In addition to its function as a neurotransmitter and vascular active molecule, serotonin is also a mitogen for hepatocytes and promotes liver regeneration. A possible role in hepatocellular cancer ...has not yet been investigated. Human hepatocellular cancer cell lines Huh7 and HepG2 were used to assess the function of serotonin in these cell lines. Characteristics of autophagy were detected with transmission electron microscopy, immunoblots of microtubule‐associated protein light chain 3(LC3) and p62 (sequestosome 1). Immunoblots of the mammalian target of rapamycin (mTOR) and its downstream targets p70S6K and 4E‐BP1 were used to investigate signaling pathways of serotonin. Two different animal models served as principle of proof of in vitro findings. Clinical relevance of the experimental findings was evaluated with a tissue microarray from 168 patients with hepatocellular carcinoma. Serotonin promotes tumor growth and survival in starved hepatocellular carcinoma cells. During starvation hepatocellular carcinoma cells exhibited characteristics of autophagy, which disappeared in serotonin‐treated cells. Rapamycin, an inhibitor of mTOR, is known to induce autophagy. Serotonin could override rapamycin by an mTOR‐independent pathway and activate common downstream signals such as p70S6K and 4E‐BP1. In two tumor models of the mouse, inhibition of serotonin signaling consistently impaired tumor growth. Human biopsies revealed expression of the serotonin receptor HTR2B, correlating with downstream signals, e.g., phosphorylated p70S6K and proliferation. Conclusion: This study provides evidence that serotonin is involved in tumor growth of hepatocellular cancer by activating downstream targets of mTOR, and therefore serotonin‐related pathways might represent a new treatment strategy. (HEPATOLOGY 2010.)
The transforming growth factor-β (TGF-β) signalling pathway is a key mediator of fibroblast activation that drives the aberrant synthesis of extracellular matrix in fibrotic diseases. Here we ...demonstrate a novel link between transforming growth factor-β and the canonical Wnt pathway. TGF-β stimulates canonical Wnt signalling in a p38-dependent manner by decreasing the expression of the Wnt antagonist Dickkopf-1. Tissue samples from human fibrotic diseases show enhanced expression of Wnt proteins and decreased expression of Dickkopf-1. Activation of the canonical Wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo. Transgenic overexpression of Dickkopf-1 ameliorates skin fibrosis induced by constitutively active TGF-β receptor type I signalling and also prevents fibrosis in other TGF-β-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-β-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases.
Cancer-associated fibroblasts (CAF) are a poorly characterized cell population in the context of liver cancer. Our study investigates CAF functions in intrahepatic cholangiocarcinoma (ICC), a highly ...desmoplastic liver tumor. Genetic tracing, single-cell RNA sequencing, and ligand-receptor analyses uncovered hepatic stellate cells (HSC) as the main source of CAF and HSC-derived CAF as the dominant population interacting with tumor cells. In mice, CAF promotes ICC progression, as revealed by HSC-selective CAF depletion. In patients, a high panCAF signature is associated with decreased survival and increased recurrence. Single-cell RNA sequencing segregates CAF into inflammatory and growth factor-enriched (iCAF) and myofibroblastic (myCAF) subpopulations, displaying distinct ligand-receptor interactions. myCAF-expressed hyaluronan synthase 2, but not type I collagen, promotes ICC. iCAF-expressed hepatocyte growth factor enhances ICC growth via tumor-expressed MET, thus directly linking CAF to tumor cells. In summary, our data demonstrate promotion of desmoplastic ICC growth by therapeutically targetable CAF subtype-specific mediators, but not by type I collagen.
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•The majority of CAF in ICC are derived from hepatic stellate cells•Inflammatory CAF promote ICC through HGF and its receptor MET•myCAF promote ICC through Has2/hyaluronic acid•CAF-derived type I collagen contributes to stiffness but does not promote ICC growth
Intrahepatic cholangiocarcinoma (ICC) is an extraordinarily stiff liver tumor due to abundant scar-forming cancer-associated fibroblasts (CAF). Here, Affo et al. determine the origin and functions of CAF, and uncover distinct CAF subsets, promoting ICC growth via different therapeutically targetable mediators. Thus, CAF and their mediators may serve as therapeutic targets for ICC.
Intraductal papillary neoplasms of the bile duct are still poorly characterized regarding (1) their molecular alterations during the development to invasive carcinomas, (2) their subtype ...stratification and (3) their biological behavior. We performed a multicenter study that analyzed these issues in a large European cohort. Intraductal papillary neoplasms of the bile duct from 45 patients were graded and subtyped using mucin markers and CDX2. In addition, tumors were analyzed for common oncogenic pathways, and the findings were correlated with subtype and grade. Data were compared with those from 22 extra- and intrahepatic cholangiocarcinomas. Intraductal papillary neoplasms showed a development from preinvasive low- to high-grade intraepithelial neoplasia to invasive carcinoma. Molecular and immunohistochemical analysis revealed mutated KRAS, overexpression of TP53 and loss of p16 in low-grade intraepithelial neoplasia, whereas loss of SMAD4 was found in late phases of tumor development. Alterations of HER2, EGFR, β-catenin and GNAS were rare events. Among the subtypes, pancreato-biliary (36%) and intestinal (29%) were the most common, followed by gastric (18%) and oncocytic (13%) subtypes. Patients with intraductal papillary neoplasm of the bile duct showed a slightly better overall survival than patients with cholangiocarcinoma (hazard ratio (cholangiocarcinoma versus intraductal papillary neoplasm of the bile duct): 1.40; 95% confidence interval: 0.46–4.30; P=0.552). The development of biliary intraductal papillary neoplasms of the bile duct follows an adenoma-carcinoma sequence that correlates with the stepwise activation of common oncogenic pathways. Further large trials are needed to investigate and verify the finding of a better prognosis of intraductal papillary neoplasms compared with conventional cholangiocarcinoma.
Hepatocellular carcinomas (HCCs) and bile duct carcinomas (BDCs) have a poor prognosis. Therefore, surveillance strategies including sensitive and specific serum markers for early detection are ...needed. Recently, Golgi Phosphoprotein 2 (GOLPH2) has been proposed as a serum marker for HCC, but GOLPH2 expression data in liver tissues was not available. Using tissue microarrays and immunohistochemistry, we semiquantitatively analyzed GOLPH2 protein expression in patients with HCC (n = 170), benign liver tumors (n = 22), BDC (n = 114) and normal liver tissue (n = 105). A newly designed sandwich enzyme‐linked immunoassay (ELISA) was used to analyze GOLPH2 levels in the sera of patients with HCC (n = 62), hepatitis C virus (HCV) (n = 29), BDC (n = 10), and healthy control persons (n = 12). By immunohistochemistry 121/170 (71%) of HCC showed strong GOLPH2 expression, which was significantly associated with a higher tumor grade (P = 0.01). A total of 97/114 (85%) BDCs showed a strong GOLPH2 expression which proved to be an independent prognostic factor for overall survival (P < 0.05). Serum levels of GOLPH2 measured by ELISA were significantly elevated in patients with HCC with underlying HCV infection (median 18 mg/L, P < 0.05) and patients with BDC (median = 14.5 mg/L, P < 0.01) in comparison to healthy controls (median 4 mg/L). Conclusion: GOLPH2 protein is highly expressed in tissues of HCC and BDC. GOLPH2 protein levels are detectable and quantifiable in sera by ELISA. In patients with hepatitis C, serial ELISA measurements in the course of the disease appear to be a promising complementary serum marker in the surveillance of HCC. GOLPH2 should be further evaluated as a serum tumor marker in BDC on a larger scale. (HEPATOLOGY 2009.)
Serotonin is a well-known neurotransmitter and vasoactive substance. Recent research indicates that serotonin contributes to liver regeneration and promotes tumor growth of human hepatocellular ...cancer. The aim of this study is to investigate the expression of serotonin receptors in hepatocellular cancer and analyze their potential as a cytotoxic target.
Using a tissue microarray and immunohistochemistry, we analyzed the expression of serotonin receptors in the liver from 176 patients with hepatocellular carcinoma, of which nontumor tissue was available in 109 patients. Relevant clinicopathologic parameters were compared with serotonin receptor expression. Two human hepatocellular cancer cell lines, Huh7 and HepG2, were used to test serotonin antagonists as a possible cytotoxic drug.
The serotonin receptors 1B and 2B were expressed, respectively, in 32% and 35% of the patients with hepatocellular cancer. Both receptors were associated with an increased proliferation index, and receptor 1B correlated with the size of the tumor. Serotonin antagonists of receptors 1B and 2B consistently decreased viability and proliferation in Huh7 and HepG2 cell lines.
We identified two serotonin receptors that are often overexpressed in human hepatocellular cancer and may serve as a new cytotoxic target.
Post‐bariatric patients undergoing abdominoplasty have a relatively high risk of complications due to residual obesity and major comorbidities. Also, conventional electrosurgery and the associated ...thermal tissue damage may compromise outcomes. This retrospective randomised clinical study evaluated the effect of low‐thermal plasma dissection device (PEAK pulsed electron avalanche knife PlasmaBlade) in comparison with conventional electrosurgery. A total of 52 post‐bariatric patients undergoing abdominoplasty were randomised to PEAK PlasmaBlade (n = 26) and to monopolar electrosurgery (n = 26). Wounds of 20 patients per group were examined histologically for acute thermal injury depth. In PEAK PlasmaBlade incisions, acute thermal damage was significantly reduced compared with standard of care (40% vs 75%; P = .035). Also, acute thermal injury depth from PEAK PlasmaBlade was less than that from electrosurgery (2780 μm vs 4090 μm). Significantly less total complication rate (30.8% vs 69.2%; P = .012) was found by PEAK PlasmaBlade compared with electrosurgery. Moreover, the PEAK PlasmaBlade showed less than half as many wound healing problems (19.2% vs 46.2%; P = .075), far fewer secondary bleeding (7.7% vs 30.8%; P = .075), and no seroma compared with four seroma with the standard of care (0% vs 15.4%; P = .11). PEAK PlasmaBlade appears to be superior to traditional monopolar electrosurgery for post‐bariatric abdominoplasty, because it demonstrated significantly less tissue damage, less total complication rate, and fewer postoperative seroma resulting in faster wound healing.
To define clinical outcome after definitive chemoradiotherapy (CRT) of anal carcinoma in HIV-infected patients treated with highly active antiretroviral therapy (HAART).
A multicentric cohort ...comparison of 40 HIV-positive patients with HAART and 81 HIV-negative patients treated with radiotherapy (RT) or CRT was retrospectively performed. Local disease control (LC), relapse-free survival (RFS), overall survival (OS), cancer-specific survival (CSS), toxicity, and prognostic factors were investigated.
HIV-positive patients were younger (mean age, 48 v 62 years; P < .0005), predominantly male (93% v 25%; P < .0005), and with early-stage (P = .06) and large-cell histology (90% v 67%; P = .005) disease. RT or CRT resulted in complete response in 92% (HIV positive) and 96% (HIV negative) of cases. Five-year OS was 61% (95% CI, 44% to 78%) in HIV-positive and 65% (95% CI, 53% to 77%) in HIV-negative patients (median follow-up, 36 months). Five-year LC was 38% (95% CI, 5% to 71%) in HIV-positive and 87% (95% CI, 79% to 95%) in HIV-negative patients (P = .008) compromising CSS and sphincter preservation. Grade 3/4 acute skin (35% v 17% HIV negative; P = .04) and hematologic (33% v 12% HIV negative; P = .08) toxicity together approximated 50% in HIV-positive patients. RFS in HIV-positive patients was associated with RT dose (P = .08) and severe acute skin toxicity (P = .04).
Long-term LC and acute toxicity represent major clinical challenges in HIV-positive patients with anal carcinoma. Even if fluoropyrimidine-based CRT is feasible and may result in similar response rates and OS as in HIV-negative patients, improved treatment strategies with better long-term outcome are warranted.
Subcutaneous mastectomy, the first step in sexual reassignment surgery of female‐to‐male transsexuals, is associated with high rates of complication and revision surgery. Also, conventional ...electrosurgery and the associated thermal tissue damage may compromise outcome. This retrospective randomised clinical study evaluated the effect of low‐thermal plasma dissection device (PEAK PlasmaBlade, Medtronic, Minneapolis, Minnesota) in comparison with conventional electrosurgery. A total of 17 female‐to‐male transsexuals undergoing mastectomy were randomised to PEAK PlasmaBlade on one breast side and to monopolar electrosurgery on the other side of the same patient. Wounds of 17 patients were examined histologically for acute thermal injury. Significantly less total volume of drain output (58.8 ± 37.4 mL vs 98.5 ± 76.4 mL; P = .012) was found on the PEAK PlasmaBlade side compared with the electrosurgery side. Duration of drain was significantly shorter on the PEAK PlasmaBlade side (2.5 ± 0.7 days vs 3.2 ± 0.6 days; P = .010). Furthermore, the PEAK PlasmaBlade side showed fewer thermal damages (41.2% vs 82.4%; P = .039) and thermal injury depth from PEAK PlasmaBlade side was less (3170 vs 4060 μm). PEAK PlasmaBlade appears to be superior to monopolar electrosurgery for mastectomy in female‐to‐male transsexuals, because it demonstrated less thermal tissue damage, less total volume of drain output, and shorter duration of drain, resulting in faster wound healing.
Postoperative wound‐healing problems are relatively high in post‐bariatric body‐contouring procedures, partly because of electrosurgery and the associated thermal tissue damage. This study is a ...retrospective randomised evaluation of the effect of a low‐thermal plasma dissection device (PEAK PlasmaBlade, Medtronic, Minneapolis, Minnesota) in comparison with conventional electrosurgery. A total of 24 patients undergoing upper arm or medial thigh lifting were randomised to PEAK PlasmaBlade on one side and to monopolar electrosurgery on the other side of the same patient. Wounds of 10 patients were examined histologically for acute thermal injury depth. Significantly lower total volume of drain output (61,1 ± 70,2 mL versus 95,1 ± 176,0 mL; P = .04) was found on the PEAK PlasmaBlade side compared with the electrosurgery side. Furthermore, the PEAK PlasmaBlade side showed fewer seromas (no case of seroma versus three seromas in the electrosurgery group) and less thermal damage (40% versus 70%; P = .26). Acute thermal injury depth from the PEAK PlasmaBlade was less than from monopolar electrosurgery (425 ± 171 μm versus 686 ± 1037 μm; P = .631). PEAK PlasmaBlade appears to be superior to traditional monopolar electrosurgery for post‐bariatric body‐contouring procedures because it demonstrated less tissue damage, lower total volume of drain output, and fewer postoperative seromas resulting in faster wound healing.
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