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Cellular and Molecular Biology

Cancer-associated fibroblasts mediate cancer progression and remodel the tumouroid stroma



Cancer-associated fibroblasts (CAFs) are highly differentiated and heterogeneous cancer-stromal cells that promote tumour growth, angiogenesis and matrix remodelling.


We utilised an adapted version of a previously developed 3D in vitro model of colorectal cancer, composed of a cancer mass and the surrounding stromal compartment. We compared cancer invasion with an acellular stromal surround, a “healthy” or normal cellular stroma and a cancerous stroma. For the cancerous stroma, we incorporated six patient-derived CAF samples to study their differential effects on cancer growth, vascular network formation and remodelling.


CAFs enhanced the distance and surface area of the invasive cancer mass whilst inhibiting vascular-like network formation. These processes correlated with the upregulation of hepatocyte growth factor (HGF), metallopeptidase inhibitor 1 (TIMP1) and fibulin-5 (FBLN5). Vascular remodelling of previously formed endothelial structures occurred through the disruption of complex networks, and was associated with the upregulation of vascular endothelial growth factor (VEGFA) and downregulation in vascular endothelial cadherin (VE-Cadherin).


These results support, within a biomimetic 3D, in vitro framework, the direct role of CAFs in promoting cancer invasion, and their key function in driving vasculogenesis and angiogenesis.

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Fig. 1: Experimental setups.
Fig. 2: Patient-specific CAF tissue sample characterisation.
Fig. 3: Average invasion into an acellular or healthy cellular stroma.
Fig. 4: Invasion into the cancerous CAF stroma and subsequent gene upregulation.
Fig. 5: Endothelial structures formed within the cancerous CAF stroma.
Fig. 6: Disruption of a mature endothelial network caused by the addition of CAFs.


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Author information




J.P. planned the work and carried out experiments and subsequent analyses. T.M. conducted preceding optimisation and advised on the interpretation of the data. K.S. and A.N. received the tissue samples, processed and cultivated them in the first instance. M.E., M.L. and U.C. delivered design and guidance for the project. All authors read, provided edits and approved the paper.

Corresponding author

Correspondence to Umber Cheema.

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Ethics approval and consent to participate

Primary human colorectal cancer-associated fibroblasts were obtained in accordance with the Declaration of Helsinki. Samples were isolated from tumour tissues acquired from surgeries at the Royal Free Hospital. Patients provided informed consent for tissue donation for research under ethics reference 11/WA/0077 obtained through the North Wales Research Ethics Committee (Central and East) through TAPb biobank.

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Not applicable.

Data availability

The data that support the findings of this study are available from the corresponding author (U.C.) on reasonable request.

Competing interests

The authors declare no competing interests.

Funding information

Judith Pape receives a stipend and EU fee funding from the EPSRC as part of the doctoral training programme (DTP). Mark Emberton receives research support from the United Kingdom’s National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre and became an NIHR Senior Investigator in 2015. This work was funded by the NIHR Invention for Innovation (i4i) programme. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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Pape, J., Magdeldin, T., Stamati, K. et al. Cancer-associated fibroblasts mediate cancer progression and remodel the tumouroid stroma. Br J Cancer 123, 1178–1190 (2020).

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