Hepatocellular carcinomas (HCC) exhibit genetic heterogeneity. Most of the HCC tumors are associated with activation of insulin/IGF-1/IRS-1/Ras/Raf/MAPK/Erk and a WNT/Frizzled receptors/β catenin signaling cascade which provides targets for therapy. All the pathways are mediated by genetic mutations and signaling compounds and the loss of regulatory proteins also contributes for tumor generation. Two signaling pathways are involved in the carcinogenesis which includes insulin/IGF 1/IRS 1/MAPK and Wnt/FZD/β catenin pathways.
The insulin/IGF-1/IRS-1/MAPK cascade plays a crucial role in regulating regeneration of liver and embryonic development. The constitutive activation of these cascades which is due to IRS 1 over expression leads to HCC and also increases in tumor size.IRS-1 protein is the main substrate for insulin/IGF-1 receptor. The activated ERK translocates to the nucleus which regulates gene expression through the process of phosphorylation of transcriptional factors.IGF-1 stimulation of HCC cells generally results in p-ERK accumulation in the cytoplasm. The down regulation of RKIP expression observed in HCC tumors contributes constitutive activation in ERK/MAPK pathway and proliferation migration of HCC cells. KIP acts as attractive target for regulation of HCC proliferation and also differentiation.
The constitutive activation of Wnt/β catenin signaling cascade has major importance in hepatic oncogenesis.Wnt proteins are rich in cysteines with glycoprotein which acts as extracellular signaling molecules and play major role in normal and pathological developmental processes. Wnt consists of proteins which are frizzled ligand for FZD receptors. Wnt/β catenin signaling is important in proliferation of hepatocytes and early embryonic liver development. It is also involved in liver regeneration. In presence of high level FZD7 expression, HCC will contain only wild-type β-catenin gene.FZD7 over expression leads to HCC tumor development.
Aberrant levels of β catenin accumulation in the cytoplasm or the nucleus generally leads to inappropriate transcription of target genes which are involved in proliferation of the cell and their migration. Increased levels of cytoplasm β catenin immunoreactivity is observed in transgenic livers and higher levels were observed in cytoplasm and nuclei of double transgenic than single transgenic lines which is evidenced by immunohistochemical staining and western blot analysis.
The three human ras genes namely H-ras,N-ras and K-ras encodes four proteins binded by GTP proteins. The Ras proteins are positioned inner surface of the plasma membrane and they serve as molecular switches for transduction of extracellular signals into the cytoplasm and control the pathways which influence growth differentiation and apoptosis of the cell. Biologically active ras forms has high affinity towards raf-1.The Ras-Raf promotes the translocation of cytoplasm Raf proteins to the plasma membrane. Raf phosphorylates and activates MAPK kinases such as MKKs, MEK1, MEK2.MEK1 and MEK2 exhibit dual specificity kinases which are involved in phosphorylation of Erk 1 and 2 on tyrosine and threonine residues after translocation. The downstream targets such as transcription factors control cellular responses which includes growth and differentiation.
Over expression of Ras and members of signaling pathways such as p21 are involved in HCC studies. The inhibitors of Ras pathway down regulates HCC.The gene clusters are identified to be essential for HCC development. Micro array data from genome with expression analysis of HCC reveals that individual genes are involved in causing HCC in humans and pathways are crucial for the development of tumor and metastasis with tumor recurrence. It also suggests that HCC should not be regarded as single tumor entity but, it represents several subtypes in the samples.
In HCC, p53 mutations vary with geographic areas which reflect various etiological agents and host susceptibility factors. The amplifications of chromosomes 1q, 8q, 6p and 17 q play a key role in HCC.
Constitutive expression of IR-1 and HBx generally promote hepatocytes dysplasia and HCC.The HCC can lead to chronic liver disease which is generally caused by hepatitis C virus. These viruses have a capacity to infect persistently and create a global burden. The symptoms generally observed in this HCC are abdominal pain especially in the upper right part, easy bruising and bleeding, enlarged abdomen and yellow skin as seen in jaundicitis.the complications involved are gastrointestinal bleeding, liver failure and metastasis.
The HCC can be prevented by early diagnosis of viral hepatitis and childhood vaccination plays a critical role in reducing liver cancer. Alcohol consumption should be avoided and frequent screening for hemochromatosis will yield good results. Periodic screening with liver ultrasound and measurement of blood alpha fetoprotein will help in detecting cancer at early stages. The liver profile and prothrombin time are essential for planning treatment. Elevated levels of tumor markers such as serum alpha fetoprotein also called as AFP which is detected over 400 µg/l is diagnostic and generally seen in 60% of the patients with HCC.
HCC is a due to the constitutive effect of several pathways and clusters of genes. Novel technologies were used to examine the patient hepatocytes and techniques such as PCR and RT PCR are promising in detection of HCC.
References
Bengochea A,de souza MM,Lefrancois Let al,(2008) Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellukar carcinoma Br J Cancer 99(1):43-150
Kim M,Lee HC,Tsedensodnam O et al (2008) Functional interaction between Wnt3 and Frizzled 7 leads to activation of the Wn/beta catenin signaling pathway in Hepatocellular carcinoma cells.J Haptol 48(5):780-791
Llovet J,Ricci S,mazzaferro V et al(2008) sorafenib in advanced hepatocellular carcinoma.N Engl J med 359(4):378-390
