HB-EGF and PDGF mediate reciprocal interactions of carcinoma cells with cancer-associated fibroblasts to support progression of uterine cervical cancers.
Tumor stroma drives the growth and progression of cancers. A heparin-binding epidermal growth factor-like growth factor, HB-EGF, is an EGF receptor ligand that stimulates cell growth in an autocrine or paracrine fashion. While elevated expression of HB-EGF in cancer cells and its contribution to tumor progression are well documented, the effects of HB-EGF expression in the tumor stroma have not been clarified. Here, we show that HB-EGF is expressed in stromal fibroblasts where it promotes cancer cell proliferation. In uterine cervical cancers, HB-EGF was detected immunohistochemically in the stroma proximal to the cancer epithelium. Proliferation of cervical cancer cells in vitro was enhanced by coculture with fibroblasts isolated from tumor tissues of patients with cervical cancer. Inhibition of HB-EGF function or treatment with platelet-derived growth factor (PDGF) inhibitors abrogated cancer cell growth enhanced by cervical cancer-associated fibroblast (CCF) coculture. Furthermore, tumor formation in a mouse xenograft model was enhanced by cotransplantation of CCF or mouse embryonic fibroblasts, but not with embryonic fibroblasts from HB-EGF-deficient mice. Conversely, conditioned medium from cancer cells induced HB-EGF expression in CCF. Mechanistic investigations established that PDGF was the primary factor responsible. Together, our findings indicate that HB-EGF and PDGF reciprocally mediate the interaction of cancer cells with cancer-associated fibroblasts, promoting cancer cell proliferation in a paracrine manner that has implications for novel combinatorial cancer therapies.
Obstetrics and Gynecology, Osaka-Saiseikai-Nakatsu Hospital, Japan.
Takuya
T
Murata
Hiroto
H
Mizushima
Ichino
I
Chinen
Hiroki
H
Moribe
Shigeo
S
Yagi
Robert M
RM
Hoffman
Tadashi
T
Kimura
Kiyoshi
K
Yoshino
Yutaka
Y
Ueda
Takayuki
T
Enomoto
Eisuke
E
Mekada
D000818:Animals; D001549:Benzamides; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D000068877:Imatinib Mesylate; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D019899:Paracrine Communication; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
C407689:6,7-dimethoxy-2-phenylquinoxaline; D001549:Benzamides; D017077:Culture Media, Conditioned; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D020032:Tyrphostins; D000068877:Imatinib Mesylate