In Search Of Definitions: Cancer‐associated Fibroblasts And Their Markers
Martin Nurmik, P. Ullmann, Fabien Rodriguez, S. Haan, E. Letellier
Published 2019 · Medicine
Download PDFAnalyze on Scholarcy
The tumor microenvironment has been identified as one of the driving factors of tumor progression and invasion. Inside this microenvironment, cancer‐associated fibroblasts (CAFs), a type of perpetually activated fibroblasts, have been implicated to have a strong tumor‐modulating effect and play a key role in areas such as drug resistance. Identification of CAFs has typically been carried based on the expression of various “CAF markers”, such as fibroblast activation protein alpha (FAP) and alpha smooth muscle actin (αSMA), which separates them from the larger pool of fibroblasts present in the body. However, as outlined in this Review, the expression of various commonly used fibroblast markers is extremely heterogeneous and varies strongly between different CAF subpopulations. As such, novel selection methods based on cellular function, as well as further characterizing research, are vital for the standardization of CAF identification in order to improve the cross‐applicability of different research studies in the field. The aim of this review is to give a thorough overview of the commonly used fibroblast markers in the field and their various strengths and, more importantly, their weaknesses, as well as to highlight potential future avenues for CAF identification and targeting.
This paper references
Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis
Chris D. Madsen (2015)
Identification of fibroblast heterogeneity in the tumor microenvironment
H. Sugimoto (2006)
Understanding the Impact of 2D and 3D Fibroblast Cultures on In Vitro Breast Cancer Models
K. E. Sung (2013)
Increased expression of seprase, a membrane-type serine protease, is associated with lymph node metastasis in human colorectal cancer.
S. Iwasa (2003)
Tumor-Driven Paracrine Platelet-Derived Growth Factor Receptor α Signaling Is a Key Determinant of Stromal Cell Recruitment in a Model of Human Lung Carcinoma
M. Tejada (2006)
Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression
N. Kramer (2017)
Expression of cancer-associated fibroblast 904 Cancer-associated fibroblasts and their markers
R Nishishita (2020)
Cancer-Associated Fibroblasts Connect Metastasis-Promoting Communication in Colorectal Cancer
J. Tommelein (2015)
Expression of smooth muscle cell markers and co-activators in calcified aortic valves.
N. Latif (2015)
Concise Medical Dictionary
E. A. Martin (2010)
Tenascin C in metastasis: A view from the invasive front
Camille M Lowy (2015)
A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets.
Dongyu Jia (2016)
Expression of cancer-associated fibroblast markers in advanced colorectal cancer
Rie Nishishita (2018)
Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A
F. Lotti (2013)
High interstitial fluid pressure — an obstacle in cancer therapy
C. Heldin (2004)
The role of pericytes in blood-vessel formation and maintenance.
G. Bergers (2005)
Isolation of normal and cancer-associated fibroblasts from fresh tissues by Fluorescence Activated Cell Sorting (FACS).
Y. Sharon (2013)
The Roles of PDGF in Development and During Neurogenesis in the Normal and Diseased Nervous System
K. Funa (2013)
Paracrine interactions of cancer-associated fibroblasts, macrophages and endothelial cells: tumor allies and foes
Roberto Ronca (2018)
Podoplanin, a novel marker of tumor-initiating cells in human squamous cell carcinoma A431.
N. Atsumi (2008)
Melanoma-associated fibroblasts decrease tumor cell susceptibility to NK cell-mediated killing through matrix-metalloproteinases secretion
Linda Ziani (2017)
Cancer‐associated fibroblast and M2 macrophage markers together predict outcome in colorectal cancer patients
M. Herrera (2013)
Stromal gene expression defines poor-prognosis subtypes in colorectal cancer
A. Calon (2015)
Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion
A. Orimo (2005)
IL-1-induced JAK/STAT signaling is antagonized by TGF-beta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma
G Biffi (2018)
Fibroblasts for all seasons
E. Wagner (2016)
Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB.
K. Forsberg (1993)
Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–α
Matthew Kraman (2010)
The hypoxic tumour microenvironment
V. Petrova (2018)
The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma.
M. Erkan (2008)
Cancer - associated fi broblasts are activated in incipient neoplasia to orchestrate tumor - promoting in fl ammation in an NF - κ B - dependent manner
C Osterreicher (2010)
IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma.
G. Biffi (2019)
Integrin α11β1: a major collagen receptor on fibroblastic cells.
Cédric Zeltz (2014)
Silencing of TGF-β1 in tumor cells impacts MMP-9 in tumor microenvironment
Lakisha Moore-Smith (2017)
Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors
Huipeng Li (2017)
Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-kappaB-Dependent Manner.
Neta Erez (2010)
Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer
R. Navab (2011)
COL11A1/(pro)collagen 11A1 expression is a remarkable biomarker of human invasive carcinoma-associated stromal cells and carcinoma progression
F. Vázquez-Villa (2015)
Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages
Hideyuki Takahashi (2017)
The Prognostic Significance of Cancer-Associated Fibroblasts in Esophageal Squamous Cell Carcinoma
S. Y. Ha (2014)
Tyrosine kinase inhibitor sensitive PDGFRΑ mutations in GIST: Two cases and review of the literature
Pieter A Boonstra (2017)
Cancerassociated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 2010;17:135–47
N Erez (2010)
Cancer-associated fibroblasts modify lung cancer metabolism involving ROS and TGF-β signaling
A Cruz-Bermúdez (2020)
Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms
C. Unger (2017)
Vimentin filament organization and stress sensing depend on its single cysteine residue and zinc binding
D. Pérez-Sala (2015)
Myofibroblasts are distinguished from activated skin fibroblasts by the expression of AOC3 and other associated markers
Lin-ting Hsia (2016)
Dasatinib reverses Cancer-associated Fibroblasts (CAFs) from primary Lung Carcinomas to a Phenotype comparable to that of normal Fibroblasts
Silke Haubeiss (2010)
Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling.
E. Y. T. Lau (2016)
GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1β/IL1R1 response
P. De Marco (2016)
Expression of fibroblast activation protein in human pancreatic adenocarcinoma and its clinicopathological significance.
M. Shi (2012)
Twist1 is highly expressed in cancer-associated fibroblasts of esophageal squamous cell carcinoma with a prognostic significance.
So-Young Yeo (2017)
CAF reprogramming inhibits ovarian cancer progression
Tsz-Lun Yeung (2014)
Integrin α11β1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer
R. Navab (2016)
tinct populations of in fl ammatory fi broblasts and myo fi broblasts in pancreatic cancer
D Öhlund (2017)
IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis
C. Pallangyo (2015)
CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness
Shicheng Su (2018)
High expression of PDGFR-β in prostate cancer stroma is independently associated with clinical and biochemical prostate cancer recurrence
Y. Nordby (2017)
Differences between CAFs and their paired NCF from adjacent colonic mucosa reveal functional heterogeneity of CAFs, providing prognostic information.
M. Berdiel-Acer (2014)
thesis and secretion of platelet - derived growth factor by human breast cancer cell lines
C Jotzu (1987)
Adipose tissue derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor derived factors
Constantin Jotzu (2011)
Capturing tumor complexity in vitro: Comparative analysis of 2D and 3D tumor models for drug discovery
Kristin Stock (2016)
Cancer: Fibroblasts for all seasons
E. Wagner (2016)
Friend or foe? The tumour microenvironment dilemma in colorectal cancer.
T. Colangelo (2017)
Targeting the PDGF signaling pathway in tumor treatment
C. Heldin (2013)
Rationale Behind Targeting Fibroblast Activation Protein–Expressing Carcinoma-Associated Fibroblasts as a Novel Chemotherapeutic Strategy
W. Brennen (2012)
The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas
Yoshihiro Mezawa (2016)
TSPAN12 is a critical factor for cancer–fibroblast cell contact-mediated cancer invasion
Ryo Otomo (2014)
Tumor-Initiating Cells: a criTICal review of isolation approaches and new challenges in targeting strategies
Komal Qureshi-Baig (2017)
Cell culture and passaging alters gene expression pattern and proliferation rate in rheumatoid arthritis synovial fibroblasts
E. Neumann (2010)
Tenascin‐C and SF/HGF produced by myofibroblasts in vitro provide convergent proinvasive signals to human colon cancer cells through RhoA and Rac
O. De Wever (2004)
Identification of Prognostic Molecular Features in the Reactive Stroma of Human Breast and Prostate Cancer
A. Planche (2011)
Matrix metalloproteinases in tumor invasion and metastasis.
I. Stamenković (2000)
Cancer Stem Cells Regulate Cancer-Associated Fibroblasts via Activation of Hedgehog Signaling in Mammary Gland Tumors.
Giovanni Valenti (2017)
Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts.
E. Zeisberg (2007)
Fibroblast heterogeneity in the cancer wound
D. Öhlund (2014)
Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts
Yasushi Kojima (2010)
Occurence of stromal myofibroblasts in the invasive ductal breast cancer tissue is an unfavourable prognostic factor.
Paweł Surowiak (2007)
miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers
Anne-Marie Givel (2018)
Stromal contribution to the colorectal cancer transcriptome
C. Isella (2015)
Phase II trial of single agent Val-boroPro (talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer
Kalyani Narra (2007)
CD10GPR77 Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness
Shicheng Su (2018)
Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
D. Öhlund (2017)
Friend or FoE?
D. Pressey (1983)
Carcinoma-associated fibroblasts: orchestrating the composition of malignancy.
Philippe Gascard (2016)
Tumor-produced, active Interleukin-1 β regulates gene expression in carcinoma-associated fibroblasts
József Dudás (2011)
Tumor-Infiltrating Podoplanin+ Fibroblasts Predict Worse Outcome in Solid Tumors
G. Hu (2018)
Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness
Alexandra Avgustinova (2016)
Hypoxia Selectively Enhances Integrin α5β1 Receptor Expression in Breast Cancer to Promote Metastasis
Julia A Ju (2017)
Synthesis and secretion of platelet-derived growth factor by human breast cancer cell lines.
D. Bronzert (1987)
Stromal Myofibroblasts Predict Disease Recurrence for Colorectal Cancer
T. Tsujino (2007)
Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer.
Ana Costa (2018)
CD10 + GPR77 + cancer-associated fibroblasts promote cancer formation and Chemoresistance by sustaining cancer
S Su (2018)
pression of antitumor immunity by stromal cells expressing fi broblast activation protein
M Kraman (2010)
Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.
A. Calon (2012)
The myofibroblast, multiple origins for major roles in normal and pathological tissue repair
L. Micallef (2012)
Functional Heterogeneity of Cancer-Associated Fibroblasts from Human Colon Tumors Shows Specific Prognostic Gene Expression Signature
M. Herrera (2013)
Proteomic Analysis of Cancer-Associated Fibroblasts Reveals a Paracrine Role for MFAP5 in Human Oral Tongue Squamous Cell Carcinoma.
Simona Principe (2018)
The biology and function of fibroblasts in cancer
R. Kalluri (2016)
Colon cancer-derived myofibroblasts increase endothelial cell migration by glucocorticoid-sensitive secretion of a pro-migratory factor
Z. Drebert (2017)
Defining the Role of Solid Stress and Matrix Stiffness in Cancer Cell Proliferation and Metastasis
M. Kalli (2018)
CD90 Expression on human primary cells and elimination of contaminating fibroblasts from cell cultures
Lynn Kisselbach (2009)
Prognostic relevance of cancer-associated fibroblasts in human cancer.
Janna Paulsson (2014)
IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer
V. Koliaraki (2015)
From sentinel cells to inflammatory culprits: cancer-associated fibroblasts in tumour-related inflammation.
Charlotte Servais (2013)
The basics of epithelialmesenchymal transition
R Kalluri (2010)
Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver
Christoph H. Österreicher (2010)
The basics of epithelial-mesenchymal transition (The Journal of Clinical Investigation (2009) 119, 6, (1420-1428) DOI: 10.1172/JCI39104)
R. Kalluri (2010)
Stromal Fibroblasts Activated by Tumor Cells Promote Angiogenesis in Mouse Gastric Cancer*
X. Guo (2008)
High expression of stromal PDGFRβ is associated with reduced benefit of tamoxifen in breast cancer
Janna Paulsson (2017)
A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers
Christopher J Hanley (2016)
Podoplanin-expressing inflammatory macrophages activate murine platelets via CLEC-2
A. M. Kerrigan (2012)
Fibroblast activation protein: differential expression and serine protease activity in reactive stromal fibroblasts of melanocytic skin tumors.
M. Huber (2003)
CAFs and TAMs: maestros of the tumour microenvironment.
Y. Komohara (2017)
MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer.
A. K. Mitra (2012)
Stromal Antigen Targeting by a Humanised Monoclonal Antibody: An Early Phase II Trial of Sibrotuzumab in Patients with Metastatic Colorectal Cancer
R. Hofheinz (2003)
Identification of colonic fibroblast secretomes reveals secretory factors regulating colon cancer cell proliferation.
Sun-Xia Chen (2014)
The immune contexture of primary and metastatic human tumours.
N. Giraldo (2014)
The fibroblast surface markers FAP, anti‐fibroblast, and FSP are expressed by cells of epithelial origin and may be altered during epithelial‐to‐mesenchymal transition
Zuzana Kahounová (2018)
FGF2 Overrides TGFβ1‐Driven Integrin ITGA11 Expression in Human Dermal Fibroblasts
Alexandra Grella (2016)
This paper is referenced by
Spatial Arrangements of Connexin43 in Cancer Related Cells and Re-Arrangements under Treatment Conditions: Investigations on the Nano-Scale by Super-Resolution Localization Light Microscopy
Götz Pilarczyk (2019)
The effect of ALA-PDT on reversing the activation of Cancer-associated fibroblasts in cutaneous squamous cell carcinoma.
Shan-Shan Li (2019)
Fibroblasts in the Tumor Microenvironment.
Marta Truffi (2020)
Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma
A. Hayden (2020)
Colorectal Cancer Stem Cells in the Progression to Liver Metastasis
Carlos A. Gonzalez-Villarreal (2020)
Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5
Ziqian Li (2019)
A cell-based fluorescent assay for FAP inhibitor discovery.
Bingye Zhang (2020)
What Is the Fuss about Integrins and the Tumor Microenvironment?
Johannes A Eble (2019)
Tumor microenvironment complexity and therapeutic implications at a glance
Roghayyeh Baghban (2020)
An NMF-Based Methodology for Selecting Biomarkers in the Landscape of Genes of Heterogeneous Cancer-Associated Fibroblast Populations
Flavia Esposito (2020)
Cancer-associated fibroblasts in desmoplastic tumors: emerging role of integrins.
Cédric Zeltz (2019)
The Importance of Cancer-Associated Fibroblasts in the Pathogenesis of Head and Neck Cancers.
Martina Raudenská (2020)
Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges
E. Koncina (2020)
CD36 and CD97 in Pancreatic Cancer versus Other Malignancies
C. Tanase (2020)
The tumor microenvironment and radiotherapy response; a central role for cancer-associated fibroblasts
M. Ansems (2020)
Anti-liver fibrosis effect of total flavonoids from Scabiosa comosa Fisch. ex Roem. et Schult. on liver fibrosis in rat models and its proteomics analysis.
Hongwei Yuan (2020)
FAP-specific PET signaling shows a moderately positive correlation with relative CBV and no correlation with ADC in 13 IDH wildtype glioblastomas.
M. Röhrich (2020)
Hypoxia- and MicroRNA-Induced Metabolic Reprogramming of Tumor-Initiating Cells
P. Ullmann (2019)
Cellular and Extracellular Components in Tumor Microenvironment and Their Application in Early Diagnosis of Cancers
R. Wei (2020)
Chemotherapy-induced release of circulating-tumor cells into the bloodstream in collective migration units with cancer-associated fibroblasts in metastatic cancer patients
Nerymar Ortiz-Otero (2020)
Impact of Cancer-Associated Fibroblast on the Radiation-Response of Solid Xenograft Tumors
Alizée Steer (2019)
The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview
Barbara Bellei (2020)
Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance
Colleen M. Garvey (2020)
Caveolin-1 in oncogenic metabolic symbiosis.
Martina Raudenska (2020)
Gold nanoparticles inhibit activation of cancer-associated fibroblasts by disrupting communication from tumor and microenvironmental cells
Yushan Zhang (2020)
Tumor Microenvironment: Non-Hematopoietic Cells
Alexander Birbrair (2020)
Expression of long noncoding RNAs in cancer‐associated fibroblasts linked to patient survival in ovarian cancer
E. Colvin (2020)