Liver Cancer

A Review on Liver cancer:

INTRODUCTION:

Primary liver cancer is the fifth most common cancer world wide and third most cause of death from cancer resulting in more than 600,000 death per year.The major risk factors for hepatocellular carcinoma are chronic hepatitis B or hepatitis c Virus.Alcoholic cirrhosis,and non alcoholic steatohepatitis[1]cancer probably develop in the cirrhotic liver through the induction of accelerated cycles of cell injury,death,and regeneration in an altered fibrotic and inflammatory microenviroenviroment .Abnormal immortalized cell clones arise,and these cells develop genetic and epigenetic alteration.[2]Hepatocellular carcinoma(HCC)is the most common form of liver cancer.This cancer is not only one of the most frequent,but it is also one of the most serious problem,as it usually has a poor prognosis and very lmited means of treatment.[3]It is responsible for 90% of malignant liver tumors in adults.In france,as in other Western countries,the incidence of this cancer has considerably increased over the last 20 years,mainly because of the increased number of cases of cirrhosis caused by hepatitis C virus.Hepatocellular carcinoma develop after cirrhosis.[4]Therefore hepatic function is damaged on these basis live plays a vital role in the production and catabolism plasma lipoproteins.It depends on the integrity of cellular function of liver,which ensures homeostasis of lipid lipoproteins metabolismThere is also some discussion about high density lipoprotein(HDL) metabolism in liver cancer.Cirrhotic patients with hereditary hemochromatosis(HHC)have an increased risk of primary liver cancer(PLC).Primary liver cancer was found in the explants of 10 of 37 patients(27%)and was unsuspected in 7 of 10(70%).[5]The death rate due to HCC has been increased over the last two decadesThe main causes of HCC are the hepatitis B virus(HBV),HCV,aflatoxin B1,alcohol,hemochromatosis,with lower magnitude of risk.

An effective vaccine has been available for prevention of new HbV,however,no vaccine exists against HCV infection

Risk Factors.

The major etiologies of HCC are well defined and include among the well known factors an elevated body mass index, especially in men 5 as well as diabetes mellitus 6 and some of the steps involved in the molecular pathogenesis of HCC have been elucidated in

recent years. As for most type of cancer,hepatocarcinogenesis is a multistep process involving different genetic alterations that ultimately lead to malignant

transformation of the hepatocyte.

HCCs are phenotypically (morphology, microscopy) and

genetically very heterogenous tumors. Induced by chronic liver injury and regeneration in a context of inflammation, immune response and oxidative DNA damage.This may result in genetic alterations, such as the activation of cellular oncogenes, the inactivation of tumor suppressor genes, possibly in cooperation with genomic instability, including DNA mismatch repair defects and impaired chromosomal segregation, overexpression of growth and angiogenic factors, and telomerase activation Chronic viral hepatitis B, C and D, alcohol, metabolic liver diseases such as hemochromatosis and alfa-1-antitrypsin deficiency as well as non-alcoholic fatty liver disease may act predominantly through this pathway of chronic liver injury, regeneration, and cirrhosis. Accordingly, the major clinical risk factor for HCC development is liver cirrhosis since 70-90% of HCCs develop in a cirrhotic liver. [6]

Physiological function of HDL

HDL are a hetrogenous mixture of spherical macomolecules which differ in size(80-120A)and chemical composition[7].ApoA-is present on the majority of HDL particals[8].It is involved in the metabolic intreconvesions that occur as a result of cholesteryl ester transferprotein(CETP),lecithin;cholesterol acyltransferase(LCAT)and lipase activities and their role in the formation of mature HDL.[9]The liver is a major source of the plasma lipoprotein.[10]These facts indicate that the putative primary site of human HDL synthesis is in the liver[11].Epiddemiological studies have shown that obesity is a risk factor for hepatocelular carcinoma[12].

METABOLISM OF HDL IN LIVER

It is relative balance in metabolism of cholesterol and lipoprotein under normal liver function,it was influence of metabolism in lipoprotein with liver disease[13]and an impaired lipid metabolism is often found in patients with chronic liver cancer/diseases.HL activity is suppressed by estradiol and increased by testosterone.In addition ,hepatocellular metabolism of longchain fatty acid suggestthat increased fatty acid oxidation resulting increase in production of hydrogen peroxide,Thus this oxidative stress leads to alternation in gene expressionand in DNA itself.which causes the nonneoplastic liver injury[14]. Liver diseases were classified into chronic hepatitis(CH),liver cirrhosis(LC),hepatocellular carcinoma(HCC),and metastatic liver cancer.Metastatic liver cancer showed a lower HD-fraction level,but higher level of the other parameters than HCC the HDL fraction level in HCC and metastatic liver cancer,and the LDL level in HCC and metastatic liver cancer,differ in survivors and patients who died.Lipid analysis in liver diseases by this method showed results reflecting the pathologic conditions and may be clinically useful.

METABOLISM OF HBV INDUCED HCC

HBV is a partially double stranded hepatotropic DNA virus.HBV infection causes acute or chrinic liver diseases.Recent estimate account about 400 million people chronically infected with HBV.It has been showed that the risk of developing HCC is increased by 100 folds in chronic HBV surface antigen(HBsAG) carriers .HBV infects all age groups,The main problem in patients chronically infected with HBV is the development of progressing chronic liver diseases:chronic hepatitis(CH),cirrhosis and HCC.

COMMON PATHWAY IN HBV AND HCV INDUCED HEPATOCARCINOGENESIS

IT is generally accepted that neither HBV nor HCV are directly cytopathic viruses[15].An important effect of both viruses however ,is causing chronic infection,a repeating attack of the host immune system against the viral infection.Continous cell death,mainly by apoptosis,and reactive regeneration sequence,as the basis of cirrhosis.Chronic inflammation,cell death and proliferation,as a result of oxidative stress,and up and down regulation of several growth factors and cytokines.Viral integration is a essential part of cell transformation by HBV,which does not occur in HCV infection.However,viral proteins,espacialy HBx and to certain extent the core component of HCV,may directly participate in the hepatocarcinogenesis.

Liver Cancer in Atomic-bomb Survivors: Histological

Characteristics and Relationships to Radiation

Histological feature of primary liver cancer among atomic bomb survivors and their relationship to hepatitis B(HBV) and (HCV) infections are of special interest because of the increased risk of liver cancer in persons exposed to ionizing radiation and the high and increasing liver cancer rates in Japan and elsewhere[16]

Follow up data from the life span study(LSS)cohorts of atomic bomb survivors in Japan recently have shown a significant dose response between radiation exposeure and liver cancer,indicating that low linear energy transfer(LET)radiation is capable of causing liver cancer[17]

There are several difficulties in the diagnosis and treatment of this primary liver cancer. Very often, there are no signs of the diseases or the symptoms are non specific (abdominal pain, fever,fatigue,etc.It is only therefore only diagnosed

Late, at an already advanced stage in many cases.Moreover,there are few means of treatment(Surgery,radiotherapy,chemotherapy etc.)

First New Drug Therapy in 30 Years Offers Hope to Liver Cancer Patients

Cancer has approved a new indiction for NEXAVAR(sorafenib tablets)for the treatment of patients with unresectable hepatocellular carcinoma(HCC)or liver cancer.NEXAVAR,an oral anti-cancer treatment,is the first approved drug therapy for liver cancer.

The approval of NEXAVAR in Canada for the treatment of HCC represents a major advance for this patients population.[18]

To find new therapeutic targets

Research is therefore currently being carried out to develop new targeted therapies. From this point of view, the studies of Jean Rosenbaum and his collaborators aim to idetify new mechanisms and new targets in liver cancer. By conducting an analysis of the proteoma1, they compared proteins present in cancer cells with those present in the non-cancerous part of the liver. The researchers then found that certain proteins, and in particular reptin, or RUVBL2, were present in higher quantities in the cancerous part. By collecting a hundred HCC specimens from patients, they also showed that this over-expression of reptin was associated with a worse overall prognosis.

In order to find out if reptin directly plays a role in tumoral progression, they artificially modified its level of expression in human HCC cells. The scientists then found that a reduction in the quantity of reptin in cancer cells stopped cell growth and subsequently caused cell death, whereas an increase in the quantity of reptin made it possible for cancer cells to form larger tumours after their implantation in mice.[19]

while liver resection and transplantation offer the best options for treating hepatocellular

carcinoma (HCC), only 15% of individuals meet the criteria for these surgeries due to the number, size or location of their tumor(s), cirrhosis (and other conditions that cause poor liver function), or other health problems.

Chemoembolization or Transarterial Chemoembolization (TACE)

Chemoembolization involves the insertion of a tiny catheter into the groin, which is threaded up to the hepatic artery. An interventional radiologist injects chemotherapy into the artery, followed by tiny particles to block the flow of blood through the artery. Depending on the type of particles used, the blockage may be temporary or permanent. Although the hepatic artery is blocked,Healthy liver tissue continous to receive blood from hepatic portal vein.[20]

Radiofrequency Ablation (RFA)

Radiofrequency ablation (RFA) involves the use of a probe to deliver thermal energy that destroys cancer cells. This treatment can be performed percutaneously using laparoscopy or by open celiotomy. Numerous non-randomized trials have been published in regards to RFA. Comparison of RFA to other modalities is limited. Reviewed outcomes of 232 patients who were treated with radiofrequency ablation versus those treated by ethanol injection.

Patients had less than three lesions, each less than 3 cm in size. The study endpoints included survival at four years and overall and local disease recurrence.

Results showed a 74% survival with RFA versus 57% survival with ethanol injections.

Summary and perspectives

HCC is one of the most common malignant tumors in some areas of the world with an extremely poor prognosis. HCC treatment is based on randomized controlled trials and many observational studies. Treatment options fall into five main categories: 1) surgical interventions,including tumor resection and LTx; 2) percutaneous interventions, including PEI and RFA; 3) transarterial interventions, including TAC, TAE and TACE, 4) radiation therapy and 5) drugs as well as gene- and immune-therapies. While surgery and percutaneous as well as transarterial interventions are effective in patients with limited disease (up to three lesions <3>80% patients present with multicentric HCC and advanced liver disease or comorbidities that restrict the therapeutic measures to best supportive care. In order to reduce the morbidity and mortality from HCC, therefore, early diagnosis and the development of novel systemic therapies for advanced disease, including drugs, gene- and immune-therapies as well as primary HCC prevention are of paramount importance.

Furthermore, secondary HCC prevention after successful therapeutic interventions needs to be improved to make an impact on the survival of patients with HCC. New technologies, including gene expression profiling and proteomic analyses,[21] should allow to further elucidate the molecular events underlying HCC development and to identify novel diagnostic markers as well as therapeutic and preventive targets.

REFERENCES:

1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557-76

2.. Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006;43:Suppl 1:S121-S131.

3. Paris, 30 July 2007 Institute national de la sante et de la recherché medicale

4. 4. Jiang JT, Xu N, Wu CP. Metabolism of high density lipoproteins in liver cancer. World J Gastroenterol 2007;

5. Livw Transplantation and Surgery, Vol 1, No 4 (Jub), 1995: pp 237-241

6..Simonetti RG, Camma C, Fiorello F, et al. (1991). Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci 36:962–72.

7.Assmann G, Schriewer H. HDL cholesterol: biochemical aspects (author's transl). Klin Wochenschr 1980; 58: 749-756

8. Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 2005; 96: 1221-1232

9.Skinner ER. High-density lipoprotein subclasses. Curr Opin Lipidol 1994; 5: 241-247

10.Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 2005; 96: 1221-1232

11.Eggerman TL, Hoeg JM, Meng MS, Tombragel A, Bojanovski D, Brewer HB Jr. Differential tissue-specific expression of human apoA-I and apoA-II. J Lipid Res 1991; 32: 821-828

12. Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM. Obesity and hepatocellular carcinoma. Gastroenterology 2004; 127:S97-S103

13. Garcia A, Barbaras R, Collet X, Bogyo A, Chap H, Perret B. High-density lipoprotein 3 receptor-dependent endocytosis pathway in a human hepatoma cell line (HepG2). Biochemistry 1996; 35: 13064-13071

14 Ockner RK, Kaikaus RM, Bass NM. Fatty-acid metabolism and the pathogenesis of hepatocellular carcinoma: review and hypothesis. Hepatology 1993; 18: 669-676

15.. Nakamoto Y, Kanekos S: Mechanisms of viral hepatitis induced liver injury. Curr Mol Med 3: 537-544, 2003

16.1.Department of Pathology, Hiroshima Prefectural Hospital, Hiroshima, Japan; Departments of

2. Epidemiology, 4Radiobiology, and 8Statistics, Radiation Effects Research Foundation,

Hijiyama Park, Minami-ku, Hiroshima 732–0815, Japan. National Academy of Sciences, 2101 Constitution Avenue, Washington

17. Thompson, D. E., Mabuchi, K., Ron, E., Soda, M., Tokunaga, M., Ochikubo, S., Sugimoto, S., Ikeda, T., Terasaki, M., Izumi, S. and Preston, D. L. (1994) Cancer incidence in atomic bomb survivors. Part II: Solid tumors, 1958–1987. Radiat. Res. 137S: 17–67.

18.1 World Health Organization/Hepatitis B. Web site. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/. Accessed January 15, 2008.

2. Penn State Milton S. Hershey Medical Center College of Medicine/Malignant Hepatoma. Web site.

http://www.hmc.psu.edu/healthinfo/m/malignanthepatoma.htm. Accessed January 15, 2008.

19. Dartmouth Medical School, Department of Pharmacology and of Genetics, Lebanon, NH 03756 USA.

20.Liver Disease Management and Transplant Program Center for Complex Digestive Disease California Pacific Medical Center P.O. Box 7999 San Francisco, California 94120-7999

(415) 600–1000 www.cpmc.org/liver