title: WISP1/CCN4: a potential target for inhibiting prostate cancer growth and spread to bone.
abstract: Prostate cancer (PC) is a leading cause of death in men however the factors that regulate its progression and eventual metastasis to bone remain unclear. Here we show that WISP1/CCN4 expression in prostate cancer tissues was up-regulated in early stages of the disease and, further, that it correlated with increased circulating levels of WISP1 in the sera of patients at early stages of the disease. WISP1 was also elevated in the mouse prostate cancer model TRAMP in the hypoplastic diseased tissue that develops prior to advanced carcinoma formation. When the ability of anti-WISP1 antibodies to reduce the spread of PC3-Luc cells to distant sites was tested it showed that twice weekly injections of anti-WISP1 antibodies reduced the number and overall size of distant tumors developed after intracardiac (IC) injection of PC3-Luc cells in mice. The ability of antibodies against WISP1 to inhibit growth of PC3-Luc cancer cells in mice was also evaluated and showed that twice weekly injections of anti-WISP1 antibodies reduced local tumor growth when examined in xenografts. To better understand the mechanism of action, the migration of PC3-Luc cells through membranes with or without a Matrigel™ barrier showed the cells were attracted to WISP1, and that this attraction was inhibited by treatment with anti-WISP1 antibodies. We also show the expression of WISP1 at the bone-tumor interface and in the stroma of early grade cancers suggested WISP1 expression is well placed to play roles in both fostering growth of the cancer and its spread to bone. In summary, the up-regulation of WISP1 in the early stages of cancer development coupled with its ability to inhibit spread and growth of prostate cancer cells makes it both a potential target and an accessible diagnostic marker for prostate cancer.
authors: Craniofacial and Skeletal Diseases Branch, NIDCR, NIH, Bethesda, Maryland, United States of America ; Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors: Mitsuaki
authors: M
authors: Ono
authors: Colette A
authors: CA
authors: Inkson
authors: Robert
authors: R
authors: Sonn
authors: Tina M
authors: TM
authors: Kilts
authors: Luis F
authors: LF
authors: de Castro
authors: Azusa
authors: A
authors: Maeda
authors: Larry W
authors: LW
authors: Fisher
authors: Pamela G
authors: PG
authors: Robey
authors: Agnes D
authors: AD
authors: Berendsen
authors: Li
authors: L
authors: Li
authors: Nancy
authors: N
authors: McCartney-Francis
authors: Aaron C
authors: AC
authors: Brown
authors: Nigel P S
authors: NP
authors: Crawford
authors: Alfredo
authors: A
authors: Molinolo
authors: Alka
authors: A
authors: Jain
authors: Neal S
authors: NS
authors: Fedarko
authors: Marian F
authors: MF
authors: Young
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D055511:CCN Intercellular Signaling Proteins / Q000097:blood / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D007267:Injections; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; D011518:Proto-Oncogene Proteins; D008156:Luciferases
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