Heparin-binding EGF-like growth factor in the human prostate: synthesis predominantly by interstitial and vascular smooth muscle cells and action as a carcinoma cell mitogen.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an activating ligand for the EGF receptor (HER1/ErbB1) and the high-affinity receptor for diphtheria toxin (DT) in its transmembrane form (proHB-EGF). HB-EGF was immunolocalized within human benign and malignant prostatic tissues, using monospecific antibodies directed against the mature protein and against the cytoplasmic domain of proHB-EGF. Prostate carcinoma cells, normal glandular epithelial cells, undifferentiated fibroblasts, and inflammatory cells were not decorated by the anti-HB-EGF antibodies; however, interstitial and vascular smooth muscle cells were highly reactive, indicating that the smooth muscle compartments are the major sites of synthesis and localization of HB-EGF within the prostate. In marked contrast to prostatic epithelium, proHB-EGF was immunolocalized to seminal vesicle epithelium, indicating differential regulation of HB-EGF synthesis within various epithelia of the reproductive tract. HB-EGF was not overexpressed in this series of cancer tissues, in comparison to the benign tissues. In experiments with LNCaP human prostate carcinoma cells, HB-EGF was similar in potency to epidermal growth factor (EGF) in stimulating cell growth. Exogenous HB-EGF and EGF each activated HER1 and HER3 receptor tyrosine kinases and induced tyrosine phosphorylation of cellular proteins to a similar extent. LNCaP cells expressed detectable but low levels of HB-EGF mRNA; however, proHB-EGF was detected at the cell surface indirectly by demonstration of specific sensitivity to DT. HB-EGF is the first HER1 ligand to be identified predominantly as a smooth muscle cell product in the human prostate. Further, the observation that HB-EGF is similar to EGF in mitogenic potency for human prostate carcinoma cells suggests that it may be one of the hypothesized stromal mediators of prostate cancer growth.
Freeman
M R
MR
Department of Urology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. freeman_m@al.tch.harvard.edu
Paul
S
S
Kaefer
M
M
Ishikawa
M
M
Adam
R M
RM
Renshaw
A A
AA
Elenius
K
K
Klagsbrun
M
M
D002277:Carcinoma / Q000737:chemistry / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008934:Mitogens / Q000494:pharmacology / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D011467:Prostate / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics; D014407:Tumor Cells, Cultured
C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D011498:Protein Precursors; D004815:Epidermal Growth Factor