Interleukin-6 in cervical cancer: the relationship with vascular endothelial growth factor.
OBJECTIVE
Interleukin-6 (IL-6), a central proinflammatory cytokine, has been implicated in cervical cancer, though its role remains elusive. This study was an attempt to elucidate the role of IL-6 in the pathogenesis of cervical cancer, with particular emphasis on tumor angiogenesis.


METHODS
Cytosolic IL-6, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) levels were determined via enzyme immunoassay in 60 FIGO stage IB-IIA cervical cancer patients. Immunohistochemical staining in tissue sections was performed to analyze the distributions of IL-6 and IL-6 receptors. Meanwhile, human papillomavirus (HPV) DNA was detected by polymerase chain reaction-based survey. In vitro studies of two cervical cancer cell lines, C33A and SiHa, for the interaction between IL-6 and VEGF were also performed.


RESULTS
Consistently higher expression of IL-6 and VEGF was evident in cancerous tissues than in adjacent noncancer tissues in early-stage cervical cancer patients (P < 0.01). After recombinant human IL-6 was added, VEGF was induced in a time- and dose-dependent manner in cervical cancer cell line C33A. Correspondingly, interrupting the IL-6 autocrine machinery with either anti-IL-6 or anti-IL-6 receptor antibody markedly reduced the expression of VEGF at the transcriptional level in SiHa cells. Significantly higher levels of IL-6 in cancer tissues were observed in patients older than 45 (P < 0.01), patients with tumors >2 cm (P < 0.01), patients with oncogenic HPV-16 or -18 infections (P < 0.01), and patients with squamous cell carcinoma (P = 0.02). Patients with a deeper stromal invasion, vaginal invasion, lymphovascular emboli, or lymph node metastasis appeared to have higher intratumoral IL-6 levels, although the differences were statistically insignificant.


CONCLUSIONS
Substantially high microenvironmental IL-6 levels promote tumor angiogenesis and the development of cervical cancer. Thus, inhibition of the biological activity of IL-6 may be potentially beneficial.
Wei
L H
LH
Department of Obstetrics and Gynecology, Institute of Toxicology, Tapei, Taiwan.
Kuo
M L
ML
Chen
C A
CA
Cheng
W F
WF
Cheng
S P
SP
Hsieh
F J
FJ
Hsieh
C Y
CY
D000328:Adult; D000368:Aged; D015152:Blotting, Northern; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002584:Cervix Uteri / Q000187:drug effects / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000737:chemistry*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D008207:Lymphatic Metastasis; D008222:Lymphokines / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014412:Tumor Virus Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017931:DNA Primers; D016228:Endothelial Growth Factors; D015850:Interleukin-6; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors