Chronic liver inflammation dominated by interferon-? can prevent hepatocarcinogenesis.

2012·0.24 MB·English

by  Schrader, Jorg

OncoImmunology1:2,222–223;March/April2012;G2012LandesBioscience
Chronic liver inflammation dominated by
interferon-c can prevent hepatocarcinogenesis
Jörg Schrader and Johannes Herkel*
DepartmentofMedicineI;UniversityMedicalCentreHamburg-Eppendorf;Hamburg,Germany
Keywords: inflammation, regeneration, interferon, STAT, apoptosis, p53, cancer, tumor-promotion, anti-cancer immunity
Abbreviations: IFNc, interferon-c
Inflammationisamajorstimulusforcarcinogenesis;howeverinflammationcanalsoinhibittumorgrowthanddeplete
malignant cells. The differences between cancer-promoting and cancer-inhibitory inflammation are not clear. We
identifiedInterferon-casamajormediatorofcancer-inhibitoryinflammationthatpromotesanti-cancerimmunityinthe
liverandsensitizes malignant hepatocytes for apoptosis.
© 2012 Landes Bioscience.
Inflammation is a critical promoter of activation of the NFkB pathway in liver effect of IFNc seemed to be mediated in
carcinogenesis. Indeed, a characteristic of macrophages and the secretion of inter- part by increasing tumor immune surveil-
most, if not all tumors is a microenviron- leukin-6, which, in turn, stimulates the lancebylymphocytes,indicatedbyastrong
ment of inflammatory cells and mediators STAT3 pathway in hepatocytes and infiltration of IFNc-transgenic livers with
that enables the growth of malignant cells enables the survival and proliferation of CD8 T cells, NKT and NK cells.8 In
and their acquisitionDof the o‘hallma rkns of odamagted celdls.4,5 Iinflasmmattoryrlymiphbo- audditiont, IFeNc se.emed to prevent carcino-
cancer’.1 Moreover, chronic inflammation cytes can also secrete STAT3-activating genesisalsobydirecteffectsondamagedor
predisposes toseveraltypesofcancer,such cytokines,suchasinterleukin-22,thatmay malignant hepatocytes.8 IFNc induced a
as hepatocellular carcinoma.2 However, further promote liver cancer.6 sustained and non-refractory activation of
inflammation has also the capacity to However, the common notion that the STAT1 pathway in hepatocytes, but
inhibit carcinogenesis by depleting malig- chronic liver inflammation unequivocally only transient STAT3 activation.8 This
nant cells, and even to induce regression promotes hepatocarcinogenesis may be an IFNc-induced activation of the STAT1
of established tumors.2,3 Currently, our over-simplification.Indeed,clinicalobserva- pathway was associated with an activation
knowledge of what makes the difference tions suggests that some chronic inflam- of the p53 tumor suppressor pathway.8
between tumor-promoting and tumor- matoryliverdiseases,suchasviralhepatitis, Indeed, IFNc induced accumulation of
inhibitory inflammation is rather limited. progress more commonly to liver cancer p53andsensitizedhepatocytestoapoptotic
To develop more effective anti-tumor than others; e.g., autoimmune hepatitis. cell death in response to genotoxic stress.8
therapies, we need to define key inflam- Moreover,wenoticedthattransgenicmice, These findings indicate that the carcino-
matory mediators and pathways that can which overexpress interferon-c (IFNc) in genic potential of chronic inflammation is
turn tumor-promoting inflammation into the liver and manifest lifelong liver inflam- determined by type and composition of its
anti-cancerimmunity. mation with persistent liver damage and mediators, most notably the proportion of
Hepatocellular carcinoma is a paradigm regeneration,are not prone to spontaneous IFNc-secreting lymphocytes in chronic
for inflammation-induced cancer, since it liver cancer.7,8 Therefore, we induced inflammatorytissueinfiltrates.
develops most frequently on grounds of chemicalhepatocarcinogenesisinthesemice We thus propose that the differences
chronic liver inflammation, consecutive byapplicationofdiethylnitrosamine.8Quite between tumor-promoting and tumor-
tissuedamageandcompensatoryregenera- surprisingly, chemical hepatocarcinogenesis inhibitory liver inflammation may be
tion.2 An important component of the wassuppressedintheIFNc-transgenicmice explained not only by the degree of
tumor-promoting inflammatory infiltrate despite overt liver injury.8 Indeed, IFNc- cytotoxic activity of inflammatory cells,
are tumor-associated macrophages that transgenic mice developed fewer and less but also by predominance of either
exhibit an M2 phenotype and promote advancedlesions,suggestingthatIFNcmay STAT1-activating cytokines, such as
tissue remodeling and angiogenesis.2 The suppressboththeinitiationandthepromo- IFNc, or STAT3-activating cytokines,
initiationoflivercancerhasbeenlinkedto tion ofliver cancer.The tumor-suppressive such as interleukin-6 or interleukin-22
*Correspondenceto:JohannesHerkel;Email:[email protected]
Submitted:09/15/11;Accepted:09/15/11
http://dx.doi.org/10.4161/onci.1.2.18114
222 OncoImmunology Volume1Issue2
AUTHOR'SVIEW
© 2012 Landes Bioscience.
Figure1.Amodelofcancer-promotingandcancer-inhibitoryliverinflammation.Tumor-suppressiveinflammatoryliverinfiltratesarecharacterizedby
highcontentofIFNc-secretinglymphocytes(Th1,CD8T,NKandNKTcells),sustainedactivationoftheSTAT1pathwayinhepatocytes,macrophage
polarizationtowardanM1phenotypeandfibrolysis.Incontrast,tumor-promotingliverinfiltratesarecharacterizedbyhighcontentofIFNcnon-
producingorinterleukin-22producinglymphocytes,interleukin-6secretionbyvariouscelltypes,macrophageswithM2phenotype,sustainedSTAT3
activationinhepatocyteDs,fibrogoenesisa ndnangiogoenesis.t distribute.
(Fig.1). This model is compatible with whereas M2 macrophages, which are some NKT cells, may characterize tumor-
thefindingthatthebalanceofSTAT1and induced by non-IFNc producing lympho- suppressive inflammation, whereas infil-
STAT3 activation seems to predict the cytes and malignant hepatocytes, promote trates with high content of IFNc
clinicaloutcomeincutaneousmelanoma.9 fibrogenesis and angiogenesis. It is con- non-producing or interleukin-22 pro-
During tumor promotion, the presence ceivable that the presence of IFNc during ducing lymphocytes may characterize
or absence of IFNc further influences tumor promotion may prevent induction tumor-promoting infiltrates. Therefore,
the tumor microenvironment and tissue of M2 macrophages. In summary, inflam- manipulating the type of chronic inflam-
remodelling.Indeed,IFNcisknowntopro- matory infiltrates with high content of mation and the composition of tumor-
mote macrophage polarization toward an IFNc-secreting lymphocytes, i.e., Th1 associated inflammatory infiltrates may
M1 phenotype and to inhibit fibrogenesis, cells, CD8 T cells, some NK cells and servetheprevention ofcancer.
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