Blockade of the sonic hedgehog pathway effectively inhibits the growth of hepatoma in mice: An in vivo study

Sheen

et al. 2013

OTT

Self Cite

BackgroundAbnormal activation of the Sonic Hedgehog (SHH) signaling pathway contributing to carcinogenesis of some organs has been reported in the literature. We hypothesize that activation of the SHH pathway contributes to the recurrence of breast carcinoma.MethodsFifty consecutive patients with invasive breast carcinoma following curative resection were enrolled in this prospective study. The ratios of messenger RNA (mRNA) expression for Sonic Hedgehog (SHH), patched homolog-1 (PTCH-1), glioma-associated oncogene-1 (GLI-1), and smoothened (SMOH) were measured between breast carcinoma tissue and paired noncancerous breast tissue. These ratios were compared with their clinicopathologic characteristics. These factors and the mRNA ratios were compared between patients with recurrence and those without recurrence.ResultsThe size of the invasive cancer correlated significantly with the ratio of SHH mRNA (P=0.001), that of PTCH-1 mRNA (P=0.005), and that of SMOH mRNA (P=0.021). Lymph node involvement correlated significantly with the ratio of SMOH mRNA (P=0.041). The correlation between Her-2 neu and the ratio of GLI-1 mRNA was statistically significant (P=0.012). Each ratio of mRNA of SHH, PTCH-1, GLI-1, and SMOH correlated significantly with cancer recurrence (P<0.001 for each).ConclusionWe suggest that high expression of SHH mRNA, PTCH-1 mRNA, GLI-1 mRNA, and SMOH mRNA in breast cancer tissue correlates with invasiveness and is a potential biomarker to predict postoperative recurrence.

Section: Discussionmentioning

confidence: 99%

High expression of Sonic Hedgehog signaling pathway genes indicates a risk of recurrence of breast carcinoma

Sheen

et al. 2013

OTT

Self Cite

Seminars in Cancer Biology

“…Use of the SMO antagonist cyclopamine or the Hh ligand neutralizing antibody 5E1 induced terminal differentiation and loss of clonogenic growth in gastric CSCs from primary tumors [242,243]. Mouse models of CML also suggest that Hh regulates the self renewal property of the tumor cells [240], providing an important preclinical model for intervention studies with natural compounds.…”

Section: Molecular Pathways Regulating Tumor Proliferationmentioning

confidence: 99%

Sustained proliferation in cancer: Mechanisms and novel therapeutic targets

Feitelson

Arzumanyan

Kulathinal

et al. 2015

546

371

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). This data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.

Critical Reviews in Biochemistry and Molecular Biology

“…Syn et al studied the effect of cyclopamine in the methionine-choline deficient diet supplemented with ethionine mouse NASH model, and showed decreased expression of mesenchymal and fibrogenic genes, suggesting a potential role in the prevention of NASH-related fibrogenesis (Syn et al, 2009). Furthermore, in different mouse models of hepatocellular carcinoma, treatment with cyclopamine decreased tumor size (Jeng et al, 2012) and increased radiosensitivity (Tsai et al, 2015). A synthetic cyclopamine analogue, saridegib or IPI-926, achieved improved stability, kinetic profile and potency as compared to cyclopamine (Peluso et al, 2014).…”

Section: Hedgehog Pathway As a Therapeutic Target In Nonalcoholic Fatmentioning

confidence: 99%

The hedgehog pathway in nonalcoholic fatty liver disease

Machado

Diehl

2018

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.