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The inflammatory pathogenesis of colorectal cancer

Nature Reviews Immunology volume 21, pages 653–667 (2021)Cite this article

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Abstract

The mutational landscape of colorectal cancer (CRC) does not enable predictions to be made about the survival of patients or their response to therapy. Instead, studying the polarization and activation profiles of immune cells and stromal cells in the tumour microenvironment has been shown to be more informative, thus making CRC a prototypical example of the importance of an inflammatory microenvironment for tumorigenesis. Here, we review our current understanding of how colon cancer cells interact with their microenvironment, comprised of immune cells, stromal cells and the intestinal microbiome, to suppress or escape immune responses and how inflammatory processes shape the immune pathogenesis of CRC.

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Fig. 1: Mechanisms of tumour initiation and promotion in colorectal cancer.
Fig. 2: The inflammatory environment of colorectal cancer.
Fig. 3: The roles of the microbiome and mycobiome in colorectal cancer.

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Acknowledgements

Work in the laboratory of F.R.G. is supported by institutional funds from the Georg-Speyer-Haus, by the LOEWE Center Frankfurt Cancer Institute (FCI) funded by the Hessen State Ministry for Higher Education, Research and the Arts [III L 5 – 519/03/03.001 – (0015)], and by the Deutsche Forschungsgemeinschaft (FOR2438: Gr1916/11-1; SFB 815, 1177 and 1292 as well as GRK 2336). The Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, is funded jointly by the German Federal Ministry of Health and the Ministry of Higher Education, Research and the Arts of the State of Hessen (HMWK).

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  1. Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany

    Mark Schmitt & Florian R. Greten

  2. Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt/Main, Germany

    Mark Schmitt & Florian R. Greten

  3. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Florian R. Greten

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Glossary

Stage 4 colorectal cancer

The stage at which the colorectal cancer has spread to other parts of the body such as lung, liver, abdominal wall, ovary or distant lymph nodes.

Aneuploidy

The presence of an abnormal number of chromosomes in a cell.

Loss of heterozygosity

Describes a cross-chromosomal event that results in loss of the entire gene and the surrounding chromosomal region.

Microsatellite instability

(MSI). The phenotypic indication of non-functional DNA mismatch repair that results in genetic hypermutability.

Mismatch repair

A cellular system that recognizes and corrects DNA errors resulting from wrongly paired DNA bases that occur, for example, during DNA replication, DNA recombination or DNA damage.

Serrated pathway

An alternative pathway of genetic alterations occurring independently of APC mutations that is often initiated by the activation of the RAS–RAF–MEK–ERK–MAPK axis and is frequently characterized by a CpG island methylation pathway phenotype and subsequently by high-level DNA microsatellite instability, especially when located proximally and associated with BRAF mutations.

AJCC/UICC TNM classification

The AJCC/UICC staging system is a classification system developed by the American Joint Committee on Cancer and the Union Internationale Contre le Cancer for describing the extent of disease progression in patients with cancer using a system that scores for tumour size, lymph nodes affected and the presence of metastases.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous group of cells from the myeloid lineage that have immunosuppressive properties.

Immune-checkpoint blockade

A therapeutic concept that aims to block negative feedback signalling to immune cells to enhance an immune response against tumours.

AOM/DSS model

A mouse model of inflammation-associated colorectal cancer, in which intestinal tumorigenesis is triggered by injection of the mutagen azoxymethane (AOM) and subsequent cycles of inflammation induced by dextran sulfate sodium (DSS).

WNT pathway

An evolutionarily conserved pathway that is important for embryonic development and carcinogenesis, which is activated in more than 90% of colorectal cancers owing to mutations in its signalling components.

Mitophagy

Selective degradation of mitochondria by autophagy.

Immunoediting

Evolution of tumours with the result that tumour cells are no longer effectively recognized and suppressed by the immune system, resulting in the emergence of immune-resistant tumour cell variants.

Apc-mutant models

Mouse models of intestinal cancer in which tumorigenesis is driven by a loss of function of APC, resulting in the hyperactivation of the WNT pathway and the hyperproliferation of affected cells.

Apc Min/+ mouse model

A mouse model of intestinal cancer in which the Apc gene has a truncation mutation at codon 850, resulting in multiple intestinal neoplasia (Min).

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Schmitt, M., Greten, F.R. The inflammatory pathogenesis of colorectal cancer. Nat Rev Immunol 21, 653–667 (2021). https://doi.org/10.1038/s41577-021-00534-x

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