Wnt, Notch, and TGF-β Pathways Impinge on Hedgehog Signaling Complexity: An Open Window on Cancer

Pelullo, Maria; Zema, Sabrina; Nardozza, Francesca; Checquolo, Saula; Screpanti, Isabella; Bellavia, Diana

doi:10.3389/fgene.2019.00711

Cited by 109 publications

(74 citation statements)

References 236 publications

(256 reference statements)

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“…Dysregulation of Hh signaling has been implicated in several cancers including esophageal [67], gastric [68], pancreatic [69], as well as liver [70]. Previous studies showed activated Hh signaling may attenuate Wnt activity through the high expression of the Wnt inhibitor, SFRP1 [63,71,72].…”

Section: Involvement Of Sfrp1 In the Hedgehog Signaling Pathwaymentioning

confidence: 99%

“…Hh pathway activation is achieved by the interaction of Hh ligands to the Patched receptor (Ptch), and thus allows the accumulation of the transducer smoothened (SMO) at the cell surface. The accumulated SMO stimulates downstream components of the signaling pathway including Gli1 molecules, which then translocate into the nucleus and further activate the Hh target genes [72,73]. SFRP1 is a Hh target gene and is significantly regulated by Gli1 [71].…”

Section: Involvement Of Sfrp1 In the Hedgehog Signaling Pathwaymentioning

confidence: 99%

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Epigenetics of SFRP1: The Dual Roles in Human Cancers

Baharudin

Tieng

Lee

et al. 2020

Cancers

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Secreted frizzled-related protein 1 (SFRP1) is a gene that belongs to the secreted glycoprotein SFRP family. SFRP1 has been classified as a tumor suppressor gene due to the loss of expression in various human cancers, which is mainly attributed by epigenetic inactivation via DNA methylation or transcriptional silencing by microRNAs. Epigenetic silencing of SFRP1 may cause dysregulation of cell proliferation, migration, and invasion, which lead to cancer cells formation, disease progression, poor prognosis, and treatment resistance. Hence, restoration of SFRP1 expression via demethylating drugs or over-expression experiments opens the possibility for new cancer therapy approach. While the role of SFRP1 as a tumor suppressor gene is well-established, some studies also reported the possible oncogenic properties of SFRP1 in cancers. In this review, we discussed in great detail the dual roles of SFRP1 in cancers—as tumor suppressor and tumor promoter. The epigenetic regulation of SFRP1 expression will also be underscored with additional emphasis on the potentials of SFRP1 in modulating responses toward chemotherapeutic and epigenetic-modifying drugs, which may encourage the development of novel drugs for cancer treatment. We also present findings from clinical trials and patents involving SFRP1 to illustrate its clinical utility, extensiveness of each research area, and progression toward commercialization. Lastly, this review provides directions for future research to advance SFRP1 as a promising cancer biomarker.

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Section: Involvement Of Sfrp1 In the Hedgehog Signaling Pathwaymentioning

confidence: 99%

Section: Involvement Of Sfrp1 In the Hedgehog Signaling Pathwaymentioning

confidence: 99%

Epigenetics of SFRP1: The Dual Roles in Human Cancers

Baharudin

Tieng

Lee

et al. 2020

Cancers

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“…Few pathway analyses have shown that, Molecular signaling such as beta pathway on hedgehog signaling may lead to tumorigenesis [25,26]. PI3K/AKT/mTOR signaling pathways and NKX6, a transcription factor for Wnt/β-catenin and Rho-GTPase signaling-related genes play key role for carcinogenesis [40,41].…”

Section: Resultsmentioning

confidence: 99%

“…Molecular signaling pathways, such as Wnt (WNT) and Notch Signaling pathways (NOTCH a highly conserved cell signaling system, 4 different receptors i.e. NOTCH 1,2,3 and 4), Sonic hedgehog (SHH signaling is intricate signal transduction), and MYC for apoptosis and cellular transformation play critical role in the pathogenesis of GC[25]. Nuclear factor-kB (NF-kB), epidermal growth factor receptor (EGR)[26] and some epigenetic alterations such as DNA methylation, histone modifications, histone acetylation and histone phosphorylation observed in all type of Cancers.…”

mentioning

confidence: 99%

Unveiling the Genomic Landscape of Gastric Cancer Diagnosis, a Snapshot

Uthansingh¹,

Agarwala²,

Sahu³

2020

Act Scie Canbio

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Gastric cancer (GC) still one of the most prevalent malignancies across the globe. So far, the majority of research studies have not come up with a proper diagnostic and therapeutic approach which may be due to lack of external validation. Attempts have been undertaken but due to methodological shortcomings and insufficient reporting, the breach between biomarker discovery and its clinical use not been explored. So, there should be an improved systematized tunnel of diagnostic marker approach focusing on correct methodology, quality of support, and emphasis on external validation which could have an impact on better clinical diagnosis and prognostication. This review aimed at the early diagnosis of GC through biomarkers and their potential applications in cellular proliferation, apoptosis, and angiogenesis. Moreover, this review highlights the genetic, epigenetic modifications, signaling pathways, and NGS advancement that could identify the novel therapeutic targets as well as noninvasive biomarkers for therapeutic response.

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“…Highly advantageous effects have been observed after losartan treatment [121,123], and in addition, this drug is considered safe, it is relatively inexpensive, and it is already widely prescribed as an antihypertensive agent [147,148]. In contrast, routine clinical use of treatments targeting the Hh pathway lies further up the road, as inhibition of Hh signaling has provided conflicting findings both in animal models and patients, despite it being crosstalk between the TGF-β and Hh pathways in cancerous tissue [118,149]. Also therapeutic strategies aiming to degrade and/or destabilize the ECM directly as well as treatments targeting CAFs, such as ATRA treatment, have to be investigated further before their clinical potential can be assessed.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Antifibrotic therapy to normalize the tumor microenvironment

Hauge

Rofstad

2020

J Transl Med

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Most tumors develop abnormal fibrotic regions consisting of fibroblasts, immune cells, and a dense extracellular matrix (ECM) immersed in a viscous interstitial fluid, and an abundant fibrotic tumor microenvironment (TME) is associated with poor outcome of treatment. It has been hypothesized that the treatment of cancer may be improved by interventions aiming to normalize this TME. The approaches used in attempts to normalize the fibrotic TME can be categorized into three strategies of targeted antifibrotic therapy: targeting of components of the ECM, targeting of the producers of the ECM components-the activated cancer-associated fibroblasts (CAFs), and targeting of the signaling pathways activating CAFs. To target the ECM, enzymes against components of the ECM have been used, including collagenase, relaxin, hyaluronidase, and lyxyl oxidase. Targeting of CAFs have been investigated by using agents aiming to eliminate or reprogram CAFs. CAFs are activated primarily by transforming growth factor-β (TGF-β), hedgehog, or focal adhesion kinase signaling, and several agents have been used to target these signaling pathways, including angiotensin II receptor I blockers (e.g., losartan) to inhibit the TGF-β pathway. Taken together, these studies have revealed that antifibrotic therapy is a two-edged sword: while some studies suggest enhanced response to treatment after antifibrotic therapy, others suggest that antifibrotic therapy may lead to increased tumor growth, metastasis, and impaired outcome of treatment. There are several possible explanations of these conflicting observations. Most importantly, tumors contain different subpopulations of CAFs, and while some subpopulations may promote tumor growth and metastasis, others may inhibit malignant progression. Furthermore, the outcome of antifibrotic therapy may depend on stage of disease, duration of treatment, treatment-induced activation of alternative profibrotic signaling pathways, and treatment-induced recruitment of tumor-supporting immune cells. Nevertheless, losartan-induced suppression of TGF-β signaling appears to be a particularly promising strategy. Losartan is a widely prescribed antihypertensive drug and highly advantageous therapeutic effects have been observed after losartan treatment of pancreatic cancer. However, improved understanding of the mechanisms governing the development of fibrosis in tumors is needed before safe antifibrotic treatments can be established.

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Wnt, Notch, and TGF-β Pathways Impinge on Hedgehog Signaling Complexity: An Open Window on Cancer

Cited by 109 publications

References 236 publications

Epigenetics of SFRP1: The Dual Roles in Human Cancers

Epigenetics of SFRP1: The Dual Roles in Human Cancers

Unveiling the Genomic Landscape of Gastric Cancer Diagnosis, a Snapshot

Antifibrotic therapy to normalize the tumor microenvironment

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