Cancers

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Open AccessReview

TCF/LEF Transcription Factors: An Update from the Internet Resources

by Dusan Hrckulak, Michal Kolar, Hynek Strnad and Vladimir Korinek

Cancers 2016, 8(7), 70; https://doi.org/10.3390/cancers8070070 - 20 Jul 2016

Cited by 122 | Viewed by 14175

T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) proteins (TCFs) from the High Mobility Group (HMG) box family act as the main downstream effectors of the Wnt signaling pathway. The mammalian TCF/LEF family comprises four nuclear factors designated TCF7, LEF1, TCF7L1, and TCF7L2 (also known as [...] Read more.

T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) proteins (TCFs) from the High Mobility Group (HMG) box family act as the main downstream effectors of the Wnt signaling pathway. The mammalian TCF/LEF family comprises four nuclear factors designated TCF7, LEF1, TCF7L1, and TCF7L2 (also known as TCF1, LEF1, TCF3, and TCF4, respectively). The proteins display common structural features and are often expressed in overlapping patterns implying their redundancy. Such redundancy was indeed observed in gene targeting studies; however, individual family members also exhibit unique features that are not recapitulated by the related proteins. In the present viewpoint, we summarized our current knowledge about the specific features of individual TCFs, namely structural-functional studies, posttranslational modifications, interacting partners, and phenotypes obtained upon gene targeting in the mouse. In addition, we employed several publicly available databases and web tools to evaluate the expression patterns and production of gene-specific isoforms of the TCF/LEF family members in human cells and tissues. Full article

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Open AccessReview

Wnt Lipidation and Modifiers in Intestinal Carcinogenesis and Cancer

by Elke Kaemmerer and Nikolaus Gassler

Cancers 2016, 8(7), 69; https://doi.org/10.3390/cancers8070069 - 18 Jul 2016

Cited by 25 | Viewed by 6846

Abstract

The wingless (Wnt) signaling is suggested as a fundamental hierarchical pathway in regulation of proliferation and differentiation of cells. The Wnt ligands are small proteins of about 40 kDa essentially for regulation and initiation of the Wnt activity. They are secreted proteins requiring [...] Read more.

The wingless (Wnt) signaling is suggested as a fundamental hierarchical pathway in regulation of proliferation and differentiation of cells. The Wnt ligands are small proteins of about 40 kDa essentially for regulation and initiation of the Wnt activity. They are secreted proteins requiring acylation for activity in the Wnt signaling cascade and for functional interactivity with transmembrane proteins. Dual lipidation is important for posttranslational activation of the overwhelming number of Wnt proteins and is probably involved in their spatial distribution. The intestinal mucosa, where Wnt signaling is essential in configuration and maintenance, is an established model to study Wnt proteins and their role in carcinogenesis and cancer. The intestinal crypt-villus/crypt-plateau axis, a cellular system with self-renewal, proliferation, and differentiation, is tightly coordinated by a Wnt gradient. In the review, some attention is given to Wnt3, Wnt3A, and Wnt2B as important members of the Wnt family to address the role of lipidation and modifiers of Wnt proteins in intestinal carcinogenesis. Wnt3 is an important player in establishing the Wnt gradient in intestinal crypts and is mainly produced by Paneth cells. Wnt2B is characterized as a mitochondrial protein and shuttles between mitochondria and the nucleus. Porcupine and ACSL5, a long-chain fatty acid activating enzyme, are introduced as modifiers of Wnts and as interesting strategy to targeting Wnt-driven carcinogenesis. Full article

(This article belongs to the Special Issue Wnt Signaling in Cancer)

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Open AccessReview

Ptk7 and Mcc, Unfancied Components in Non-Canonical Wnt Signaling and Cancer

by Norris Ray Dunn and Nicholas S. Tolwinski

Cancers 2016, 8(7), 68; https://doi.org/10.3390/cancers8070068 - 16 Jul 2016

Cited by 26 | Viewed by 12712

Abstract

Human development uses a remarkably small number of signal transduction pathways to organize vastly complicated tissues. These pathways are commonly associated with disease in adults if activated inappropriately. One such signaling pathway, Wnt, solves the too few pathways conundrum by having many alternate [...] Read more.

Human development uses a remarkably small number of signal transduction pathways to organize vastly complicated tissues. These pathways are commonly associated with disease in adults if activated inappropriately. One such signaling pathway, Wnt, solves the too few pathways conundrum by having many alternate pathways within the Wnt network. The main or “canonical” Wnt pathway has been studied in great detail, and among its numerous downstream components, several have been identified as drug targets that have led to cancer treatments currently in clinical trials. In contrast, the non-canonical Wnt pathways are less well characterized, and few if any possible drug targets exist to tackle cancers caused by dysregulation of these Wnt offshoots. In this review, we focus on two molecules—Protein Tyrosine Kinase 7 (Ptk7) and Mutated in Colorectal Cancer (Mcc)—that do not fit perfectly into the non-canonical pathways described to date and whose roles in cancer are ill defined. We will summarize work from our laboratories as well as many others revealing unexpected links between these two proteins and Wnt signaling both in cancer progression and during vertebrate and invertebrate embryonic development. We propose that future studies focused on delineating the signaling machinery downstream of Ptk7 and Mcc will provide new, hitherto unanticipated drug targets to combat cancer metastasis. Full article

(This article belongs to the Special Issue Wnt Signaling in Cancer)

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Open AccessReview

Molecular Genetics of Intracranial Meningiomas with Emphasis on Canonical Wnt Signalling

by Nives Pećina-Šlaus, Anja Kafka and Mirna Lechpammer

Cancers 2016, 8(7), 67; https://doi.org/10.3390/cancers8070067 - 15 Jul 2016

Cited by 37 | Viewed by 6729

Abstract

Research over the last decade recognized the importance of novel molecular pathways in pathogenesis of intracranial meningiomas. In this review, we focus on human brain tumours meningiomas and the involvement of Wnt signalling pathway genes and proteins in this common brain tumour, describing [...] Read more.

Research over the last decade recognized the importance of novel molecular pathways in pathogenesis of intracranial meningiomas. In this review, we focus on human brain tumours meningiomas and the involvement of Wnt signalling pathway genes and proteins in this common brain tumour, describing their known functional effects. Meningiomas originate from the meningeal layers of the brain and the spinal cord. Most meningiomas have benign clinical behaviour and are classified as grade I by World Health Organization (WHO). However, up to 20% histologically classified as atypical (grade II) or anaplastic (grade III) are associated with higher recurrent rate and have overall less favourable clinical outcome. Recently, there is emerging evidence that multiple signalling pathways including Wnt pathway contribute to the formation and growth of meningiomas. In the review we present the synopsis on meningioma histopathology and genetics and discuss our research regarding Wnt in meningioma. Epithelial-to-mesenchymal transition, a process in which Wnt signalling plays an important role, is shortly discussed. Full article

(This article belongs to the Special Issue Wnt Signaling in Cancer)

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Open AccessReview

A Second WNT for Old Drugs: Drug Repositioning against WNT-Dependent Cancers

by Kamal Ahmed, Holly V. Shaw, Alexey Koval and Vladimir L. Katanaev

Cancers 2016, 8(7), 66; https://doi.org/10.3390/cancers8070066 - 14 Jul 2016

Cited by 46 | Viewed by 9457

Abstract

Aberrant WNT signaling underlies cancerous transformation and growth in many tissues, such as the colon, breast, liver, and others. Downregulation of the WNT pathway is a desired mode of development of targeted therapies against these cancers. Despite the urgent need, no WNT signaling-directed [...] Read more.

Aberrant WNT signaling underlies cancerous transformation and growth in many tissues, such as the colon, breast, liver, and others. Downregulation of the WNT pathway is a desired mode of development of targeted therapies against these cancers. Despite the urgent need, no WNT signaling-directed drugs currently exist, and only very few candidates have reached early phase clinical trials. Among different strategies to develop WNT-targeting anti-cancer therapies, repositioning of existing drugs previously approved for other diseases is a promising approach. Nonsteroidal anti-inflammatory drugs like aspirin, the anti-leprotic clofazimine, and the anti-trypanosomal suramin are among examples of drugs having recently revealed WNT-targeting activities. In total, 16 human-use drug compounds have been found to be working through the WNT pathway and show promise for their prospective repositioning against various cancers. Advances, hurdles, and prospects of developing these molecules as potential drugs against WNT-dependent cancers, as well as approaches for discovering new ones for repositioning, are the foci of the current review. Full article

(This article belongs to the Special Issue Wnt Signaling in Cancer)

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Open AccessReview

Mammary Development and Breast Cancer: A Wnt Perspective

by Qing Cissy Yu, Esther M. Verheyen and Yi Arial Zeng

Cancers 2016, 8(7), 65; https://doi.org/10.3390/cancers8070065 - 13 Jul 2016

Cited by 91 | Viewed by 15874

Abstract

The Wnt pathway has emerged as a key signaling cascade participating in mammary organogenesis and breast oncogenesis. In this review, we will summarize the current knowledge of how the pathway regulates stem cells and normal development of the mammary gland, and discuss how [...] Read more.

The Wnt pathway has emerged as a key signaling cascade participating in mammary organogenesis and breast oncogenesis. In this review, we will summarize the current knowledge of how the pathway regulates stem cells and normal development of the mammary gland, and discuss how its various components contribute to breast carcinoma pathology. Full article

(This article belongs to the Special Issue Wnt Signaling in Cancer)

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Open AccessReview

A Perspective of Immunotherapy for Prostate Cancer

by Ida Silvestri, Susanna Cattarino, Sabrina Giantulli, Cristina Nazzari, Giulia Collalti and Alessandro Sciarra

Cancers 2016, 8(7), 64; https://doi.org/10.3390/cancers8070064 - 7 Jul 2016

Cited by 27 | Viewed by 7869

Abstract

In cancer patients, the immune system is often altered with an excess of inhibitory factors, such as immunosuppressive cytokines, produced by regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC). The manipulation of the immune system has emerged as one of new promising [...] Read more.

In cancer patients, the immune system is often altered with an excess of inhibitory factors, such as immunosuppressive cytokines, produced by regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC). The manipulation of the immune system has emerged as one of new promising therapies for cancer treatment, and also represents an attractive strategy to control prostate cancer (PCa). Therapeutic cancer vaccines and immune checkpoint inhibitors have been the most investigated in clinical trials. Many trials are ongoing to define the effects of immune therapy with established treatments: androgen deprivation therapy (ADT) and chemotherapy (CT) or radiotherapy (RT). This article discusses some of these approaches in the context of future treatments for PCa. Full article

(This article belongs to the Special Issue Cancer Immunotherapies)

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Open AccessReview

Advancing Clostridia to Clinical Trial: Past Lessons and Recent Progress

by Alexandra M. Mowday, Christopher P. Guise, David F. Ackerley, Nigel P. Minton, Philippe Lambin, Ludwig J. Dubois, Jan Theys, Jeff B. Smaill and Adam V. Patterson

Cancers 2016, 8(7), 63; https://doi.org/10.3390/cancers8070063 - 28 Jun 2016

Cited by 30 | Viewed by 8383

Abstract

Most solid cancers contain regions of necrotic tissue. The extent of necrosis is associated with poor survival, most likely because it reflects aggressive tumour outgrowth and inflammation. Intravenously injected spores of anaerobic bacteria from the genus Clostridium infiltrate and selectively germinate in these [...] Read more.

Most solid cancers contain regions of necrotic tissue. The extent of necrosis is associated with poor survival, most likely because it reflects aggressive tumour outgrowth and inflammation. Intravenously injected spores of anaerobic bacteria from the genus Clostridium infiltrate and selectively germinate in these necrotic regions, providing cancer-specific colonisation. The specificity of this system was first demonstrated over 60 years ago and evidence of colonisation has been confirmed in multiple tumour models. The use of “armed” clostridia, such as in Clostridium Directed Enzyme Prodrug Therapy (CDEPT), may help to overcome some of the described deficiencies of using wild-type clostridia for treatment of cancer, such as tumour regrowth from a well-vascularised outer rim of viable cells. Successful preclinical evaluation of a transferable gene that metabolises both clinical stage positron emission tomography (PET) imaging agents (for whole body vector visualisation) as well as chemotherapy prodrugs (for conditional enhancement of efficacy) would be a valuable early step towards the prospect of “armed” clostridia entering clinical evaluation. The ability to target the immunosuppressive hypoxic tumour microenvironment using CDEPT may offer potential for synergy with recently developed immunotherapy strategies. Ultimately, clostridia may be most efficacious when combined with conventional therapies, such as radiotherapy, that sterilise viable aerobic tumour cells. Full article

(This article belongs to the Special Issue Cancers Gene Therapy)

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Open AccessReview

Modulating Dickkopf-1: A Strategy to Monitor or Treat Cancer?

by Mélody Mazon, Delphine Masi and Madeleine Carreau

Cancers 2016, 8(7), 62; https://doi.org/10.3390/cancers8070062 - 28 Jun 2016

Cited by 25 | Viewed by 5298

Abstract

Dickkopf-1 (DKK1) is a secreted Wnt/β-catenin pathway antagonist involved in embryogenesis. It was first described 25 years ago for its function in head induction and limb morphogenesis. Since then, this protein has been widely studied in the context of active Wnt/β-catenin signalling during [...] Read more.

Dickkopf-1 (DKK1) is a secreted Wnt/β-catenin pathway antagonist involved in embryogenesis. It was first described 25 years ago for its function in head induction and limb morphogenesis. Since then, this protein has been widely studied in the context of active Wnt/β-catenin signalling during cellular differentiation and development. Dysregulation of DKK1 has been associated with bone pathologies and has now emerged as a potential biomarker of cancer progression and prognosis for several types of malignancies. Reducing the amount of circulating DKK1 may reveal a simple and efficient strategy to limit or reverse cancer growth. This review will provide an overview of the role of Dickkopf-1 in cancer and explore its potential use as a biomarker and therapeutic target. Full article

(This article belongs to the Special Issue Wnt Signaling in Cancer)

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Open AccessReview

Optimizing the Detection of Circulating Markers to Aid in Early Lung Cancer Detection

by Vasudha Murlidhar, Nithya Ramnath, Sunitha Nagrath and Rishindra M. Reddy

Cancers 2016, 8(7), 61; https://doi.org/10.3390/cancers8070061 - 28 Jun 2016

Cited by 11 | Viewed by 6001

Abstract

Improving early detection of lung cancer is critical to improving lung cancer survival. Studies have shown that computerized tomography (CT) screening can reduce mortality from lung cancer, but this involves risks of radiation exposure and can identify non-cancer lung nodules that lead to [...] Read more.

Improving early detection of lung cancer is critical to improving lung cancer survival. Studies have shown that computerized tomography (CT) screening can reduce mortality from lung cancer, but this involves risks of radiation exposure and can identify non-cancer lung nodules that lead to unnecessary interventions for some. There is a critical need to develop alternative, less invasive methods to identify patients who have early-stage lung cancer. The detection of circulating tumor cells (CTCs) are a promising area of research, but current technology is limited by a low yield of CTCs. Alternate studies are investigating circulating nucleic acids and proteins as possible tumor markers. It is critical to develop innovative methods for early lung cancer detection that may include CTCs or other markers that are low-risk and low-cost, yet specific and sensitive, to facilitate improved survival by diagnosing the disease when it is surgically curable. Full article

(This article belongs to the Special Issue Lung Cancer Biomarkers)

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Open AccessReview

Wnt Signaling in Cancer Stem Cell Biology

by Felipe De Sousa e Melo and Louis Vermeulen

Cancers 2016, 8(7), 60; https://doi.org/10.3390/cancers8070060 - 27 Jun 2016

Cited by 190 | Viewed by 14675

Abstract

Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like [...] Read more.

Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like tumor cells that are responsible for fueling tumor growth. As therapeutic targeting of these tumor stem cells is an intense area of investigation, a concise understanding on how Wnt activity relates to cancer stem cell traits is needed. This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer. Full article

(This article belongs to the Special Issue Wnt Signaling in Cancer)

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Cancers, Volume 8, Issue 7 (July 2016) – 11 articles

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