UMLS:C0027627 - FACTA Search

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Query: UMLS:C0027627 (metastases)
103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenesis, the formation of new blood vessels from preexisting ones, is a fundamental stage in the metastatic pathway. For the primary tumor, this neovascularization provides nutrients and oxygen as well as a route by which metastatic tumor cells gain access to the circulatory system. Among these metastatic tumor cells, there are subgroups of cells that express an angiogenesis-inducing cells phenotype (AICs) as well as others that do not. Tumor cells not expressing the angiogenesis-inducing cells phenotype (non-AICs) invade new tissues and remain as dormant micrometastases unless they accompany AICs. Thus, either alone or with non-AICs, angiogenesis-inducing cells form rapidly growing, clinically detectable metastases. Much of the current research in this area is concentrated on the vascularization of primary tumors, but the regulation of angiogenesis by extravasating or invading tumor cells has not being extensively studied. We have developed a working model, which demonstrates that human metastatic prostate cancer cells (PC-3) appear to induce human vascular endothelial cells (HUVECs) to translocate across a Matrigel-coated 8 mm membrane. The parameters of this model (i.e. pore size, seeding-cell density, seeding times) were established using highly invasive murine melanoma cells (B16F10) seeded on murine microvascular endothelial cells (CD3). We have further modified our model in order to include a host compartment made of collagen gel, in order to mimic the in vivo site of metastases-induced angiogenesis.
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PMID:A novel in vitro system to study extravasated tumor cell-induced angiogenesis. 976 42

A novel monoclonal antibody has been developed that reacts strongly with human prostatic cancer, especially tumors of high grade. This antibody (7E11C-5) is currently in Phase 3 trials as an imaging agent for metastatic disease. We have cloned the gene that encodes the antigen that is recognized by the 7E11C-5 monoclonal antibody and have designated this unique protein prostate-specific membrane (PSM) antigen. PSM antigen is a putative class II transmembranous glycoprotein exhibiting a molecular size of Mr 94,000. Functionally, class II membrane proteins serve as transport or binding proteins or have hydrolytic activity. Preliminary studies have demonstrated binding of pteroylmonoglutamate (folate) to membrane fractions that also cross-reacted with the PSM monoclonal antibody. We observed substantial carboxypeptidase activity as folate hydrolase associated with PSM antigen. The purpose of our study was to demonstrate that human prostatic carcinoma cells expressing PSM antigen exhibit folate hydrolase activity using methotrexate triglutamate (MTXGlu3) and pteroylpentaglutamate (PteGlu5) as substrates. Isolated membrane fractions from four human prostate cancer cell lines (LNCaP, PC-3, TSU-Prl, and Duke-145) were examined for folate hydrolase activity using capillary electrophoresis. After timed incubations at various pH ranges and in the presence and absence of thiol reagents, separation of pteroyl(glutamate)n derivatives was achieved with an electrolyte of sodium borate and SDS, while absorbance was monitored at 300 nm. The results demonstrate clearly that LNCaP cells, which highly express PSM, hydrolyze gamma-glutamyl linkages of MTXGlu3. The membrane-bound enzyme is an exopeptidase, because it progressively liberates glutamates from MTXGlu3 and PteGlu5 with accumulation of MTX and PteGlu1, respectively. The semipurified enzyme has a broad activity from pH 2.5 to 9.5 and exhibits activity maxima at pH 5 and 8. Enzymatic activity is maintained in the presence of reduced glutathione, homocysteine, and p-hydroxymercuribenzoate (0.05-0.5 mm) but was inhibited weakly by DTT (>/=0.2 mm). By contrast to LNCaP cell membranes, membranes isolated from other human prostate adenocarcinoma cells (PC-3, Duke-145, and TSU-Pr1) did not exhibit comparable hydrolase activity, nor did they react with 7E11-C5 monoclonal antibody. After transfection of PC-3 cells with a full-length 2.65-kb PSM cDNA subcloned into a pREP7 eukaryotic expression vector, non-PSM antigen-expressing PC-3 cells developed immunoreactivity to 7E11-C5 monoclonal antibody and demonstrated folate hydrolase activities and optimum pH activity profiles identical to those of LNCaP cells. The membrane-bound enzymes from both LNCaP- and PC-3-transfected cells also have a capacity to hydrolyze an alpha-linked glutamyl moiety from N-acetyl-alpha-aspartylglutamate. We have identified that PSM antigen is a pteroyl poly-gamma-glutamyl carboxypeptidase (folate hydrolase) and is expressed strongly in human prostate cancer. Cancer cells that express this enzyme are resistant to methotrexate therapy. Those developing future therapeutic strategies in the treatment of prostate cancer that utilize folate antagonists need to consider this mechanism of resistance.
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PMID:Prostate-specific membrane antigen: a novel folate hydrolase in human prostatic carcinoma cells. 981 19

Some primary tumors are capable of suppressing the growth of their metastases by presumably generating antiangiogenic factors such as angiostatin. We hypothesized that the amount of inhibitor(s) released by a tumor increases with tumor growth. We tested this hypothesis by evaluating the relationship between the size of a primary tumor and its ability to inhibit angiogenesis at a secondary site. Furthermore, we characterized the effects of the primary tumor on physiological properties of newly formed vessels at the secondary site. Angiogenesis and physiological properties were measured using intravital microscopy of angiogenic vessels in the gels containing basic fibroblast growth factor placed into cranial windows of immunodeficient mice bearing human prostatic carcinoma (PC-3) in their flank. The PC-3 tumor inhibited angiogenesis in the gels, and surgical resection of tumor reversed this inhibition. The inhibition of angiogenesis 20 days after gel implantation (range, 0-83%) correlated positively (r = 0.625; P < 0.008) with the tumor size on the day of gel implantation (range, 19-980 mm3). The primary tumor also suppressed leukocyte-adhesion in angiogenic vessels, thus helping them evade the immune recognition. These results provide an additional rationale for combining antiangiogenic treatment with local therapies.
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PMID:Primary tumor size-dependent inhibition of angiogenesis at a secondary site: an intravital microscopic study in mice. 986 47

Bone metastases are a common complication in prostate and breast cancer patients. It leads to extensive morbidity and eventually mortality. Matrix metalloproteinases are implicated in various steps of development of metastasis, through their ability to degrade the extracellular matrix. Increased matrix metalloproteinase activity of tumor cells has been associated with a higher metastatic potential. Inhibitors of metalloproteinases have been shown to effectively reduce or prevent the formation of metastases. The family of tetracyclines is able to inhibit matrix metalloproteinase activity through chelation of the zinc ion at the active site of the enzyme. Using tumor cell lines relevant to bone metastases, i.e. PC-3, MDA-MB-231, Hs696, B16/F1, we showed that tetracycline and derivatives of tetracycline, namely doxycycline and minocycline, also induced cytotoxicity. The effective concentrations are relatively high for plasma, but are clinically achievable in the bone, since tetracyclines are osteotropic. All four bone-metastasizing tumor cells produced and secreted various matrix metalloproteinases. Doxycycline was able to inhibit the activity of 72- and 92-kDa type IV collagenase secreted by bone-metastasizing cells by 79-87%. These characteristics could make tetracycline a unique candidate as a therapeutic agent to prevent bone metastases in cancer patients with a high likelihood for development of bone metastasis. Studies using animal models of experimental bone metastasis will be necessary to confirm this.
Invasion Metastasis 1997
PMID:Use of tetracycline as an inhibitor of matrix metalloproteinase activity secreted by human bone-metastasizing cancer cells. 994 90

Here, we report a fluorescent spontaneous bone metastatic model of human prostate cancer developed by surgical orthotopic implantation of green fluorescent protein (GFP)-expressing prostate cancer tissue. Human prostate cancer PC-3 cells were transduced with the pLEIN expression retroviral vector containing the enhanced GFP and neomycin resistance genes. Stable GFP high-expression PC-3 clones were selected in vitro with G418, which were then combined and injected s.c. in nude mice. For metastasis studies, fragments of a single highly fluorescent s.c. growing tumor were implanted by surgical orthotopic implantation in the prostate of a series of nude mice. Subsequent micrometastases and metastases were visualized by GFP fluorescence throughout the skeleton, including the skull, rib, pelvis, femur, and tibia The central nervous system, including the brain and spinal cord, was also involved with tumor, as visualized by GFP fluorescence. Systemic organs, including the lung, plural membrane, liver, kidney, and adrenal gland, also had fluorescent metastases. The metastasis pattern in this model reflects the bone and other metastatic sites of human prostate cancer. Thus, this model should be very useful for the study and development of treatment for metastatic androgen-independent prostate cancer.
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PMID:A fluorescent orthotopic bone metastasis model of human prostate cancer. 1002 62

We have previously shown that alendronate, a potent bisphosphonate compound, can prevent human PC-3 ML tumor cell metastasis to the bone (Stearns and Stearns, 1996, Oncol Res, 8, 69-75). In this paper, tumor cells were injected into the bone medullary cavity of SCID mice femurs both in vivo and following isolation in vitro. ELISAs showed that the amount of collagen I released in the bone marrow (i.e. in in vitro experiments) and the blood plasma (i.e. in in vivo experiments) was a function of the time of incubation or the number of cells injected in the femurs. ELISAs also showed that the levels of matrix metalloproteinase (MMP-2 and MMP-9) secreted in the bone medullary cavity of the femurs directly correlated with the extent of collagen 1 release. In vitro experiments carried out with 'live' and 'devitalized bone' yielded similar results suggesting that the tumor cells (not the osteoclasts) were primarily responsible for the bone solubilization observed. Alendronate pretreatment of the SCID mice (0.1 mg/kg biweekly for 3 weeks) (or the tumor cells) blocked both MMP production by the tumor cells (and the osteoclasts) and collagen I release, providing direct evidence that alendronate might be utilized to prevent bone destruction by metastatic tumor cells. Zymography indicated that MMP-2 activation might be responsible for bone solubilization. In addition, the data suggest that the plasma levels of collagen I might be a marker of bone metastasis and osteolysis.
Clin Exp Metastasis 1998 Nov
PMID:Alendronate blocks metalloproteinase secretion and bone collagen I release by PC-3 ML cells in SCID mice. 1021 82

We evaluated whether AN-238, the cytotoxic analogue of somatostatin (SST) consisting of the radical 2-pyrrolinodoxorubicin (AN-201) linked covalently to the SST octapeptide carrier RC-121 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2), could be used for targeting human primary and metastatic prostate carcinomas that express SST receptors (SSTRs). The antitumor activity and toxicity of AN-238 and its components were first characterized in nude mice bearing s.c. xenografts of PC-3 human androgen-independent prostate cancer. In experiment 1, AN-238 was injected once i.v. at 200 nmol/kg when the mean volume of s.c. tumors was about 30 mm3. Administration of AN-238 inhibited tumor growth, as shown by a 74% decrease in tumor volume and by a 71% reduction in tumor weight after 7 weeks as compared with the control group. AN-201 at an equimolar dose did not show any antitumor activity. The mortality was 14.3% (one of seven mice) in the AN-238-treated group and 47% (three of seven mice) in mice that received AN-201. In experiment 2, two i.v. injections of AN-238 at 150 nmol/kg were given 10 days apart when the tumors measured 65-70 mm3. A significant inhibition of tumor volume (62.3%; P < 0.001) and tumor weight (61.1%; P < 0.01) was observed after 4 weeks of treatment. AN-201, given alone at the same dose or coadministered with RC-121, had no significant effect on PC-3 tumors. The suppression of tumor growth induced by AN-238 was accompanied by a significant enhancement of apoptosis (P < 0.01). There were similar side effects in all treated groups, which included a transient loss of body weight and leukopenia. The effectiveness of AN-238 in a metastatic model was then investigated in animals implanted orthotopically with 2 x 10(6) PC-3 cells. Two i.v. injections of AN-238 or AN-201 at 150 nmol/kg were administered 10 days apart at 10 weeks after intraprostatic inoculation of PC-3 cells. After 4 weeks of treatment, the mean weight of primary tumors in animals receiving AN-238 was 77% lower (P < 0.01) than that in controls. This reduction was also significantly greater (P < 0.05) than that in animals given AN-201, which showed only a 34% inhibition (nonsignificant versus controls). All control animals and four of six (67%) mice treated with AN-201 developed metastases in the lymph nodes; however, no lymphatic spread of cancer was found in the AN-238-treated group. Using reverse transcription-PCR analysis, we demonstrated the expression of SSTR2 and SSTR5 in intraprostatic tumors and their metastases in lymph nodes as well as in s.c. tumors. The present study demonstrates the high efficacy of SSTR-targeted chemotherapy in a model of advanced human androgen-independent prostatic carcinoma, as shown by the inhibition of primary tumors and their metastases by the cytotoxic SST analogue AN-238.
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PMID:Inhibition of PC-3 human androgen-independent prostate cancer and its metastases by cytotoxic somatostatin analogue AN-238. 1021 5

Bone metastases are a common complication in prostate and breast cancer patients. It leads to extensive morbidity and eventually mortality. Matrix metalloproteinases (MMPs) are known to be involved in the metastatic process. MMP activity can be down-regulated by transforming growth factor beta1 (TGF-beta1), a growth-modulating factor, found in high concentrations in the bone. TGF-beta1 acts through the TGF-beta1 inhibitory element (TIE) element, a cis-acting element found in the promoter region of most MMP genes, with the exception of MMP-2. We used three human cell lines relevant for bone metastases, namely prostate adenocarcinoma PC-3, breast adenocarcinoma MDA-MB-231, and adenocarcinoma cells of unknown origin, Hs696, and one human osteosarcoma cell line, SAOS-2, and showed that in these cell lines TGF-beta1 partially lost its repressing action on MMP expression. TGF-beta1 was able to induce MMP-9 activity and protein expression in all three bone-metastatic tumour cell types, whereas MMP-9 protein levels were repressed in SAOS-2 cells. In PC-3 cells, TGF-beta1 repressed MMP-1 expression, whereas in MDA-MB-231 and SAOS-2 cells, an increase in the expression of MMP-1 protein was detected. Additionally, an increase in MMP-3 expression was observed in Hs696 cells. Expression and activity of the tissue inhibitors of matrix metalloproteinases, TIMP-1 and TIMP-2, were found increased in both PC-3 and MDA-MB-231 cells. With respect to cell proliferation, TGF-beta1 was able to induce a dose-dependent growth inhibition of up to 50% in primary human mammary epithelial cells. However, in none of the tumour cell lines was TGF-beta1 able to suppress growth substantially. Data presented in this paper support the hypothesis that TGF-beta1 can potentially disrupt the balance existing between osteoclast- and osteoblast-derived MMP activity by inducing altered expression of matrix metalloproteinases and their tissue inhibitors derived from bone-metastasizing cancer cells. This could eventually lead to skeletal destruction in patients with advanced metastatic disease.
Clin Exp Metastasis 1999 Feb
PMID:Transforming growth factor beta1 acts as an inducer of matrix metalloproteinase expression and activity in human bone-metastasizing cancer cells. 1039 Jan 44

The role of the neurotrophins (NTs) and their corresponding receptors (NTRs) TrkA, TrkB, TrkC, and p75NTR in neoplasia has received relatively little attention. However, because malignant cell migration within the prostate occurs predominantly by direct extension around prostatic nerves, the presence and possible upregulation of NTs from autocrine/paracrine sources and NTR expression within prostate epithelial tumor cells may be important in metastasis. We have been addressing their expression and interactions in human prostate cancer cell lines (LNCaP, PC-3, and DU145) and their role in prostate cancer invasion. In this study, we demonstrated that nerve growth factor (NGF), the prototypic NT, and NT-4/5 increased in vitro invasion through a reconstituted basement membrane and induced time- and dose-dependent expression of heparanase, a heparan sulfate-specific endo-beta-D-glucuronidase, an important molecular determinant of tumor metastasis. The NT effects were most marked in the DU 145 brain-metastatic cells and were detected at NT concentrations sufficient to fully saturate both low- and high-affinity NTRs. Additionally, we characterized the molecular expression of NT high-affinity (Trk) and low-affinity (p75NTR) receptors in these cell lines by reverse transcription-polymerase chain reaction. These lines had negligible trkA and trkC expression, although trkB was expressed in the three prostatic tumor cell lines examined. The brain-metastatic DU 145 cells were also positive for p75NTR. Our data showed that the NTs and NTRs are important in metastasis and that their expression coincides with transformation to a malignant phenotype capable of invasion along the perineural space and extracapsular metastasis to distant sites. These findings set the stage for more research into this area as related to prostate cancer evolution and may improve therapy for prostate cancer metastasis.
Clin Exp Metastasis 1999 Jun
PMID:Role of neurotrophins and neurotrophins receptors in the in vitro invasion and heparanase production of human prostate cancer cells. 1054 17

J-107088 (6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo [3,4-c]carbazole-5,7(6H)-dione) is a derivative of NB-506, an indolocarbazole compound previously reported as an anti-tumor agent targeting topoisomerase I. The optimal administration schedule of J-107088 was found to be intermittent injections. The GID75 (75% growth inhibiting total dose) values of J-107088 against LX-1 lung cancer and PC-3 prostate cancer when given by intermittent injection (twice a week for 2 consecutive weeks) were 200 and 15 mg/m2, respectively, whereas the 10% lethal dose (LD10) values of J-107088 against LX-1- and PC-3-bearing mice were 578 and 1200 mg/m2. The ratio of LD10/GID75 indicates the therapeutic window of an anti-tumor agent. Although the ratios of doxorubicin, paclitaxel and cisplatin against PC-3 were <0.3, <0.5 and <0.2, J-107088 showed the widest therapeutic window among the anti-tumor drugs tested. J-107088 was also effective on cells that had acquired resistance related to P-glycoprotein. Furthermore, J-107088 was found to be highly effective in inhibiting proliferation of micro-metastases of tumors to the liver in mice. Therefore, J-107088 is considered to be a promising candidate as an anti-tumor drug for treatment of solid tumors in humans.
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PMID:In vivo anti-tumor activity of a novel indolocarbazole compound, J-107088, on murine and human tumors transplanted into mice. 1059 46

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