Paracrine Hedgehog Signaling Drives Metabolic Changes in Hepatocellular Carcinoma

Chan, Isaac S.; Guy, Cynthia D.; Chen, Yuping; Lü, Jiuyi; Swiderska‐Syn, Marzena; Michelotti, Gregory A.; Karaca, Gamze; Xie, Guanhua; Krüger, Leandi; Syn, Wing Kin; Anderson, Blair R.; Pereira, Thiago A.; Choi, Steve S.; Baldwin, Albert S.; Diehl, Anna Mae

doi:10.1158/0008-5472.can-12-1068

Cited by 51 publications

(42 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In preclinical studies, a monoclonal antibody against Hh (5E1) was able to inhibit activation and proliferation of hepatic stellate cells (Sicklick et al, 2005), as well as the Shh-dependent paracrine effects of hepatic stellate cells on the proliferation of progenitor cells (Michelotti et al, 2013) and on the metabolic reprogramming and proliferation of malignant hepatoma cells (Chan et al, 2012). Shh can also be inhibited by robotnikinin, a small molecule that binds Shh, preventing it from engaging Ptch-1 and hence, inhibiting activation of the Hh pathway (Stanton et al, 2009).…”

Section: Hedgehog Pathway As a Therapeutic Target In Nonalcoholic Fatmentioning

confidence: 99%

The hedgehog pathway in nonalcoholic fatty liver disease

Machado

Diehl

2018

Critical Reviews in Biochemistry and Molecular Biology

Self Cite

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer. The pathogenesis of NAFLD is complex, and not fully understood. However, compelling evidence demonstrates that dysregulation of the hedgehog (Hh) pathway is involved in both the pathogenesis of hepatic steatosis and the progression from hepatic steatosis to more serious forms of liver damage. Inhibiting Hedgehog signaling enhances hepatic steatosis, a condition which seldom results in liver-related morbidity or mortality. In contrast, excessive Hedgehog pathway activation promotes development of NASH, cirrhosis, and primary liver cancer, the major causes of liver-related deaths. Thus, suppressing excessive Hh pathway activity is a potential approach to prevent progressive liver damage in NAFLD. Various pharmacologic agents that inhibit Hh signaling are available and approved for cancer therapeutics; more are being developed to optimize the benefits and minimize the risks of inhibiting this pathway. In this review we will describe the Hh pathway, summarize the evidence for its role in NAFLD evolution, and discuss the potential role for Hh pathway inhibitors as therapies to prevent NASH, cirrhosis and liver cancer.

show abstract

Section: Hedgehog Pathway As a Therapeutic Target In Nonalcoholic Fatmentioning

confidence: 99%

The hedgehog pathway in nonalcoholic fatty liver disease

Machado

Diehl

2018

Critical Reviews in Biochemistry and Molecular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Here, Hedgehog ligands are secreted by malignant hepatocytes, induce Gli-dependent Warburg reprogramming and lactate secretion in stromal cells (mainly myofibroblasts) and lactate signals back to malignant hepatocytes to sustain their growth and survival [137]. This metabolic reprogramming is known as the “ Reverse Warburg ”.…”

Section: Hedgehog Signalling and Metabolismmentioning

confidence: 99%

Canonical and non-canonical Hedgehog signalling and the control of metabolism

Teperino

Aberger

Esterbauer

et al. 2014

Seminars in Cell & Developmental Biology

121

110

View full text Add to dashboard Cite

Obesity and diabetes represent key healthcare challenges of our day, affecting upwards of one billion people worldwide. These individuals are at higher risk for cancer, stroke, blindness, heart and cardiovascular disease, and to date, have no effective long-term treatment options available. Recent and accumulating evidence has implicated the developmental morphogen Hedgehog and its downstream signalling in metabolic control. Generally thought to be quiescent in adults, Hedgehog is associated with several human cancers, and as such, has already emerged as a therapeutic target in oncology. Here, we attempt to give a comprehensive overview of the key signalling events associated with both canonical and non-canonical Hedgehog signalling, and highlight the increasingly complex regulatory modalities that appear to link Hedgehog and control metabolism. We highlight these key findings and discuss their impact for therapeutic development, cancer and metabolic disease.

show abstract

“…The second mode of aberrant activation is autocrine: The Hh ligand is secreted by tumor cells and also affects the tumor cells themselves (41,42). In the third mode, which is paracrine activation, tumor cells secrete Hh ligands to act on peripheral stroma cells, which activates vascular endothelial growth factor, insulin-like growth factor and Wnt signaling pathways to promote self-proliferation (43,44). A paracrine pattern in which stromal cells secret Hh ligands, thus contributing to the activation of Hh signaling in the tumor cells, has also been described (45).…”

Section: Antagonism Between Hedgehog and Wnt Signaling Pathways Regulmentioning

confidence: 99%

Antagonism between Hedgehog and Wnt signaling pathways regulates tumorigenicity (Review)

Ding

Wang

2017

Oncol Lett

View full text Add to dashboard Cite

Abstract. The crosstalk of multiple cellular signaling pathways is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation and metastasis. The Hedgehog (Hh) and Wnt signaling pathways are both considered to be essential regulators of cell proliferation, differentiation and oncogenesis. Recent studies have indicated that the Hh and Wnt signaling pathways are closely associated and involved in regulating embryogenesis and cellular differentiation. Hh signaling acts upstream of the Wnt signaling pathway, and negative regulates Wnt activity via secreted frizzled-related protein 1 (SFRP1), and the Wnt/β-catenin pathway downregulates Hh activity through glioma-associated oncogene homolog 3 transcriptional regulation. This evidence suggests that the imbalance of Hh and Wnt regulation serves a crucial role in cancer-associated processes. The activation of SFRP1, which inhibits Wnt, has been demonstrated to be an important cross-point between the two signaling pathways. The present study reviews the complex interaction between the Hh and Wnt signaling pathways in embryogenesis and tumorigenicity, and the role of SFRP1 as an important mediator associated with the dysregulation of the Hh and Wnt signaling pathways.

show abstract

Paracrine Hedgehog Signaling Drives Metabolic Changes in Hepatocellular Carcinoma

Cited by 51 publications

References 22 publications

The hedgehog pathway in nonalcoholic fatty liver disease

The hedgehog pathway in nonalcoholic fatty liver disease

Canonical and non-canonical Hedgehog signalling and the control of metabolism

Antagonism between Hedgehog and Wnt signaling pathways regulates tumorigenicity (Review)

Contact Info

Product

Resources

About