|Anti-invasive, antitumorigenic, and antimetastatic activities of the PHSCN sequence in prostate carcinoma.|
Livant, D L, et al.
Cancer Res., 60: 309-20 (2000)
Using naturally serum-free SU-ECM basement membranes as invasion substrates showed that plasma fibronectin was necessary to stimulate invasion by DU 145 human and metastatic MATLyLu (MLL) rat prostate carcinoma cells. This activity mapped to the PHSRN sequence, which induced invasion through alpha5beta1 integrin. PHSCN, a competitive inhibitor, blocked both PHSRN- and serum-induced invasion. Acetylated, amidated PHSCN (Ac-PHSCN-NH2) was 30-fold more potent; however, Ac-HSPNC-NH2 was inactive. Rats receiving injections s.c. with 100,000 MLL cells were treated systemically by i.v. injection three times weekly with 1 mg of either Ac-PHSCN-NH2 or Ac-HSPNC-NH2 beginning 24 h later, three times weekly with 1 mg of Ac-PHSCN-NH2 beginning only after surgery to remove large (2 cm) MLL tumors, or were left untreated. MLL tumors grew rapidly in Ac-HSPNC-NH2-treated and in untreated rats. MLL tumor growth in rats treated with Ac-PHSCN-NH2 beginning 1 day after MLL cell injection was reduced by 99.9% during the first 16 days of treatment, although subsequent tumor growth occurred. MLL tumor cryosections immunostained with anti-PECAM-1 showed that Ac-PHSCN-NH2 inhibited neovascularization by 12-fold during this time. Whether initiated after MLL cell injection or only after MLL tumor removal, Ac-PHSCN-NH2 treatment reduced the numbers of MLL lung colonies and micrometastases by 40- to >100-fold, whereas Ac-HSPNC-NH2 was inactive. Thus, Ac-PHSCN-NH2 may be a potent antitumorigenic and antimetastatic agent for postsurgical use prior to extensive metastasis.
|An interferon-inducible molecule on brain endothelium which controls lymphocyte adhesion mediated by integrins.|
Male, D, et al.
Immunology, 84: 453-60 (1995)
We undertook a search for cytokine-inducible molecules present on brain endothelium and which are involved in the control of lymphocyte adhesion. We screened 39 monoclonal antibodies (mAb) against rat brain endothelium in vitro, and identified five recognizing cytokine-inducible molecules. None of the 39 antibodies blocked lymphocyte adhesion, but one antibody (4A2), produced a 400% enhancement of lymphocyte binding. The 4A2 antigen is induced on brain endothelium by interferon-gamma (INF-gamma) but not tumour necrosis factor-alpha (TNF-alpha), at 6-48 hr. It is preferentially expressed near inter-endothelial cell junctions, but it also expressed on all lymphocytes and weakly on aortic endothelium in vitro. In vivo, it is not detectable on cells in the normal central nervous system (CNS), however it appears in the CNS during T-cell mediated immune reactions. Triggering of cells via this molecule enhances integrin-mediated adhesion of lymphocytes to brain endothelium, primarily via LFA-1. Unlike ICAM-1, 4A2 antigen is induced on endothelium of both Lewis and PVG strains. Although, it has some functional properties of human CD31, the 4A2 antigen is not rat CD31. The cellular localization of this molecule, its actions on integrin-mediated adhesion and its induction by IFN-gamma, all indicate that the 4A2 antibody recognizes a molecule involved in the control of lymphocyte migration into the brain.
|Characterization of microglia and macrophages in the central nervous system of rats: definition of the differential expression of molecules using standard and novel monoclonal antibodies in normal CNS and in four models of parenchymal reaction.|
Flaris, N A, et al.
Glia, 7: 34-40 (1993)
This report describes the development of a new panel of monoclonal antibodies produced following immunization of mice with cultured rat microglial cells. Using these new reagents and previously defined antibodies that bind to microglia or macrophages, the responses of parenchymal microglia, perivascular "microglial" cells, and infiltrating macrophage/monocytes were examined in 4 divergent models of central nervous system reaction. These were brain abscess, experimental allergic encephalomyelitis, Wallerian degeneration, and stab wound. No single new antibody was specific only for microglia; all antibodies positively staining microglial cells also labeled various subsets of macrophage/monocytic cells in normal tissues of the immune system. Moreover, the results indicate that microglia are capable of different levels and a variety of types of response, as defined by the molecules they elaborate. These findings suggest that these CNS resident cells belong to the extended monocyte/macrophage/dendritic cell family and that they do not respond in a stereotypic manner to all forms of CNS insult.