PMID- 9362425
OWN - NLM
STAT- MEDLINE
DCOM- 19971120
LR  - 20190620
IS  - 0008-543X (Print)
IS  - 0008-543X (Linking)
VI  - 80
IP  - 8 Suppl
DP  - 1997 Oct 15
TI  - Mechanisms of the development of osteoblastic metastases.
PG  - 1581-7
AB  - Although several neoplasms may produce osteoblastic metastases, carcinoma of the 
      prostate is by far the most common. Biochemical and histologic studies indicate 
      that osteolysis also is a manifestation of prostate carcinoma. Furthermore, 
      factors such as parathyroid hormone-related peptide, which mediate osteolysis in 
      other cancers, also appear to be operative in the bone breakdown induced by 
      prostate carcinoma. However, the most unique skeletal effect of this tumor is its 
      consistent capacity to stimulate osteoblasts to deposit new bone. Several bone 
      growth factors have been detected in prostatic tissue and may contribute to this 
      process. These include transforming growth factor-beta, fibroblast growth factor, 
      and bone morphogenetic proteins. The author isolated an amino-terminal fragment 
      (ATF) of the protease urokinase (uPA) from the conditioned medium of the prostate 
      carcinoma cell line PC-3 and demonstrated that this fragment has mitogenic 
      activity for osteoblastic cells. The activity appears to reside in an epidermal 
      growth factor-like growth factor domain (GFD) within the ATF. Subsequently, the 
      author cloned the rat uPA receptor (uPAR). uPAR is known to bind the ATF and can 
      permit the uPA molecule to exhibit focal proteolysis. It was shown that the ATF 
      also can induce c-myc, c-jun, and c-fos in osteoblastic cells. This effect of ATF 
      can be mimicked by the GFD and suggests that this signalling pathway in 
      osteoblasts is via the uPAR. Consequently, the uPA molecule may contribute to 
      growth factor effects in osteoblasts via the NH2-terminal fragment and to tumor 
      invasiveness via its COOH-terminal proteolytic domain. This scenario is supported 
      by results from studies with uPA-overexpressing prostate carcinoma cells in rats. 
      Additional studies will be required to further define the mechanisms of 
      interaction of prostate carcinoma and other cancers with bone but each site of 
      molecular interaction may provide a therapeutic window for curtailing the effects 
      of these tumors on the skeleton.
FAU - Goltzman, D
AU  - Goltzman D
AD  - Department of Medicine, Royal Victoria Hospital and McGill University, Montreal, 
      Quebec, Canada.
LA  - eng
GR  - 5R01-CA37126/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 0 (Growth Substances)
RN  - 0 (Neoplasm Proteins)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
MH  - Animals
MH  - Bone Neoplasms/*secondary
MH  - Growth Substances/*physiology
MH  - Humans
MH  - Male
MH  - Neoplasm Proteins/*physiology
MH  - Osteoblasts/*physiology
MH  - Osteolysis/*etiology
MH  - Prostatic Neoplasms/complications/metabolism/*pathology
MH  - Rats
MH  - Urokinase-Type Plasminogen Activator/*physiology
RF  - 29
EDAT- 1997/11/15 13:26
MHDA- 2000/06/20 09:00
CRDT- 1997/11/15 13:26
PHST- 1997/11/15 13:26 [pubmed]
PHST- 2000/06/20 09:00 [medline]
PHST- 1997/11/15 13:26 [entrez]
AID - 10.1002/(SICI)1097-0142(19971015)80:8+<1581::AID-CNCR8>3.0.CO;2-N [pii]
AID - 10.1002/(sici)1097-0142(19971015)80:8+<1581::aid-cncr8>3.3.co;2-8 [doi]
PST - ppublish
SO  - Cancer. 1997 Oct 15;80(8 Suppl):1581-7. doi: 
      10.1002/(sici)1097-0142(19971015)80:8+<1581::aid-cncr8>3.3.co;2-8.