| RRC ID |
18640
|
| 著者 |
Murata T, Mizushima H, Chinen I, Moribe H, Yagi S, Hoffman RM, Kimura T, Yoshino K, Ueda Y, Enomoto T, Mekada E.
|
| タイトル |
HB-EGF and PDGF mediate reciprocal interactions of carcinoma cells with cancer-associated fibroblasts to support progression of uterine cervical cancers.
|
| ジャーナル |
Cancer Res
|
| Abstract |
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.
|
| 巻・号 |
71(21)
|
| ページ |
6633-42
|
| 公開日 |
2011-11-1
|
| DOI |
10.1158/0008-5472.CAN-11-0034
|
| PII |
0008-5472.CAN-11-0034
|
| PMID |
22009535
|
| MeSH |
Animals
Benzamides
Carcinoma, Squamous Cell / metabolism
Carcinoma, Squamous Cell / pathology*
Coculture Techniques
Culture Media, Conditioned / pharmacology
Disease Progression
Female
Fibroblasts / drug effects
Fibroblasts / metabolism
HeLa Cells / drug effects
HeLa Cells / metabolism
Heparin-binding EGF-like Growth Factor
Humans
Imatinib Mesylate
Intercellular Signaling Peptides and Proteins / deficiency
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / pharmacology
Intercellular Signaling Peptides and Proteins / physiology*
Mice
Mice, Knockout
Mice, Nude
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / pharmacology
Neoplasm Proteins / physiology*
Paracrine Communication
Piperazines / pharmacology
Platelet-Derived Growth Factor / antagonists & inhibitors
Platelet-Derived Growth Factor / physiology*
Pyrimidines / pharmacology
Stromal Cells / drug effects
Stromal Cells / metabolism*
Tumor Cells, Cultured / drug effects
Tumor Cells, Cultured / metabolism
Tyrphostins / pharmacology
Uterine Cervical Neoplasms / metabolism
Uterine Cervical Neoplasms / pathology*
Xenograft Model Antitumor Assays
|
| IF |
9.727
|
| 引用数 |
58
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
TCS(RCB0638)
Ca Ski(RCB1947) |
