title: Identification of two distinct carcinoma-associated fibroblast subtypes with differential tumor-promoting abilities in oral squamous cell carcinoma.
abstract: Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functional significance remains poorly understood. Here, we report the distinction of two CAF subtypes in oral squamous cell carcinoma (OSCC) that have differential tumor-promoting capability, one with a transcriptome and secretome closer to normal fibroblasts (CAF-N) and the other with a more divergent expression pattern (CAF-D). Both subtypes supported higher tumor incidence in nonobese diabetic/severe combined immunodeficient (NOD/SCID) Ilγ2(null) mice and deeper invasion of malignant keratinocytes than normal or dysplasia-associated fibroblasts, but CAF-N was more efficient than CAF-D in enhancing tumor incidence. CAF-N included more intrinsically motile fibroblasts maintained by high autocrine production of hyaluronan. Inhibiting CAF-N migration by blocking hyaluronan synthesis or chain elongation impaired invasion of adjacent OSCC cells, pinpointing fibroblast motility as an essential mechanism in this process. In contrast, CAF-D harbored fewer motile fibroblasts but synthesized higher TGF-β1 levels. TGF-β1 did not stimulate CAF-D migration but enhanced invasion and expression of epithelial-mesenchymal transition (EMT) markers in malignant keratinocytes. Inhibiting TGF-β1 in three-dimensional cultures containing CAF-D impaired keratinocyte invasion, suggesting TGF-β1-induced EMT mediates CAF-D-induced carcinoma cell invasion. TGF-β1-pretreated normal fibroblasts also induced invasive properties in transformed oral keratinocytes, indicating that TGF-β1-synthesizing fibroblasts, as well as hyaluronan-synthesizing fibroblasts, are critical for carcinoma invasion. Taken together, these results discern two subtypes of CAF that promote OSCC cell invasion via different mechanisms.
authors.affiliation: Section for Pathology, The Gade Institute, Haukeland University Hospital, 5021 Bergen, Norway. daniela.costea@gades.uib.no
authors.forename: Daniela Elena
authors.initials: DE
authors.lastname: Costea
authors.forename: Allison
authors.initials: A
authors.lastname: Hills
authors.forename: Amani H
authors.initials: AH
authors.lastname: Osman
authors.forename: Johanna
authors.initials: J
authors.lastname: Thurlow
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kalna
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Huang
authors.forename: Claudia
authors.initials: C
authors.lastname: Pena Murillo
authors.forename: Himalaya
authors.initials: H
authors.lastname: Parajuli
authors.forename: Salwa
authors.initials: S
authors.lastname: Suliman
authors.forename: Keerthi K
authors.initials: KK
authors.lastname: Kulasekara
authors.forename: Anne Chr
authors.initials: AC
authors.lastname: Johannessen
authors.forename: Max
authors.initials: M
authors.lastname: Partridge
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement; D004149:Dioxoles / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000145:classification / Q000378:metabolism* / Q000502:physiology; D015870:Gene Expression; D006820:Hyaluronic Acid / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009062:Mouth Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D006820:Hyaluronic Acid