HB-EGF is a potent inducer of tumor growth and angiogenesis.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been shown to stimulate the growth of a variety of cells in an autocrine or paracrine manner. Although HB-EGF is widely expressed in tumors compared with normal tissue, its contribution to tumorigenicity is unknown. HB-EGF can be produced as a membrane-anchored form (pro-HB-EGF) and later processed to a soluble form (s-HB-EGF), although a significant amount of pro-HB-EGF remains uncleaved on the cell surface. To understand the roles of two forms of HB-EGF in promoting tumor growth, we have studied the effects of HB-EGF expression in the process of tumorigenesis using in vitro and in vivo systems. We demonstrate here that in EJ human bladder cancer cells containing a tetracycline-regulatable s-HB-EGF or pro-HB-EGF expression system, s-HB-EGF expression increased their transformed phenotypes, including growth rate, colony-forming ability, and activation of cyclin D1 promoter, as well as induction of vascular endothelial growth factor in vitro. Moreover, s-HB-EGF or wild-type HB-EGF induced the expression and activities of the metalloproteases, MMP-9 and MMP-3, leading to enhanced cell migration. In vivo studies also demonstrated that tumor cells expressing s-HB-EGF or wild-type HB-EGF significantly enhanced tumorigenic potential in athymic nude mice and exerted an angiogenic effect, increasing the density and size of tumor blood vessels. However, cells expressing solely pro-HB-EGF did not exhibit any significant tumorigenic potential. These findings establish s-HB-EGF as a potent inducer of tumor growth and angiogenesis and suggest that therapeutic intervention aimed at the inhibition of s-HB-EGF functions may be useful in cancer treatment.
Cancer Biology Program, Hematology and Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, 4 Blackfan Circle, Boston, MA 02115, USA.
Pat P
PP
Ongusaha
Jennifer C
JC
Kwak
Andrew J
AJ
Zwible
Salvador
S
Macip
Shigeki
S
Higashiyama
Naoyuki
N
Taniguchi
Li
L
Fang
Sam W
SW
Lee
D000818:Animals; D015152:Blotting, Northern; D002455:Cell Division; D002462:Cell Membrane / Q000737:chemistry; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003114:Colony-Forming Units Assay; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003600:Cytosol; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing
C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9