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Cytokines, inflammation and cancer
Alexandre Corthay
Department of Immunology
Oslo University Hospital Rikshospitalet and University of Oslo
Oslo, Norway
Tumor Necrosis Factor-a
(TNF-a)
Tumor Necrosis Factor-a
(TNF-a)
TNF-a is a major inflammatory cytokine that was first identified for
its ability to induce rapid haemorrhagic necrosis of experimental
cancers.
Balkwill Nature Reviews Cancer 2009 9:361
Balkwill Nature Reviews Cancer 2009 9:361
In studying "hemorrhagic necrosis" of tumors produced by endotoxin, it was found
that the serum of bacillus Calmette-Guerin (BCG)-infected mice treated with
endotoxin contains a substance (tumor necrosis factor; TNF) which mimics the
tumor necrotic action of endotoxin itself. TNF-positive serum is as effective as
endotoxin itself in causing necrosis of the sarcoma Meth A and other transplanted
tumors. A variety of tests indicate that TNF is not residual endotoxin, but a factor
released from host cells, probably macrophages, by endotoxin. Corynebacteria and
Zymosan, which like BCG induce hyperplasia of the reticulo-endothelial system, can
substitute for BCG in priming mice for release of TNF by endotoxin. TNF is toxic in
vitro for two neoplastic cell lines; it is not toxic for mouse embryo cultures. We
propose that TNF mediates endotoxin-induced tumor necrosis, and that it may be
responsible for the suppression of transformed cells by activated macrophages.
Balkwill Nature Reviews Cancer 2009 9:361
-TNF-a is a master regulator of inflammation.
-TNF-a is a master regulator of inflammation.
-Research during the past three decades has shown the existence
of a superfamily of TNF proteins consisting of 19 members that
signal through 29 receptors.
-TNF-a is a master regulator of inflammation.
-Research during the past three decades has shown the existence
of a superfamily of TNF proteins consisting of 19 members that
signal through 29 receptors.
-After binding to the receptor, members of the TNF superfamily
either mediate apoptosis (such as TNF-a, Lymphotoxin, CD95L,
TRAIL, VEGI, TWEAK and LIGHT), survival (such as RANKL and
BAFF), differentiation (such as TNF-a, RANKL and DR6) or
proliferation (such as TNF-a, CD27L, CD30L, CD40L, OX40L, 41BBL, APRIL and BAFF).
Cellular signalling pathways leading to activation of the main cellular
responses by members of the TNF superfamily.
Balkwill Nature Reviews Cancer 2009 9:361
-We suggest that the inflammatory cells and cytokines found in tumours
are more likely to contribute to tumour growth, progression, and
immunosuppression than they are to mount an effective host antitumour
response.
-We suggest that the inflammatory cells and cytokines found in tumours
are more likely to contribute to tumour growth, progression, and
immunosuppression than they are to mount an effective host antitumour
response.
-In this article we have provided a rationale for the use of cytokine and
chemokine blockade, and further investigation of non-steroidal antiinflammatory drugs, in the chemoprevention and treatment of malignant
diseases.
Interferon-g
(IFN-g)
Immunodeficient mice are highly susceptible to tumour development
induced by the chemical carcinogen methylcholanthrene (MCA).
Immunodeficient mice are highly susceptible to spontaneous cancer
Lymphocytes and IFN-g collaborate to protect against development
of carcinogen-induced sarcomas and spontaneous epithelial
carcinomas and also to select for tumour cells with reduced
immunogenicity. The immune response thus functions as an
effective extrinsic tumour-suppressor system. However, this
process also leads to the immunoselection of tumour cells that are
more capable of surviving in an immunocompetent host, which
explains the apparent paradox of tumour formation in
immunologically intact individuals.
Tumor-infiltrating lymphocytes
Collectively, the immunological data (the type, density, and location of
immune cells within the tumor samples) were found to be a better
predictor of patient survival than the histopathological methods
currently used to stage colorectal cancer. The results were validated in
two additional patient populations. These data support the hypothesis
that the adaptive immune response influences the behavior of human
tumors. In situ analysis of tumor-infiltrating immune cells may therefore
be a valuable prognostic tool in the treatment of colorectal cancer and
possibly other malignancies.