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Friends or foes — bipolar effects of the tumour stroma in cancer

Key Points

  • Cancer cells can alter their adjacent stroma to form a permissive and supportive environment for tumour progression — this is known as the 'reactive' tumour stroma.

  • Cancer cells produce a range of growth factors and proteases that modify their stromal environment.

  • These factors disrupt normal tissue homeostasis and act in a paracrine manner to induce angiogenesis and inflammation, as well as activation of surrounding stromal cell types such as fibroblasts, smooth-muscle cells and adipocytes, leading to the secretion of additional growth factors and proteases.

  • Activated fibroblasts in the stroma promote tumour progression by secreting growth factors and pro-migratory extracellular-matrix (ECM) components, as well as upregulating the expression of serine proteases and matrix metalloproteinases that degrade and remodel the ECM.

  • The induction of inflammation in the tumour stroma also results in production of a range of factors that promote tumour progression.

  • Angiogenesis promotes not only tumour growth, but also progression from a pre-malignant to a malignant and invasive tumour phenotype.

  • The tumour stroma can have a more direct role in tumorigenesis, by acting as a mutagen.

  • By 'normalizing' the tumour stroma, it is possible to slow or reverse tumour progression.

Abstract

The restricted view of tumour progression as a multistep process defined by the accumulation of mutations in cancer cells has largely ignored the substantial contribution of the tumour microenvironment to malignancy. Even though the seed and soil hypothesis of Paget dates to 1889, it has been less than two decades since researchers have included the tumour microenvironment in their analyses of tumour progression. What have we recently learned from studying tumour–stroma interactions, and will this help to define new targets for therapy?

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Figure 1: Tumour stage depends on stromal activation.
Figure 2: Reversion of tumour phenotype by stromal normalization.
Figure 3: Crosstalk between tumour cells and their activated stromal surroundings.

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Acknowledgements

We would like to thank all the co-workers and collaborators who have contributed to his article with their results and their helpful comments and discussions. We apologize to the authors of the numerous papers on this interesting subject who we were unable to quote because of space limitations.

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Correspondence to Norbert E. Fusenig.

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DATABASES

Entrez Gene

angiopoietin 1

bFGF

CCL2

CSF1

EGFR

G-CSF

GM-CSF

HGF

IGF1

MMP1

MMP13

MMP9

MT1-MMP

PDGF

TGFβ

TSP1

tumour-necrosis factor-α

uPA

VEGF

VEGFR2

National Cancer Institute

breast cancer

cervical cancer

colorectal cancer

prostate cancer

skin cancer

stomach cancer

FURTHER INFORMATION

Angiogenesis Inhibitors in Clinical Trials web site

Epidemiology: Nonsteroidal Anti-Inflammatory Drugs and Cancer Prevention

Special Project Angiogenesis

Glossary

PAGET'S SEED AND SOIL HYPOTHESIS

The English surgeon Stephen Paget compared tumour cells with the seed of plants, in that they are both “carried in all directions; but they can only live and grow if they fall on congenial soil”. Similarly, he argued that metastatic cells must thrive only where conditions are in some way favourable.

TUMOUR STROMA

Compartment providing the connective-tissue framework of the tumour. It includes fibroblasts, immune and inflammatory cells, fat cells and blood-vessel cells.

EXTRACELLULAR MATRIX (ECM)

Complex three-dimensional network of macromolecular protein fibres as well as non-fibrous proteoglycans that is present between clusters of cells in the stroma of all tissues. The ECM provides architectural structure and strength and contextual information for cellular communication, adhesion and migration.

DESMOPLASIA

The growth of fibrous or connective tissue that is induced by tumours and is characterized by activated fibroblasts, recruited inflammatory and immune cells, and angiogenic blood vessels.

ANGIOGENESIS

The formation of new blood vessels from pre-existing ones.

BASEMENT MEMBRANE

Amorphous, dense, sheet-like, proteinaceous structure that is 50–100 nm thick and that separates epithelial and stromal tissues, and delineates the endothelial lining of vessels.

MYOFIBROBLASTS

Activated fibroblasts that express α-smooth-muscle actin, specific growth factors and proteases. They are similar to the carcinoma-associated fibroblasts present in the tumour stroma.

ENDOTHELIAL PROGENITOR CELLS

Undifferentiated cells that reside in the adult bone marrow or circulate in the blood (circulating progenitors) that can be recruited to the sites of ongoing angiogenesis, where they differentiate and mature into endothelial cells. They are identified by co-expression of haematopoietic stem-cell markers (CD34, AC133) and vascular endothelial cell markers (VEGFR2, TIE2)

ANGIOGENIC SWITCH

Transition of tumours from an avascular state to the active recruitment of blood vessels into the tumour.

HEMISDESMOSOME

Specialized junction between an epithelial cell and its basal lamina that mediates their interactions.

PERINEURAL CELLS

The outermost layer of stromal cells that surround peripheral nerves.

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Mueller, M., Fusenig, N. Friends or foes — bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4, 839–849 (2004). https://doi.org/10.1038/nrc1477

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