Hepatocellular Carcinoma (HCC)

• Different types of cancer can behave very differently.

For example, lung cancer and breast cancer are very different diseases. They grow at different rates and respond to

different treatments. That is why people with cancer need treatment that is aimed at their particular kind of cancer.

• Cancer attack manly epithelial cells

epithelial cells cover the skin, line the respiratory and alimentary tracts, and metabolize ingested carcinogens. over 90% of cancers occur in epithelia.

• Part of cancer reason

- Life expectancy is steadily rising and most cancers are morecommon in an ageing population. - More significantly, a globalization of unhealthy lifestyles, (smoking and the adoption of many features of the modernWestern diet (high fat, low fibre content)) each account for about 30% of new cancer cases

- Pollution

-Infectious agents associated with increased cancer risk include hepatitis B virus (liver),

Patients carrying the virus have a 100-fold greater risk of developing HCC.

It was identified 399 sites at which HBV was integrated into the genome, and found that they were distributed across the whole genome, but that most were clustered within a small number of ‘hotspots’. The vast majority of the integration sites (344 out of 399; more than 86%) were found only in the samples obtained from liver tumors.

The researchers analyzed breakpoints in the HBV genome — sites at which the circular genome of the virus breaks before being integrated into the genome of the host cell. They found that about 40% of breakpoints occur within a restricted region where three critical genetic elements are located.

This region, approximately 400 base pairs in length, contains the enhancer, a short regulatory sequence that binds proteins and enhances expression of the viral genes; the X gene, which plays critical roles in infection and replication; and the core gene, which encodes a protein envelope for the viral DNA.

The high number of breakpoints in the region may facilitate HBV insertion into the host genome, which in turn may promote cancer formation by interrupting the coding sequences of tumor suppressor genes.

Mechanism of HBV as tumor promoter

More than 92% of the patients in the sample had HBV integrated into their genomes, and the majority of these were found only in DNA from the tumors.

Non-cancerous tissues were also found to contain integrated viral genomes, but DNA isolated from the tumors tended to have more HBV integration sites.

Thus, HBV integration patterns differ between cancerous and non-cancerous tissues, and there is a complex relationship between HBV integration and cancer development.

- This type of cancer occurs more often in men than women.

- Alcohol abuse

- Inflammation of the liver that is long-term (chronic)

- Iron overload in the body (hemochromatosis)

- Aflatoxin

After continuous cycles of destructive–regenerative process accumulate to some extent, the liver will suffer from cirrhosis.

The main characteristic of cirrhosis is that abnormal nodules appear in the liver surrounded by collagens and scarring.

Subsequently, the hyperplastic nodules will turn into dysplastic nodules (DNs) inducing a high risk of developing HCC for those patients.

DNs are classified into low-grade and high-grade according to cytological and on microscopic examination

Processes of HCC

The HCC can be classified into:

well differentiated, moderately differentiated and poorly differentiated tumors, The last of which is the most severe.

One-third of high-grade DNs will progress to HCC in two years, and the rate increases to 81% in five years.

● Symptoms

- Abdominal pain or tenderness, especially in the upper-right part.- Easy bruising or bleeding.

- Enlarged abdomen.

- Yellow skin or eyes (jaundice)

● Exams and Tests

Physical examination may show an enlarged, tender liver.

Tests include:

Abdominal CT scanAbdominal ultrasoundLiver biopsyLiver enzymes (liver function tests)Liver Magnetic Resonance Imaging MRISerum alpha fetoprotein

• Treatment

- Cancer screening programmes are designed to detect not only early asymptomatic malignant tumours but also

premalignant lesions

Cancer does not develop overnight, instead often evolving over many years with detectable premalignant lesions presaging the development of full-blown malignancy.

Prevention, Researchers are looking at ways to prevent (make a vaccine to prevent hepatitis C) or treat hepatitis before it causes liver cancer (treated with drugs that make the patient's immune system stronger). This could prevent about half of liver cancer cases worldwide.

- Radiotherapy is another option, as are combinations of anticancer drugs.

- Surgery

* Most conventional anticancer drugs have been designedwith deoxyribonucleic acid (DNA) synthesis as theirtarget. Therein lies the problem, in that tumour cells arenot the only proliferating cells in the body; cells that line the alimentary tract, bone marrow cells that generate redblood cells and cells to fight infection, and epidermal cellsincluding those that generate hair are all highly

proliferative.Thus, patients with cancer receiving chemotherapy commonly suffer unwanted (hair loss) and sometimes potentially life-threatening (anaemia and proneness to infections) side effects that limit treatment.

HER signaling:

Human epidermal growth factor receptor (HER) pathways play a critical role in cancer biology and are an area of intense research at Genentech, HER-mediated signaling pathways results in the growth and spread of cancer cells.

The HER family consists of 4 structurally related receptors: HER1 (EGFR), HER2, HER3, and HER4.

HER family receptors are activated by ligand-induced dimerization, or receptor pairing.

Dimerization is a critical step in HER family-mediated signaling, and HER receptors are able to homodimerize or heterodimerize with other HER family members, allowing for multiple receptor combinations.

The formation of dimers leads to activation of the intrinsic tyrosine kinase domain and subsequent phosphorylation on specific tyrosine residues, which serve as docking sites for a variety of molecules. Recruitment of these molecules leads to the activation of different downstream signaling cascades, which may lead to:

Increased/uncontrolled cell proliferationDecreased apoptosis (programmed cell death)Enhanced cancer cell motilityAngiogenesis

- The new generation of drugs have targets removed fromthe direct synthesis of DNA;

They affect the signals that promote or regulate the cell cycle. They affect growth factors and their receptors. They affect signal transduction pathways and pathways affecting DNA repair. They affect apoptosis.

Virus therapy.Virus therapy , A newer approach to treatment is the use of a virus known as JX-594. This is the same virus that was used to make the smallpox vaccine, but it has been altered in the lab so that it mainly infects cancer cells and not normal cells. It is injected into the blood and enters the cancer cells, where it causes them to die or to make proteins that result in them being attacked by the body’s immune system.Early results against advanced liver cancer have been promising, even in patients who have already had other treatments, and larger studies of this treatment are now being done.

☻ Other strategies focus on either attempting to target tumour cells specifically by conjugating cell toxins to tumour-

specific antibodies (magic bullets).

☻ Slowing down cancer progression by affecting cell adhesion, proteolytic enzyme activity and angiogenesis.

☻ Each of these pathways may be affected by activating mutations that predispose to cancer and, thus, offer cancer inhibition.

● Anti-cancer drug

Health Canada has approved a new indication 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, and the only one shown to significantly improve overall survival in HCC patients.

1- NEXAVAR (2008)

NEXAVAR is a simple, non-invasive and effective treatment for HCC, offering patients a greater chance of significantly extending their overall survival by 44 per cent in patients with HCC versus placebo .

Median overall survival was 10.7 months in NEXAVAR-treated patients compared to 7.9 months in those taking placebo.

NEXAVAR targets both the tumour cell and tumour vasculature and is the only oral multi-kinase inhibitor that does not require liver cancer patients to interrupt their treatment schedule.

In preclinical studies, NEXAVAR has been shown to target members of two classes of kinases known to be involved in both cell proliferation (growth) and angiogenesis (growth of new blood vessels) – two important processes that enable cancer growth..

NEXAVAR works by slowing tumor growth and by cutting off the blood supply to the tumor (angiogenesis). NEXAVAR acts on proteins called kinases which include RAF kinase, VEGFR-2, VEGFR-3, PDGFR-β, KIT, FLT-3 and RET

Overall, the most common adverse events ( ≥ 20 per cent) which were considered to be related to NEXAVAR in patients with HCC or RCC are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea, and abdominal pain.

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