TY - JOUR
T1 - Cancer-associated fibroblasts
T2 - Versatile players in the tumor microenvironment
AU - Ganguly, Debolina
AU - Chandra, Raghav
AU - Karalis, John
AU - Teke, Martha
AU - Aguilera, Todd
AU - Maddipati, Ravikanth
AU - Wachsmann, Megan B.
AU - Ghersi, Dario
AU - Siravegna, Giulia
AU - Zeh, Herbert J.
AU - Brekken, Rolf
AU - Ting, David T.
AU - Ligorio, Matteo
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
KW - CAF therapeutics
KW - Cancer-associated fibroblasts
KW - Chemoresistance
KW - Clinical trials targeting CAFs
KW - Hallmarks of cancer
KW - Heterogeneity
KW - Immunomodulation
KW - Tumor microenvironment
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U2 - 10.3390/cancers12092652
DO - 10.3390/cancers12092652
M3 - Review article
C2 - 32957515
AN - SCOPUS:85091185493
SN - 2072-6694
VL - 12
SP - 1
EP - 35
JO - Cancers
JF - Cancers
IS - 9
M1 - 2652
ER -