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标题: 确定用于早期发现和预防肝癌的潜在标志物 [打印本页]

作者: StephenW 时间: 2018-12-14 17:20 标题: 确定用于早期发现和预防肝癌的潜在标志物

Potential markers identified for early detection and prevention of liver cancer

Posted on December 5, 2018 in Featured News, Science

Illustration of a cirrhotic liver. 90% of all hepatocellular carcinoma cases start with liver cirrhosis. Image: ShutterstockA shift in glucose metabolism hails progression from liver cirrhosis to liver cancer, finds a new study
— By D. Rachael Bishop, Frontiers science writer
Liver cancer is the second leading cause of cancer-related mortality worldwide, claiming 700,000 lives each year. Most cases are discovered too late for a cure — but now a study offers hope of early detection, and targets for new treatments. Published in Frontiers in Cell and Developmental Biology, the results show a dramatic increase in expression of sugar-burning ‘glycolytic’ enzymes in precancerous cirrhotic livers. This increase is associated with a significantly higher risk of developing hepatocellular carcinoma (HCC) — the main type of liver cancer — and could lead to a biomarker which identifies those at risk of malignancy.

High Expression of Glycolytic Genes in Cirrhosis Correlates With the Risk of Developing Liver Cancer
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“We know that 90% of all hepatocellular carcinoma cases start with liver cirrhosis,” explains study senior authors Dr Salvatore Papa of the University of Leeds and Dr Concetta Bubici of Brunel University London, UK. “So by pinpointing when cirrhosis progresses to cancer, we could improve early detection and treatment — with surgery, chemo and radiotherapy, but perhaps also with new treatments which reverse the transition.”
Metabolic changes in cancer cells
In cirrhosis, chronic damage caused by hepatitis viruses B or C, alcohol, or obesity leads to scarring and formation of regenerative nodules in the liver. High cell turnover in these nodules, with accumulation of genetic damage, can eventually produce cancerous cells.
“We set out to find features of cirrhotic cells that might predict cancerous change,” says Papa.
For nearly a century, scientists have recognized that cancer cells shift the way they generate energy. Normally the body obtains energy from macronutrients — sugars, fats, proteins and their intermediaries — primarily using oxygen. But our cells can also extract energy from sugars without using oxygen. This anaerobic process, called glycolysis, produces the lactate that ‘burns’ our muscles during intense exercise — and is also used by cancers to fuel their rampant growth.
“Like virtually all cancers, highly-proliferating HCC cells seem to readjust their energy metabolism towards glycolysis, irrespective of oxygen availability.”
The cause of this shift in glucose metabolism — known as the Warburg effect — remains unknown, but inflammation is thought to play a role.
“Given that cirrhosis is an inflammatory process, we decided to look at whether the metabolic shift to glycolysis is present already in cirrhotic cells — and whether this predicts progression to hepatocellular carcinoma.”
Cancer metabolic changes are present in cirrhotic cells
Papa and colleagues analyzed normal, cirrhotic and cancerous (HCC) liver samples from patients followed up over 10 years following a liver biopsy.
“To have a complete overview of energy metabolism changes in HCC and premalignant stages of disease, we measured the expression of genes encoding enzymes involved in glycolysis and other metabolic pathways.”
They found that glycolysis-related genes — including hexokinase 2 (HK2), aldolase A (ALDOA) and pyruvate kinase M2 (PKM2) — are highly expressed not only in HCC, but also in cirrhosis as compared to normal liver samples.
“In other words: the shift to glycolysis occurs in the precancerous stage,” says Bubici.
Even more striking, the level of expression of glycolysis-related genes showed positive correlation with progression of cirrhosis to HCC — and with poor outcome in those with HCC already at the time of biopsy.
“This suggests expression of glycolytic enzymes could be used as a new biomarker to predict the risk of later development of HCC in patients with cirrhosis,” claims Bubici.

Towards early detection
The team stresses the study is preliminary: “Further studies are needed to establish whether these changes in gene expression are borne out as changes in glycolytic activity.”
Nevertheless, the findings reveal a promising means to improve HCC survival through early detection and treatment. According to Papa, the shift to a glycolytic expression profile in cirrhotic cells could even be a target for new HCC therapies.
“For example, clinical trials are currently underway to explore the effect of statins — which are used to help prevent cardiovascular disease — on HCC development in cirrhotic patients or HCC recurrence following surgical removal.”It is very likely that by blocking cholesterol synthesis, statins would also suppress glycolysis as these chemical pathways overlap. If these trials show that statins reduce HCC risk, further studies would be necessary to establish whether inhibition of glycolysis in cirrhotic cells is responsible,” says Papa.
The research is part of a special article collection on the Warburg effect, of which Papa and Bubici are co-editors.

Original article: High Expression of Glycolytic Genes in Cirrhosis Correlates With the Risk of Developing Liver Cancer

作者: StephenW 时间: 2018-12-14 17:23

确定用于早期发现和预防肝癌的潜在标志物

发表于2018年12月5日的特色新闻，科学
肝硬化肝脏的图像。葡萄糖代谢的转变支持从肝硬化到肝癌的进展，在肝细胞和发育生物学的前沿中发现了一项新的研究肝硬化。所有肝细胞癌病例中有90％起始于肝硬化。图片：Shutterstock

一项新研究发现，葡萄糖代谢的转变可以预示肝硬化进展为肝癌

- 前沿科学作家D. Rachael Bishop

肝癌是全球癌症相关死亡的第二大原因，每年夺去70万人的生命。大多数病例被发现太晚无法治愈 - 但现在一项研究为早期检测提供了希望，并为新疗法提供了目标。发表在细胞和发育生物学的前沿，结果显示在癌前期肝硬化肝脏中糖燃烧'糖酵解'酶的表达显着增加。这种增加与发生肝细胞癌（HCC） - 肝癌的主要类型 - 的风险显着增加相关，并且可能导致生物标志物识别具有恶性风险的人。

肝硬化中糖酵解基因的高表达与发展肝癌的风险相关
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“我们知道所有肝细胞癌病例中有90％起始于肝硬化，”英国伦敦布鲁内尔大学的资深作者Salvatore Papa博士和英国伦敦布鲁内尔大学的Concetta Bubici博士解释道。 “因此，通过精确定位肝硬化进展到癌症，我们可以改善早期发现和治疗 - 手术，化疗和放疗，但也许还有新的治疗方法可以逆转过渡。”

癌细胞的代谢变化

在肝硬化中，由肝炎病毒B或C，酒精或肥胖引起的慢性损伤导致肝脏中的瘢痕形成和再生结节的形成。这些结节中的高细胞更新，伴随着遗传损伤的累积，最终可能产生癌细胞。

“我们开始寻找可能预测癌变的肝硬化细胞的特征，”爸爸说。

近一个世纪以来，科学家们已经认识到癌细胞会改变它们产生能量的方式。通常身体从常量营养素 - 糖，脂肪，蛋白质及其中间体 - 获得能量 - 主要使用氧气。但我们的细胞也可以在不使用氧气的情况下从糖中提取能量。这种称为糖酵解的厌氧过程产生乳酸，在剧烈运动过程中“烧伤”我们的肌肉 - 并且癌症也会使用它来促进其猖獗的生长。

“与几乎所有癌症一样，高度增殖的HCC细胞似乎将其能量代谢重新调整为糖酵解，无论氧气供应情况如何。”

葡萄糖代谢转变的原因 - 被称为Warburg效应 - 仍然未知，但炎症被认为起作用。

“鉴于肝硬化是一个炎症过程，我们决定研究肝硬化细胞中是否存在代谢转变为糖酵解 - 以及这是否预示肝细胞癌的进展。”

肝硬化细胞中存在癌症代谢变化

Papa及其同事分析了肝活检后患者的正常，肝硬化和癌性（HCC）肝脏样本随访超过10年。

“为了全面了解HCC和癌症前期的能量代谢变化，我们测量了编码参与糖酵解和其他代谢途径的酶的基因的表达。”

他们发现，与正常肝脏样本相比，糖酵解相关基因 - 包括己糖激酶2（HK2），醛缩酶A（ALDOA）和丙酮酸激酶M2（PKM2） - 不仅在HCC中高表达，而且在肝硬化中高表达。

“换句话说：转向糖酵解发生在癌前期，”Bubici说。

更引人注目的是，糖酵解相关基因的表达水平与肝硬化进展为HCC呈正相关 - 并且在活检时HCC患者的预后较差。

“这表明糖酵解酶的表达可以作为一种新的生物标志物，用于预测肝硬化患者晚期HCC发生的风险，”Bubici说。

相关：与前列腺癌进展相关的嗅觉受体

迈向早期发现

该团队强调该研究是初步的：“需要进一步的研究来确定基因表达的这些变化是否被认为是糖酵解活性的变化。”

然而，这些发现揭示了通过早期检测和治疗来改善HCC存活的有希望的方法。根据Papa的说法，肝硬化细胞中糖酵解表达谱的转变甚至可能成为新的HCC疗法的目标。
“例如，目前正在进行临床试验以探讨他汀类药物（用于预防心血管疾病）对肝硬化患者HCC发展或手术切除后HCC复发的影响。”很可能通过阻断胆固醇合成，他汀类药物当这些化学途径重叠时，也会抑制糖酵解。如果这些试验表明他汀类药物可降低HCC风险，那么进一步的研究有必要确定肝硬化细胞中糖酵解的抑制是否有责任，“Papa说。

该研究是关于Warburg效应的特别文章集的一部分，其中Papa和Bubici是共同编辑。

原创文章：肝硬化中糖酵解基因的高表达与发展肝癌的风险相关

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