Transforming growth factor-beta1 induces tumor stroma and reduces tumor infiltrate in cervical cancer.
Cervical carcinomas consist of tumor cell nests surrounded by varying amounts of intratumoral stroma containing different quantities and types of immune cells. Besides controlling (epithelial) cell growth, the multifunctional cytokine transforming growth factor-beta(1) (TGF-beta(1)) is involved in the formation of stroma and extracellular matrix (ECM) and in immunosuppression. Several malignancies are known to be associated with enhanced production of TGF-beta(1), repression or mutation of TGF-beta transmembrane receptors, or mutations at the postreceptor intracellular signaling pathway. The aim of our study was to investigate the role of tumor cell-derived TGF-beta(1) on the amount of intratumoral stroma; the deposition of collagen IV, fibronectin, and laminin; and the tumor infiltrate in cervical carcinoma. The expression of TGF-beta(1) mRNA in 108 paraffin-embedded cervical carcinomas was detected by mRNA in situ hybridization. Immunohistochemistry was used to investigate the amount of tumor stroma and ECM proteins and the extent of the tumor infiltrate. Plasminogen activator inhibitor-1 (PAI-1) protein expression in tumor cells was determined to verify the biological activity of TGF-beta(1.) Cytoplasmatic TGF-beta(1) mRNA expression in tumor cells was significantly correlated with the amount of intratumoral stroma and the deposition of collagen IV. TGF-beta(1) mRNA expression in every tumor was accompanied by PAI-1 expression, indicating biological activity of TGF-beta(1). An inverse relationship between TGF-beta(1) mRNA expression in tumor cells and the extent of the tumor infiltrate was demonstrated. Our results indicate that cervical cancer cells affect the amount and the composition of the intratumoral stroma and the tumor infiltrate by the production and secretion of TGF-beta(1).
Hazelbag
Suzanne
S
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Gorter
Arko
A
Kenter
Gemma G
GG
van den Broek
Lambert
L
Fleuren
Gertjan
G
D024141:Collagen Type IV / Q000032:analysis; D005109:Extracellular Matrix / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000032:analysis; D005260:Female; D005353:Fibronectins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007797:Laminin / Q000032:analysis; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D017154:Stromal Cells / Q000473:pathology; D016610:Tissue Embedding; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D002583:Uterine Cervical Neoplasms / Q000473:pathology*
D024141:Collagen Type IV; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D007797:Laminin; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1