Cytokines, inflammation and cancer Alexandre Corthay Department of Immunology Oslo University Hospital Rikshospitalet and University of Oslo Oslo, Norway

Tumor Necrosis Factor-  (TNF-  )

Tumor Necrosis Factor-  (TNF-  ) TNF-  is a major inflammatory cytokine that was first identified for its ability to induce rapid haemorrhagic necrosis of experimental cancers.

Balkwill Nature Reviews Cancer :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 :361

-TNF-  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-  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- , Lymphotoxin, CD95L, TRAIL, VEGI, TWEAK and LIGHT), survival (such as RANKL and BAFF), differentiation (such as TNF- , RANKL and DR6) or proliferation (such as TNF- , CD27L, CD30L, CD40L, OX40L, 4- 1BBL, APRIL and BAFF).

Cellular signalling pathways leading to activation of the main cellular responses by members of the TNF superfamily.

Balkwill Nature Reviews Cancer :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.

-In this article we have provided a rationale for the use of cytokine and chemokine blockade, and further investigation of non-steroidal anti- inflammatory drugs, in the chemoprevention and treatment of malignant diseases.

Interferon-  (IFN-  )

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-  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.