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Review
. 2020 Sep 17;12(9):2652.
doi: 10.3390/cancers12092652.

Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment

Debolina Ganguly  1 , Raghav Chandra  1 , John Karalis  1 , Martha Teke  1 , Todd Aguilera  2   3 , Ravikanth Maddipati  3   4 , Megan B Wachsmann  5 , Dario Ghersi  6 , Giulia Siravegna  7 , Herbert J Zeh 3rd  1 , Rolf Brekken  1 , David T Ting  7 , Matteo Ligorio  1
Affiliations
Review

Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment

Debolina Ganguly et al. Cancers (Basel). .

Abstract

Cancer-associated fibroblasts (CAFs) are indispensable architects of the tumor microenvironment. They perform the essential functions of extracellular matrix deposition, stromal remodeling, tumor vasculature modulation, modification of tumor metabolism, and participation in crosstalk between cancer and immune cells. In this review, we discuss our current understanding of the principal differences between normal fibroblasts and CAFs, the origin of CAFs, their functions, and ultimately, highlight the intimate connection of CAFs to virtually all of the hallmarks of cancer. We address the remarkable degree of functional diversity and phenotypic plasticity displayed by CAFs and strive to stratify CAF biology among different tumor types into practical functional groups. Finally, we summarize the status of recent and ongoing trials of CAF-directed therapies and contend that the paucity of trials resulting in Food and Drug Administration (FDA) approvals thus far is a consequence of the failure to identify targets exclusive of pro-tumorigenic CAF phenotypes that are mechanistically linked to specific CAF functions. We believe that the development of a unified CAF nomenclature, the standardization of functional assays to assess the loss-of-function of CAF properties, and the establishment of rigorous definitions of CAF subpopulations and their mechanistic functions in cancer progression will be crucial to fully realize the promise of CAF-targeted therapies.

Keywords: CAF therapeutics; cancer-associated fibroblasts; chemoresistance; clinical trials targeting CAFs; hallmarks of cancer; heterogeneity; immunomodulation; tumor microenvironment.

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Conflict of interest statement

D.T.T. has received consulting fees from ROME Therapeutics, Foundation Medicine, Inc., NanoString Technologies, EMD Millipore Sigma, and Pfizer that are not related to this work. D.T.T. is a founder and has equity in ROME Therapeutics, PanTher Therapeutics and TellBio, Inc., which is not related to this work. D.T.T. receives research support from ACD-Biotechne, PureTech Health LLC, and Ribon Therapeutics, which was not used in this work. Dr. Ting’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. All other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
History of cancer associated fibroblasts (CAFs). This figure represents a timeline of CAF related discoveries. Here we highlight the major landmarks in CAF research that helped advance this field.
Figure 2
Figure 2
Origin, function, and heterogeneity of CAFs. This is a schematic representation of the (A) different cell origins of CAFs, (B) various functions of CAFs, and (C) heterogeneity of CAFs as found in different organs based on current studies. The yellow squares in (C) indicates yet un-characterized CAF subtype for that particular tumor. Abbreviations: FA, functional assay; FACs fluorescence-associated cell sorting; scRNA-seq, single-cell RNA sequencing.
Figure 3
Figure 3
CAFs’ effect on the hallmarks of cancer. This diagram highlights the processes in tumor development that CAFs play a role in especially immunomodulation, tumor progression, tumor metabolism, tumorigenesis, and chemoresistance.
Figure 4
Figure 4
Clinical trials targeting CAFs or CAFs’ functions. This lists most of the clinical trials targeting CAF biology. The results of these clinical trials are highlighted in light green (published clinical trials with positive results), yellow (ongoing or unpublished clinical trials), red (failed/discontinued), dark green (trials producing an FDA approval). References for all these clinical studies are from https://clinicaltrials.gov/. Abbreviations: BCC, basal cell carcinoma; CAF, cancer-associated fibroblast; FGFR, fibroblast growth factor receptor; HCC, hepatocellular carcinoma; NSCLC, non-small cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; SCC, squamous cell carcinoma; SCLC, small cell lung cancer.
Figure 4
Figure 4
Clinical trials targeting CAFs or CAFs’ functions. This lists most of the clinical trials targeting CAF biology. The results of these clinical trials are highlighted in light green (published clinical trials with positive results), yellow (ongoing or unpublished clinical trials), red (failed/discontinued), dark green (trials producing an FDA approval). References for all these clinical studies are from https://clinicaltrials.gov/. Abbreviations: BCC, basal cell carcinoma; CAF, cancer-associated fibroblast; FGFR, fibroblast growth factor receptor; HCC, hepatocellular carcinoma; NSCLC, non-small cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; SCC, squamous cell carcinoma; SCLC, small cell lung cancer.
Figure 4
Figure 4
Clinical trials targeting CAFs or CAFs’ functions. This lists most of the clinical trials targeting CAF biology. The results of these clinical trials are highlighted in light green (published clinical trials with positive results), yellow (ongoing or unpublished clinical trials), red (failed/discontinued), dark green (trials producing an FDA approval). References for all these clinical studies are from https://clinicaltrials.gov/. Abbreviations: BCC, basal cell carcinoma; CAF, cancer-associated fibroblast; FGFR, fibroblast growth factor receptor; HCC, hepatocellular carcinoma; NSCLC, non-small cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; SCC, squamous cell carcinoma; SCLC, small cell lung cancer.
Figure 5
Figure 5
Account of clinical trials targeting CAFs or CAFs’ functions. The graph represents number of clinical trials (non-cumulative) targeting CAFs over time. Total number of clinical trials are indicated in orange (n = 175), ongoing clinical trials in blue (n = 135), failed or terminated or withdrawn trials in red (n = 37), and FDA-approved drugs in green. Arrows indicate the time period when the trial of the FDA-approved drug was published (n = 3)
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