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Inflammation and necrosis promote tumour growth

Abstract

In children, cancer probably arises from a combination of inherited genetic mutations and genetic alterations that are acquired during the rapid cellular expansion that occurs during embryogenesis, and it is rarely associated with immune cell infiltrates. Conversely, in adults, cancer is frequently preceded by a long period of subclinical inflammatory disease and micronecrosis that provides a setting in which the epigenetic regulation of genes, cell death, cell proliferation and mutagenesis occurs. Here, we provocatively suggest that adult cancer results from rounds of disordered and unscheduled necrotic cell death, subsequent epithelial proliferation and the resulting suppressed immunity, rather than from a process that is dictated solely by cell growth. This paradigm shift regarding the development of cancer and this 'sixth sense' of the immune system indicates new strategies for cancer prevention and therapy.

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Figure 1: The crucial role of dendritic cells, natural killer cells and T cells in the tumour microenvironment.
Figure 2: Tumour-infiltrating macrophages.
Figure 3: Several mutagenic hits are required for carcinogenesis.

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Acknowledgements

J.V. has received support from the Nona and Kullervo Väre Foundation, Finland, and the Finnish Cultural Foundation. M.T.L. has received grant support from the National Institutes of Health, United States.

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Correspondence to Michael T. Lotze.

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DATABASES

Entrez Gene

arginase

COX1

COX2

C-reactive protein

HMGB1

IDO

IFN-α

IFN-γ

IL-6

IL-12

IL-23

LETAL

MICA

MICB

nitric-oxide synthase

NKG2D

RAGE

STAT3

TNF

Glossary

ANTHRACYCLINES

Antibiotics with antitumour activity, which were originally isolated from a microbial broth. They avidly bind to DNA and also interfere with the function of topoisomerases, which regulate the three-dimensional shape of DNA.

DYSPLASIA

Loss in the uniformity of individual cells, as well as loss in their orientation. It is frequently a precursor to cancer and occurs mainly in epithelia.

HYPERPLASIA

An increase in the number of cells in a tissue or organ.

NEOPLASIA

From the Greek for 'new formations'. New growths or tumours, which can be either benign or malignant.

ONCOGENES

Altered or mutant forms of proto-oncogenes, which drive the proliferation of cells. Proto-oncogenes are usually involved in the control of cell growth and division.

PLATINATING AGENTS

Cisplatin and carboplatin are used in the treatment of various adult and childhood cancers. They exert their cytotoxic effects by forming reactive intermediates that covalently bind to DNA and form intrastrand and interstrand DNA crosslinks, which are sites for binding of the high-mobility group box 1 protein (HMGB1).

T HELPER 1 CELL

(TH1 cell). TH cells secrete cytokines after activation, which occurs through ligation of cell-surface T-cell receptors with their cognate ligands (peptide–MHC complexes), together with recognition of the appropriate co-stimulatory molecules. Undifferentiated TH0 cells differentiate (or polarize) into TH1 or TH2 cells, depending on the cytokines and co-stimulatory molecules that are presented to them by antigen-presenting cells in the lymph node. In addition, antigen concentration influences the outcome of this differentiation. TH1 cells provide help for cytotoxic T-cell responses by secreting high concentrations of interleukin-2 (IL-2), tumour-necrosis factor and interferon-γ. By contrast, the typical TH2 cytokines, IL-4, IL-5 and IL-10, are more important for the induction of antibody-mediated immune responses.

TUMOUR-SUPPRESSOR GENES

Genes that limit the generation of cancer. Many of these genes regulate scheduled entry into the cell cycle or promote apoptosis of damaged cells. Loss-of-function mutations in such genes enhance susceptibility to cancer.

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Vakkila, J., Lotze, M. Inflammation and necrosis promote tumour growth. Nat Rev Immunol 4, 641–648 (2004). https://doi.org/10.1038/nri1415

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