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Putting tumours in context

Key Points

  • Cell–cell and cell–ECM signalling contributes to epithelial structure and function and creates innate anticancer mechanisms that suppress tumorigenicity.

  • The development of carcinomas involves progressive changes in the malignant cells, in the associated stromal compartment and in the extracellular milieu. These changes lead to an ever-changing functional disorder, in which the aberrant context affects cell–cell and tissue–tissue interactions.

  • The tumour context includes both normal cells and tissues that aid in the progression of the tumour. The tumour, in turn, modifies the behaviour of the 'normal' component of the tumour.

  • The tumour context is both self-sustaining and progressive, but can be modified through alterations in signalling that affect the structure and function of tumour cells; malignant epithelial cells can be reverted to a normal phenotype despite the aberrant genotype.

  • To achieve reversion of a tumour tissue, both the tumour cells and their microenvironment need to be modified. As such, a combination of signalling inhibitors and agents that 'deactivate' the reactive stroma is required.

  • Haematologic tumours develop (and can now be treated) according to many of these same principles.

  • A better understanding of the mechanisms by which the tumour context creates the functional disorder within the tumour organ is a means of potentiating existing anticancer therapies and of developing a new generation of even more successful therapies.

Abstract

The interactions between cancer cells and their micro- and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.

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Figure 1: Normal versus malignant breast tumours.
Figure 2: Mechanisms of cell–cell and cell–ECM interactions.
Figure 3: Differences in stroma between tumours.
Figure 4: The tumour microenvironment assay.

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Acknowledgements

The research performed in the laboratory of M.J.B. and summarized in this review was supported by the United States Department of Energy (DOE), the Office of Biological and Environmental Research, and by the NCI. D.R. was supported by a Distinguished Hollaender Postdoctoral Fellowship from the DOE.

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Correspondence to Mina J. Bissell.

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DATABASES

CancerNet

bladder carcinoma

breast cancer

cervical carcinoma

colon cancer

hepatocellular carcinoma

squamous cell carcinomas

 LocusLink

ABL

BCR

E-cadherin

α-catenin

β-catenin

COX2

Cx32

Cx43

EGFR

HER2

IFN-γ

β1-integrin

MIF

MMPs

MMP-7

MMP-11

MT1-MMP

stromelysin-1

TGF-β

 Medscape DrugInfo

herceptin

STI-571

 OMIM

Shwachman–Diamond syndrome

FURTHER INFORMATION

Biology of the mammary gland

Mina Bissell's lab

Glossary

ORGAN

An anatomically discrete collection of tissues, integrated to perform specific functions.

TISSUE

A relatively homogenous structure, composed of an organized collection of cells of similar morphology and function.

EXTRACELLULAR MATRIX

(ECM). A complex, three-dimensional network of very large macromolecules that provides contextual information and an architectural scaffold for cellular adhesion and migration.

STROMA

Organ compartment serving as the connective tissue framework; includes fibroblasts, immune defence cells and fat cells.

EPITHELIUM

A diverse group of tissues that covers or lines nearly all body surfaces, cavities and tubes, functioning as interfaces between different biological compartments. Epithelial layers provide physical protection and containment, and also mediate organ-specific transport properties.

BASEMENT MEMBRANE

A specialized form of ECM that consists of laminins, collagen IV, nidogen (entactin), proteoglycans and a number of other glycoproteins that separates epithelia from underlying supporting tissues. Different organs have different compositions of basement membrane.

ADHERENS JUNCTION

A physical junction that links apicolaterally localized belts of actin in adjacent epithelial cells.

GAP JUNCTION

An aqueous channel that interconnects the cytoplasms of adjacent cells and allows direct exchange of small cytoplasmic components. It is created by the association of two hemichannels, each a hexamer of connexin subunits.

TIGHT JUNCTION

A component of cell–cell adhesion in epithelial and endothelial cell sheets. Acts as a mediator of the diffusion of solutes through the intercellular space. Also acts as a boundary between the apical and basal plasma-membrane domains.

DESMOSOME

An adhesive junction that anchors intermediate filaments between adjoining cells.

E-CADHERIN

The main adhesion receptor in adherens junctions. Mediates Ca2+-dependent interactions between adjacent epithelial cells and regulates cell proliferation. It also sequesters the transcriptional co-activator β-catenin, a protein that can stimulate cell-cycle entry. The loss of E-cadherin from the cell surface might trigger epithelial–mesenchymal transition.

EPITHELIAL–MESENCHYMAL TRANSITION

Conversion from an epithelial to a mesenchymal phenotype, which is a normal component of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

CONNEXIN

Functions as a subunit of the gap junction hemichannel. Several members of the connexin family have been identified.

INTERSTITIAL MATRIX

The extracellular matrix (ECM) contained within the stroma.

INTERMEDIATE FILAMENT

A component of the eukaryotic cytoskeleton. Intermediate filaments form a dense network extending from the nucleus to the plasma membrane.

TERATOCARCINOMA

A malignant germ-cell tumour arising from the ovary or testis that is composed of embryonal carcinoma cells.

INTEGRINS

A family of more than 20 heterodimeric cell-surface extracellular matrix (ECM) receptors. They connect the structure of the ECM with the cytoskeleton and can transmit signalling information bidirectionally.

HEPATIC STELLATE CELLS

The principal fibrogenic cell type of the liver. They are located in a perivascular orientation and contain long cytoplasmic processes that interact with neighbouring cells.

HEMIDESMOSOME

An adhesion complex located at the interface of epithelial cells with the basement membranes. Responsible for linking keratin intermediate filaments to components of the extra-cellular matrix.

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Bissell, M., Radisky, D. Putting tumours in context. Nat Rev Cancer 1, 46–54 (2001). https://doi.org/10.1038/35094059

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