Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

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Abstract

In this review, Gascard and Tlsty focus on novel insights into the contributions of carcinoma-associated fibroblasts (CAFs) to disease progression. They also discuss the generation of CAFs and recent therapeutic approaches aimed at blunting or reverting detrimental protumorigenic phenotypes associated with CAFs.

Abstract

The tumor stroma is no longer seen solely as physical support for mutated epithelial cells but as an important modulator and even a driver of tumorigenicity. Within the tumor stromal milieu, heterogeneous populations of fibroblast-like cells, collectively termed carcinoma-associated fibroblasts (CAFs), are key players in the multicellular, stromal-dependent alterations that contribute to malignant initiation and progression. This review focuses on novel insights into the contributions of CAFs to disease progression, emergent events leading to the generation of CAFs, identification of CAF-specific biomarkers predictive of disease outcome, and recent therapeutic approaches aimed at blunting or reverting detrimental protumorigenic phenotypes associated with CAFs.

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New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

E A Eisenhauer, P Therasse, J. Bogaerts … (2009)

Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.

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Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.

Berna C. Özdemir, Tsvetelina Pentcheva-Hoang, Julienne Carstens … (2014)

Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC. Copyright © 2014 Elsevier Inc. All rights reserved.

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Stromal gene expression predicts clinical outcome in breast cancer.

Greg Finak, Nicholas Bertos, François Pépin … (2008)

Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor-derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node-negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.

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Author and article information

Journal

Journal ID (nlm-ta): Genes Dev

Journal ID (iso-abbrev): Genes Dev

Journal ID (hwp): genesdev

Journal ID (pmc): genesdev

Journal ID (publisher-id): GAD

Title: Genes & Development

Publisher: Cold Spring Harbor Laboratory Press

ISSN (Print): 0890-9369

ISSN (Electronic): 1549-5477

Publication date (Print): 1 May 2016

Volume: 30

Issue: 9

Pages: 1002-1019

Affiliations

[1 ]Department of Pathology, University of California at San Francisco, San Francisco, California 94143, USA;

[2 ]Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143, USA

Author notes

Corresponding author: thea.tlsty@ 123456ucsf.edu

Article

Medline ID: 8711660

DOI: 10.1101/gad.279737.116

PMC ID: 4863733

PubMed ID: 27151975

SO-VID: 6d13bede-a2e2-404a-a7df-4b7640943a46

License:

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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Pages: 18

Funding

Funded by: National Institutes of Health http://dx.doi.org/10.13039/100000002

Award ID: PO1 CA107584

Award ID: R01 CA097214

Award ID: U54 CA143803

Award ID: R01 CA187800

Award ID: R01 CA197977

Award ID: R35 CA197674

Funded by: Pfizer Research Foundation

Award ID: WS2067777

Funded by: Susan G. Komen for the Cure Foundation Scientific Advisory Council

Award ID: SAC

Award ID: 100011

Funded by: California Breast Cancer Research Program http://dx.doi.org/10.13039/100004802

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

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Most cited references 146

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival.

Stromal gene expression predicts clinical outcome in breast cancer.

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