Mutual paracrine effects of oral squamous cell carcinoma cells and normal oral fibroblasts: induction of fibroblast to myofibroblast transdifferentiation and modulation of tumor cell proliferation.
Several lines of evidence demonstrated that the stroma surrounding the tumors plays an important role in the growth and progression of several neoplasms, including oral squamous cell carcinomas (OSCC). We evaluated the presence of myofibroblasts in OSCC and determined whether their presence is associated with clinicopathological features of the tumors. We also investigated the mutual paracrine effects of tumor cells and myofibroblasts on fibroblast-myofibroblast transdifferentiation and tumor cell proliferation. Immunohistochemical analysis showed the approximately 60% of the OSCCs contained myofibroblasts in the stroma of the tumor. Abundant presence of myofibroblasts significantly correlated with N stage, disease stage, regional recurrence, and proliferative potential of the tumor cells. Using OSCC cell lines and primary oral normal fibroblasts (ONF), we demonstrated that tumor cells induced transdifferentiation of ONFs to myofibroblasts via secretion of transforming growth factor-beta 1 (TGF-beta 1). In turn, myofibroblasts secreted factors that stimulated OSCC cell proliferation, as revealed by measuring BrdU incorporation and Ki67 expression. The results of the study suggest that during tumor invasion OSCC-derived TGF-beta 1 promote fibroblast-myofibroblast transdifferentiation, and that tumor cellular proliferation can be induced by factors released from myofibroblasts, which may favor tumor growth.
Kellermann
Michele G
MG
Department of Oral Diagnosis, School of Dentistry, State University of Campinas, Piracicaba, São Paulo, Brazil.
Sobral
Lays M
LM
da Silva
Sabrina Daniela
SD
Zecchin
Karina G
KG
Graner
Edgard
E
Lopes
Marcio A
MA
Kowalski
Luis Paulo
LP
Coletta
Ricardo D
RD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D002471:Cell Transformation, Neoplastic / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication / Q000502:physiology*; D010641:Phenotype; D017154:Stromal Cells / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000166:cytology