a component of a general Hh (Hedgehog)-signaling pathway. Instead we find that kn has a specific role in those cells of the wing imaginal disc that are subject to ptc-mediated Hh-signaling. Our results suggest a model for patterning the medial portion of the Drosophila wing, whereby the separation of veins 3 and 4 is maintained by kn activation in the intervening region in response to Hh-signaling across the adjacent anterior-posterior compartment boundary.

scholarly journals Chemokines—What Is Their Role in Colorectal Cancer?

2020 ◽  
Vol 27 (1) ◽  
pp. 107327482090338 ◽  
Author(s):  
Sara Pączek ◽  
Marta Łukaszewicz-Zając ◽  
Barbara Mroczko
Keyword(s):  
Colorectal Cancer ◽  
Current Knowledge ◽  
Early Stage ◽  
Distant Metastases ◽  
Cell Types ◽  
Diagnosis And Prognosis ◽  
Novel Biomarkers ◽  
Specific Receptors ◽  
Common Malignancy

Colorectal cancer (CRC) is one of the leading causes of cancer-related death. It is the second most frequently diagnosed malignancy in Europe and third worldwide. Colorectal malignancies diagnosed at an early stage offer a promising survival rate. However, advanced tumors often present distant metastases even after the complete resection of a primary tumor. Therefore, novel biomarkers of CRC are sorely needed in the diagnosis and prognosis of this common malignancy. A family of chemokines are composed of small, secreted proteins. They are best known for their ability to stimulate the migration of several cell types. Some investigations have indicated that chemokines are involved in cancer development, including CRC. This article presents current knowledge regarding chemokines and their specific receptors in CRC progression. Moreover, the prime aim of this review is to summarize the potential role of these proteins as biomarkers in the diagnosis and prognosis of CRC.

Trefoil factor family peptides – friends or foes?

2015 ◽  
Vol 6 (5-6) ◽  
pp. 343-359 ◽  
Author(s):  
Maike Busch ◽  
Nicole Dünker
Keyword(s):  
Cancer Research ◽  
Tumor Suppressors ◽  
Current Knowledge ◽  
Tumor Biology ◽  
Epigenetic Mechanisms ◽  
Trefoil Factor ◽  
Protective Function ◽  
Trefoil Factor Family ◽  
Tff Peptides

AbstractTrefoil factor family (TFF) peptides are a group of molecules bearing a characteristic three-loop trefoil domain. They are mainly secreted in mucous epithelia together with mucins but are also synthesized in the nervous system. For many years, TFF peptides were only known for their wound healing and protective function, e.g. in epithelial protection and restitution. However, experimental evidence has emerged supporting a pivotal role of TFF peptides in oncogenic transformation, tumorigenesis and metastasis. Deregulated expression of TFF peptides at the gene and protein level is obviously implicated in numerous cancers, and opposing functions as oncogenes and tumor suppressors have been described. With regard to the regulation of TFF expression, epigenetic mechanisms as well as the involvement of various miRNAs are new, promising aspects in the field of cancer research. This review will summarize current knowledge about the expression and regulation of TFF peptides and the involvement of TFF peptides in tumor biology and cancerogenesis.

scholarly journals Role of the Hedgehog Signaling Pathway in Regulating the Behavior of Germline Stem Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Shiqin Li ◽  
Meng Wang ◽  
Yanghui Chen ◽  
Wei Wang ◽  
Junying Wu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Adult Stem Cells ◽  
Reproductive Function ◽  
Future Research ◽  
Germline Stem Cells ◽  
Proliferation And Differentiation ◽  
Hh Signaling

Germline stem cells (GSCs) are adult stem cells that are responsible for the production of gametes and include spermatogonial stem cells (SSCs) and ovarian germline stem cells (OGSCs). GSCs are located in a specialized microenvironment in the gonads called the niche. Many recent studies have demonstrated that multiple signals in the niche jointly regulate the proliferation and differentiation of GSCs, which is of significance for reproductive function. Previous studies have demonstrated that the hedgehog (Hh) signaling pathway participates in the proliferation and differentiation of various stem cells, including GSCs in Drosophila and male mammals. Furthermore, the discovery of mammalian OGSCs challenged the traditional opinion that the number of primary follicles is fixed in postnatal mammals, which is of significance for the reproductive ability of female mammals and the treatment of diseases related to germ cells. Meanwhile, it still remains to be determined whether the Hh signaling pathway participates in the regulation of the behavior of OGSCs. Herein, we review the current research on the role of the Hh signaling pathway in mediating the behavior of GSCs. In addition, some suggestions for future research are proposed.

scholarly journals Considerações sobre hormônios e sexo / Considerations on hormones and sex

2021 ◽  
Vol 66 (1u) ◽  
pp. 1
Author(s):  
Sônia Maria Rolim Rosa Lima
Keyword(s):  
Sexual Function ◽  
Ovarian Function ◽  
Current Knowledge ◽  
Serum Concentrations ◽  
Local Synthesis ◽  
Low Concentrations ◽  
Potential Impact ◽  
Review Current ◽  
Selection Of

Os esteroides sexuais, em particular os estrogênios e os androgênios, representam papel fundamental, na modulação da função sexual feminina. As mulheres após a menopausa, devido ao declínio da função ovariana, são dependentes da síntese local de estrogênios nos tecidos alvo extragonadais. Mantendo-se o quadro carêncial ocorre progressivo estreitamento da vagina, e o sintoma genital mais comum é a secura por diminuição da transudação e da quantidade de muco cervical. Esses fenômenos explicam os processos encontrados no período do climatério ou qualquer período em que ocorra a carência estrogênica, característicos da falência hormonal: vaginite atrófica, leucorréia, prurido, dor e sangramento ao coito. Com relação aos androgênios, vários estudos investigaram associações entre androgênios e função sexual em mulheres. Muitos, mas não todos, identificam uma relação entre o desejo sexual e as concentrações séricas de androgênios circulantes. A variabilidade nos resultados provavelmente reflete as limitações em aferir com precisão suas baixas concentrações, o impacto potencial de outros esteroides, as diferenças no desenho do estudo, na seleção das participantes e nos parâmetros de função sexual. Neste artigo, revisamos o conhecimento atual sobre o papel dos estrogênios e androgênios e seu uso clínico em mulheres com declínio da função ovariana.Palavras chave: Hormônios sexuais, Esteroides, Androgênios, Pós-Menopausa, Disfunções sexuais fisiológicasABSTRACTSex steroids, in particular estrogens and androgens, play a fundamental role in the modulation of female sexual function. Postmenopausal women, due to the decline in ovarian function, are dependent on the local synthesis of estrogens in extragonadal target tissues. If the deficiency is maintained, progressive narrowing of the vagina occurs, and the most common genital symptom is dryness due to decreased transudation and the amount of cervical mucus. These phenomena explain the processes found during the climacteric period or any period in which estrogen deficiency occurs, which are characteristic of hormonal failure: atrophic vaginitis, leukorrhea, itching, pain and bleeding on intercourse. With regard to androgens, several studies have investigated associations between androgens and sexual function in women. Many, but not all, identify a relationship between sexual desire and serum concentrations of circulating androgens. The variability in the results probably reflects the limitations in accurately measuring the low concentrations of androgens in women, the potential impact of other steroids, the differences in the study design, in the selection of participants and in the parameters of sexual function. In this article, we review current knowledge about the role of estrogens and androgens and their clinical use in women with declining ovarian function.Keywords: Sex hormones, Steroids, Androgens, Postmenopause, Physiological sexual dysfunctions

MicroRNAs and other non-coding RNAs in adipose tissue and obesity: emerging roles as biomarkers and therapeutic targets

2019 ◽  
Vol 133 (1) ◽  
pp. 23-40 ◽  
Author(s):  
Silvia Lorente-Cebrián ◽  
Pedro González-Muniesa ◽  
Fermín I. Milagro ◽  
J. Alfredo Martínez
Keyword(s):  
Adipose Tissue ◽  
Current Knowledge ◽  
Metabolic Effects ◽  
Protein Coding ◽  
Non Coding Rnas ◽  
Potential Impact ◽  
Dietary Strategies ◽  
Potential Use

AbstractObesity is a metabolic condition usually accompanied by insulin resistance (IR), type 2 diabetes (T2D), and dyslipidaemia, which is characterised by excessive fat accumulation and related to white adipose tissue (WAT) dysfunction. Enlargement of WAT is associated with a transcriptional alteration of coding and non-coding RNAs (ncRNAs). For many years, big efforts have focused on understanding protein-coding RNAs and their involvement in the regulation of adipocyte physiology and subsequent role in obesity. However, diverse findings have suggested that a dysfunctional adipocyte phenotype in obesity might be also dependent on specific alterations in the expression pattern of ncRNAs, such as miRNAs. The aim of this review is to update current knowledge on the physiological roles of miRNAs and other ncRNAs in adipose tissue function and their potential impact on obesity. Therefore, we examined their regulatory role on specific WAT features: adipogenesis, adipokine secretion, inflammation, glucose metabolism, lipolysis, lipogenesis, hypoxia and WAT browning. MiRNAs can be released to body fluids and can be transported (free or inside microvesicles) to other organs, where they might trigger metabolic effects in distant tissues, thus opening new possibilities to a potential use of miRNAs as biomarkers for diagnosis, prognosis, and personalisation of obesity treatment. Understanding the role of miRNAs also opens the possibility of using these molecules on individualised dietary strategies for precision weight management. MiRNAs should be envisaged as a future therapeutic approach given that miRNA levels could be modulated by synthetic molecules (f.i. miRNA mimics and inhibitors) and/or specific nutrients or bioactive compounds.

scholarly journals The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1188
Author(s):  
Jian Yi Chai ◽  
Vaisnevee Sugumar ◽  
Mohammed Abdullah Alshawsh ◽  
Won Fen Wong ◽  
Aditya Arya ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Clinical Settings ◽  
Developmental Studies ◽  
Holistic View ◽  
Gli Transcription Factors ◽  
Cancer Initiation ◽  
The Common

The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.

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