Epidemiology
Primary liver cancer is a common malignancy worldwide; it’s the fifth most common cancer in men and the cause of a third of male cancer deaths. It is the eighth most common cancer in women and the sixth most common cause of female cancer deaths.
Etiopathogenesis
Chronic infection with hepatitis B or C viruses and alcohol consumption are considered the most important risk factors for liver cancer. A large number of epidemiological studies indicated that environmental factors can affect the risk of liver cancer, but the role of dietary factors in tumorigenesis has not yet been determined.
However in the last fiftheen years many researches have been leaded to investigate the inverse correlation between the coffee consumption and the liver cancer development.
Coffee is an infusion of ground and roasted coffee beans;it is a complex mixture of chemicals that provides significant amounts of Chlorogenic acid and caffeine (1,3,7-trimethylxanthine, a purine alkaloid that occurs naturally in coffee beans.), and it’s the most widely consumed beverages in the world: people drink approximately 2.25 billion cups of coffee everyday worldwide and Korea is a high coffee consuming country, importing more than 100 000 tonnes of coffee a year.
Unfiltered coffee is a significant source of Cafestol and Kahweol which are diterpenes that have been implicated in the cholesterolraising effects of coffee.
.
The results of epidemiological research suggest that coffee consumption may help prevent several chronic diseases, including type 2 diabetes mellitus, Parkinson’s disease and liver disease (cirrhosis and hepatocellular carcinoma).
Concerning the liver cancer the results of the studies have been processed and collected in a meta-annalysis: Consumption of coffee associated with reduced risk of liver cancer: a meta-analysis, 2013:
. .
This summary of seven prospective and nine case–control studies suggested that coffee consumption is a protective factor in the development of liver cancer, according to consumption level.
There were significant reductions of 50% in the risk of liver cancer with the highest consumption of coffee compared with non/almost never consumption.
Also other meta-analysis ( Coffee drinking and hepatocellular carcinoma risk: a meta-analysis, 2007 ) found significant reductions of 55% in the risk of liver cancer with the high drinkers compared with non-drinkers;Larsson & wolk Coffee consumption and risk of liver cancer: a meta-analysis found a risk reduction of 43% per 2 cups of coffee per day increment.
There was also an inverse association between coffee consumption and liver cancer among European and Asian populations, and the significant risk reduction was stronger among Asian than European populations.
They also found an inverse association between coffee consumption and liver cancer among male and female populations, but this result was derived from only four studies with a small number of cases, so we could not draw a firm conclusion.
Biochemical pathways
There are several potential mechanisms through which high consumption of coffee may reduce the risk of liver cancer, probably related to cafestol, kahweol, caffeine and chlorogenic acids.It
remains uncertain which ingredient of coffee is protective against liver cancer. Some studies have indicated that caffeine can prevent oxidative DNA damage, modifing the apoptotic response ( Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants., 2000 ) and reverse cell cycle checkpoint function ( Induction of a caffeine-sensitive S-phase cell cycle checkpoint by psoralen plus ultraviolet A radiation., 2003. )
Caffeine has also strong antioxidant properties ( Antioxidant and prooxidant properties of caffeine, theobromine and xanthine., 2003 ).
Caffeine increases the level of cAMP, inhibiting the cAMP-phosphodiesterase. The cAMP raising determinates an enhancement of its biological effects, including the lock of the MAP-kinase pathway, that is involved in the fibroblasts growth.
Alpha-SMA is a protein used as a fibroblasts activation marker;a study demonstrated a predictive role of strong and extensive α SMA expression in activated fibroblasts for poor survival in HCC patients ( α-smooth muscle actin-positive fibroblasts correlate with poor survival in hepatocellular carcinoma, 2013 ). Strong expression of α SMA is an excellent marker to anticipate poor 3 year survival (OR, 0.021; 95% CI, 0.002 0.234; P=0.001).
Another study found that FGF19 (fibroblasts growth factor 19) is critically involved in the development of HCCs ( Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma, 2012 ). Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.
Those hypothesis are validated by the experimentation of an new anti-tumorigenic drug, the Brivanib in the treatment of hepatocarcinoma; it inhibits VEGFR and fibroblastic growth factor receptors (FGFR) ( Phase II, Open-Label Study of Brivanib as Second-Line Therapy in Patients with Advanced Hepatocellular Carcinoma, 2012 ).
Furthermore, cafestol and kahweol have been shown to be anticarcinogenic.
.
They induce the inhibition of carcinogenesis by increased expression of phase II detoxifying enzymes (aldehyde reductase (AR), glutathione reductase (GR), epoxide hydrolase (EH), UDP glucuronosyl transferase (UGT), and c-glutamylcysteine synthetase (c-GCS) as well as glutathione S-transferase (GST), NADH-quinine oxidoreductase 1 (NQO1), and heme oxygenase 1 (HO-1)).
Environmental toxins and endogenous mutagens (with/out activation) cause DNA damage to normal cells. Detoxification system inactivates carcinogens through reduction and conjugation to render them less reactive and more easily eliminated. On the other hand, coffee components inhibit both in human and animal experiments the expression or activity of phase I activating enzymes(CYP3A2, CYP2C11, 1A1, CYP 2B6, 1A2) which take part in the activation of environmental toxins or endogenous carcinogens.
In rat primary hepatocyte cultures, C + K produces a dose-dependent increase in the intracellular GSH concentration; this effect is likely to reflect an Nrf2-mediated transcriptional activation of GCS, as described in the mouse intestine. Indeed, inductions of GCS are found upon C + K treatment in liver, kidney, colon and lung of rats which are associated with increases in the GSH content of the same organs . HO-1 is a protein belonging to the cellular stress response protein. It is rapidly induced by oxidative stress related stimuli such as glutathione depletion, heavy metal exposure and oxidative damage. HO-1 is known to play a role in free radical scavenging . Further data have indicated that C + K may induce other genes of the cellular stress response. A significant induction of heat shock protein 25 (HSP25) expression was found in rat hepatocytes following 48 h of C + K exposure treatment.
Underlying signal pathways for coffee’s anti-tumorigenic effect: Nrf2/ARE signal pathway
The cis-acting antioxidant-responsive-element (ARE) sequence has been identified on the promoter of several genes involved in detoxification processes . It has been suggested that altering the expression of these genes through ARE-mediated transcriptional activation is likely to be a key molecular mechanism explaining how many blocking agents may prevent mutagenesis. But it is still not clear what kind of transcription factor(s) that mediate ARE-driven gene induction. Nrf proteins have been found to activate gene induction through this specific enhancer . The role of Nrf2 transcription factor in the C + K-mediated activation of liver detoxifying enzymes has been addressed using a mouse line bearing a targeted disruption of the gene encoding this factor .
Since Nrf2 is significantly expressed in the liver , these results demonstrate the key role of this transcription factor in the chemoprotective activity of C + K in the liver.
.
Coffee components stimulate the ARE-regulated signal transduction for cancer prevention. Caffeine phosphorates Nrf2 via MAPK pathway and C + K makes thiol modification of cysteine residues in Keap1, which disrupt the cytoplasmic Keap1 Æ Nrf2 complex, thereby releasing Nrf2 and permitting its translocation to the nucleus where it transcriptionally activates ARE-dependent genes.
Cafestolo and kahweol have demonstrated a protective effect against aflatoxin B1- induced genotoxicity.
Aflatoxin B1 (AFB1) is a secondary metabolite produced by some strains of the fungi Aspergillus flavus, Aspergillus parasiticus and Aspergillus nomius. It is a potent hepatotoxin and hepatocarcinogen in various mammalian species.
Several epidemiological studies suggest its close association with the high incidence of liver cancer in exposed populations where contamination of foodstuffs with AFB1 is common.
Several phase I-mediated mechanisms may potentially be responsible for a protective effect of C&K against AFB1 genotoxicity.
The data collected are consistent with a potential protective effect of C&K against the hepatocarcinogenicity of AFB1.
Two complementary mechanisms may account for this chemoprotective activity: a decrease in the expression of AFB1-activating enzymes as well as an increase in the expression of the GST sub-unit known to possess the highest catalytic activity toward the reactive metabolite AFBO. Importantly, the xenobiotic metabolizing enzymes modulated by C&K are well documented to possess the capability to activate other potential carcinogens or toxicants, and therefore chemoprotective effects against other compounds may be expected. For example, experimental data have indicated that CYP2C11 is involved in the bioactivation of several pro-carcinogens such as styrene and 4-aminobiphenyl ( The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity through a dual mechanism., 1998 ) . Furthermore, 2C11 is known to metabolize the anti-inflamatory drug diclofenac into a highly reactive hepatotoxic product .
In addition, a study showed that chlorogenic acid scavenge reactive oxygen species and have an anti-tumor effect. ( Inhibition of activator protein-1, NF-kappaB, and MAPKs and induction of phase 2 detoxifying enzyme activity by chlorogenic acid., 2005 ).
.
In conclusion, many studies suggest that ingredients in coffee may play an important role in protecting against the occurrence and development of liver cancer. However it’s not clear how this effect is explicated.
At present, the patients with liver disease, and particularly those at high risk of developing a HCC, should be made aware of the current evidenceby their physicians and advised that drinking two to five cups of coffee per day might be of benefit, particularly by reducing their HCC risk. ( Coffee and the liver: a potential treatment for liver disease?, 2010 ).
Beatrice De Zolt Ponte
Daniele Filippo Andrina
