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Modelling glandular epithelial cancers in three-dimensional cultures

Key Points

  • Epithelial cells grown in 3D cultures recapitulate numerous features of the glandular epithelium in vivo. These include the formation of cyst-like spheroids with a hollow lumen, apicobasal polarization of the cells comprising these structures, tight control of cell growth and proliferation, and the establishment of a basement membrane.

  • Filling of the lumen with cells is a salient feature of early glandular epithelial cancers that remains poorly understood. Studies in 3D cultures have uncovered multiple processes and regulatory molecules that are involved in the formation and maintenance of luminal space.

  • Known cancer genes give rise to a diverse array of morphogenetic phenotypes in 3D cultures that resemble important histopathological features observed in epithelial cancers in vivo.

  • Apicobasal cell polarity is a fundamental characteristic of the glandular epithelium both in vivo and in vitro. Recent studies in 3D systems illustrate the importance of this process for an intact architecture.

  • Various invasive properties have been observed in 3D systems, including invasion through the basement membrane. Future efforts directed towards co-culture systems that more faithfully represent the histological complexity of epithelial tissue in vivo are crucial for our understanding of epithelial cancers.

Abstract

Little is known about how the genotypic and molecular abnormalities associated with epithelial cancers actually contribute to the histological phenotypes observed in tumours in vivo. 3D epithelial culture systems are a valuable tool for modelling cancer genes and pathways in a structurally appropriate context. Here, we review the important features of epithelial structures grown in 3D basement membrane cultures, and how such models have been used to investigate the mechanisms associated with tumour initiation and progression.

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Figure 1: Events in MCF-10A acinar morphogenesis.
Figure 2: Lumen formation and maintenance in epithelial acini grown in vitro.
Figure 3: The effect of cancer genes on 3D epithelial architecture.
Figure 4: Cystogenesis, tubulogenesis and regulation of polarity of MDCK cells.

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Acknowledgements

The authors wish to thank Tan Ince (Brigham and Women's Hospital, Boston, Massachusetts), Andrea Richardson (Dana Farber Cancer Institute, Boston, Massachusetts) and Dennis Sgroi (Massachusetts General Hospital, Boston, Massachusetts) for providing the images of normal and cancerous breast histology. J.S.B. receives grants from the National Cancer Institute, Sanofi-Aventis Pharmaceuticals, Department of Defense, the Breast Cancer Research Foundation and the American Cancer Society. J.D. is supported by a NCI KO8 Award and was previously supported by an HHMI Postdoctoral Fellowship for Physicians.

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Correspondence to Joan S. Brugge.

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DATABASES

Entrez Gene

AKT

β1-integrin

BCL2

BIM

CDH1

CEACAM1

CSF1

CSF1R

cyclin D1

DLG

dystroglycan 1

EGF

EGFR

epimorphin

ERBB2

HER2/NEU

HGF

ID1

laminin 5

LGL

LKB1

MT1MMP

mTOR

RAC

RAC1

SCRIB

SRC

TGFβ

National Cancer Institute

breast carcinoma

ductal carcinoma in situ

invasive lobular carcinoma

prostate cancer

Glossary

GAP JUNCTION

A channel between two cells that allows the passage of molecules.

MATRIGEL

The extracellular matrix secreted by the Engelbreth–Holm–Swarm mouse sarcoma cell-line. It contains laminin, collagen IV, nidogen/entactin and proteoglycans, and so resembles the basement membrane.

SMALL INTERFERING RNA

Short double-stranded RNA sequences that engage a cellular complex that cleaves mRNAs homologous to the short RNA sequences.

HEMIDESMOSOME

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

WOUND-SCRATCH ASSAY

An assay involving the migration of cells into a space generated by scraping a confluent monolayer of cells with a fine tipped device.

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Debnath, J., Brugge, J. Modelling glandular epithelial cancers in three-dimensional cultures. Nat Rev Cancer 5, 675–688 (2005). https://doi.org/10.1038/nrc1695

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