Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The successful growth of tumors is dependent on the process of vascularization elicited by the tumor itself. As confirmed by many authors, there is a correlation between the presence of factors that stimulate tumor growth and angiogenesis. One of the approaches we have explored to control angiogenesis has been to synthesize compounds able to complex growth factors. A number of sulphonated derivatives of distamycin A were found active in inhibiting the binding of bFGF and PDGF beta on Swiss 3T3 cells with ID50 values ranging between 142-587 microM for bFGF and 28-79 microM for PDGF beta. The effect of these new derivatives in inhibiting angiogenesis was initially explored in the chorioallantoic membrane assay. It was observed that the selected compounds were active in this model system at the concentration of 350 nm/pellet. These new molecules present low or no cytotoxic activity on M5076 murine reticulosarcoma cells, the ID50 values being higher than 60 microM after 72 h continuous exposure in vitro.
 ...
PMID:In vitro activity of novel sulphonic derivatives of distamycin A. 137 71

We have shown in previous studies that metastatically-competent variant subpopulations (B5, C1) derived from a non-metastatic murine mammary adenocarcinoma (SP1) have a pronounced growth advantage over their non-metastatic tumor cell counterparts in primary tumors. As a result, primary tumors can be progressively overgrown by cells having the competence to spread elsewhere in the body. This occurs despite any evidence to indicate an intrinsic in vivo growth rate advantage of the metastatic cells when grown as isolated populations. This suggested that cell-cell interactions between metastatic and non-metastatic tumor populations may be involved in the metastatic cell growth dominance process. Evidence was therefore sought for growth factors released by SP1 cells which could preferentially stimulate the B5 or C1 variants and thereby mediate this cell-cell interaction process. We found that cocultures of SP1 and C1 or B5 cells with irradiated C1, B5, or SP1 "feeder" cells showed significant stimulation of C1 and B5 by SP1 "feeder" cells. Cell growth stimulation in response to EGF, TGF-alpha, TGF-beta 1, bFGF, PDGF, NGF, IGF-1, or IGF-2 demonstrated that only TGF-beta 1 could duplicate this effect. A repeat of the coculture experiment in the presence of specific neutralizing anti-TGF-beta antibodies was therefore undertaken and this was found to markedly reduce the stimulation of C1 or B5 cells by irradiated SP1 cells. Conditioned media from the SP1 and C1 cell lines was quantitated for TGF-beta activity and contained 4.5 ng/ml and 2.0 ng/ml, respectively. However, the majority of the TGF-beta released by SP1 cells was found to be spontaneously active, whereas 70% of the TGF-beta released by C1 cells was in its latent form. Scatchard analysis revealed approximately four times the number of TGF-beta receptors, of similar type and affinity, present on C1 as compared with SP1 cells. The in vitro results support the hypothesis that active TGF-beta released by SP1 cells may stimulate the proliferation of metastatic variant cells in a paracrine like fashion. In vivo evidence for this was obtained by showing that coinjection of irradiated SP1 cells could selectively stimulate tumor growth of viable C1 cells and this effect was markedly diminished by neutralizing polyclonal anti-TGF-beta antibodies. Taken together, the results suggest a novel role for TGF-beta in clonal evolution of malignant tumor growth and as a molecular mediator of tumor cell-tumor cell interactions involved in facilitating tumor progression.
 ...
PMID:Reduction of TGF-beta activity abrogates growth promoting tumor cell-cell interactions in vivo. 165 15

Intact 23 kilodalton (kDa), rat PRL is enzymatically cleaved in many target tissues to a 16 kDa (16K PRL) and an 8 kDa fragment. After reduction of an internal disulfide bond the fragments are released. 16K PRL was shown to be a potent mitogen on mammary epithelial cells via PRL receptors. Since estradiol-induced prolactinomas develop a new blood supply we tested the action of intact PRL and 16K PRL on growth of new vessels (angiogenesis). The angiogenic action of intact PRL and 16K PRL was tested in cultured bovine brain and adrenal cortex endothelial cells. Basal (b) or b-fibroblast growth factor (FGF) stimulated growth was estimated by counting cells or measuring the level of incorporation of 3H-thymidine into DNA. Paradoxically, 16K PRL inhibited the basal and FGF-stimulated growth of cultured endothelial cells in a dose-dependent fashion. Intact PRL or the cleaved but not reduced PRL were inactive even at a 100-fold higher concentration. When reformation of disulfide bonds was inhibited by carbamidomethylation of 16K PRL the preparations were more potent. 16K PRL had no effect on the mitogenic action of bFGF on baby hamster kidney cells which are known to have FGF receptors. These data demonstrate that in vitro 16K PRL is a potent and specific angiolytic factor, i.e. it inhibits angiogenesis. Furthermore, the action of 16K PRL does not appear to be via the known PRL or FGF receptors. Since angiogenesis is an essential component of tumor growth 16K PRL has potential as a therapeutic agent for the treatment of cancer.
 ...
PMID:The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. 185 80

Acidic and basic fibroblast growth factors (aFGF and bFGF) are closely related peptide mitogens acting on both mesoderm- and neuroectoderm-derived cells, including fibroblasts, endothelial cells and glial cells. In order to identify the expression of mRNAs for these growth factors, in situ hybridization using human aFGF and bFGF RNA probes was performed in 24 human brain tumors. The mRNAs for aFGF and bFGF were expressed in the cells of various tumors (1/1 and 1/1 astrocytoma, 2/2 and 2/2 anaplastic astrocytomas, 6/6 and 6/6 glioblastomas, 4/4 and 4/4 meningiomas, 3/3 and 3/3 schwannomas, 1/2 and 1/2 pituitary adenomas, 4/4 and 4/4 metastatic carcinomas, 0/1 an 0/1 hemangioblastoma, 0/1 and 0/1 craniopharyngioma) and were also detected in endothelial cells and surrounding neuronal cells of brain tumors. These results suggest the possibilities that aFGF and bFGF contribute to the uncontrolled growth of tumor cells and the proliferation of endothelial cells in autocrine and paracrine manners, and that the expression of mRNAs for these growth factors in the surrounding neuronal cells results in enhancement of tumor growth.
 ...
PMID:Localization of acidic and basic fibroblast growth factor mRNA in human brain tumors. 193 97

Recently, a novel class of angiostatic steroids which block angiogenesis in several systems has been described. Since the elaboration of proteases is believed to be an important component of angiogenesis, we tested whether these steroids blocked the fibrinolytic response of endothelial cells to the angiogenic protein, basic fibroblast growth factor [bFGF]). Cultured bovine aortic endothelial (BAE) cells were incubated with bFGF and/or medroxyprogesterone acetate (MPA), an angiostatic steroid which has been shown to inhibit vascularization, collagenolysis, and tumor growth. When bFGF (3 ng/ml) was added to confluent monolayers of BAE cells, plasminogen activator (PA) activity in the medium was increased threefold. In contrast, MPA at 10(-6) M, 10(-7) M, 10(-8) M, and 10(-9) M decreased PA levels in the medium by 83%, 83%, 75%, and 39%, respectively. The stimulation of PA levels in BAE cells by bFGF (3 ng/ml) was abrogated by the presence of 10(-6) M MPA. This decrease in PA activity was found to be mediated by a significant increase in plasminogen activator inhibitor type-1 (PAI-1) production. MPA, therefore, negated one of the important enzymatic activities associated with the angiogenic process. In contrast to the decreased levels of secreted PA in cultures exposed simultaneously to MPA and bFGF, cell-associated PA levels remained high, consistent with earlier observations indicating that PAI-1 does not inhibit cell-associated PA. Thus, angiostatic steroids may exert their inhibitory effects on angiogenesis by increasing the synthesis of PAI-1. This, in turn, inhibits PA activity and, therefore, plasmin generation, which is essential for the invasive aspect of angiogenesis.
 ...
PMID:Mechanism of action of angiostatic steroids: suppression of plasminogen activator activity via stimulation of plasminogen activator inhibitor synthesis. 768 43

Growth factors, such as bFGF, have been shown to exert autocrine and paracrine effects on the growth of Kaposi's Sarcoma (KS)-derived cells, which suggested that the inhibitors of angiogenesis may be promising for KS treatment. However, KS lesions have been found to continue to enlarge after patients had been treated with FGF binding antagonists such as suramin. We investigated the effect of protamine and suramine on the growth of KS derived cells in vitro. Although both of these agents which are FGF binding antagonists were found to inhibit the incorporation of 3H thymidine in KS-derived cultured cells, increased expression of bFGF, FGF5 and the FGF receptor was observed after the KS cells were exposed to these substances. These results might explain the clinical observation that FGF binding antagonists such as suramin caused an apparent stimulation of KS tumor growth when administered systemically to patients with AIDS-related KS.
 ...
PMID:Increased expression of fibroblast growth factors (FGFs) and their receptor by protamine and suramin on Kaposi's sarcoma-derived cells. 839 79

Molecular alterations play a key role in the pathogenesis of gastrointestinal cancers. In the present paper we describe relevant molecular alterations in human pancreatic adenocarcinomas. Overexpression of growth factor receptors (EGF receptor, c-erbB2, c-erbB3, TGF beta receptor I-III), growth factors (EGF, TGF alpha, TGF beta-1-3, aFGF, bFGF), adhesion molecules (ICAM-1, ELAM-1) and gene mutations (p53, K-ras, DCC, APC) are present in a significant number of these tumors. These changes stimulate tumor growth and enhance the metastatic behavior of pancreatic cancer cells and thereby may contribute to shorter postoperative survival following tumor resection.
 ...
PMID:Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors. 883 68

The present report describes the in vitro and in vivo profile of CEP-751, a novel receptor tyrosine kinase inhibitor. CEP-751 at 100 nM inhibits the receptor tyrosine kinase activity of the neurotrophin receptors trkA, trkB and trkC. CEP-751 has no effect on activity of receptors for EGF, IGF-I, insulin or on erbB2; inhibition of receptors for PDGF and bFGF was observed but occurred with lesser potency than inhibition of trk. CEP-751 exhibited anti-tumor efficacy against tumors derived from NIH3T3 cells transfected with trkA. Inhibition of trk phosphorylation could also be measured in these tumors, suggesting that anti-tumor efficacy of CEP-751 is related to inhibition of trk receptor tyrosine kinase activity. CEP-751 was found to be without effect when administered to nude mice bearing SK-OV-3 tumors, which overexpress erbB2 receptors, providing further evidence that inhibition of tumor growth may be related to inhibition of trk receptor tyrosine kinase activity. Our data indicate that CEP-751 is a potent trk inhibitor which possesses anti-tumor activity.
 ...
PMID:CEP-751 inhibits TRK receptor tyrosine kinase activity in vitro exhibits anti-tumor activity. 925 9

Aberrant angiogenesis-the new vessels formation is a mandatory event in the process of tumor growth and expansion. Studies on mechanisms involved in tumor-induced angiogenesis (TIA) and on its possible inhibitors are needed in order to introduce in future new methods of tumor treatment. The aim of our study was to determine the usefulness of the modified cutaneous TIA (mice without immunosuppression) test for screening in vivo of the angiogenesis modifiers. In both models (classical and modified TIA) we demonstrated comparable angiogenesis activity following human lung cells inoculation and similar degree of neovascularization response inhibition caused by theobromine. We reported that in modified TIA model preincubation with theobromine significantly suppressed angiogenic potential of human lung cancer cells as well as the ability of those cells to produce proangiogenic cytokine-bFGF.
 ...
PMID:Screening of angiogenesis inhibitors by modified tumor-induced angiogenesis (TIA) test in lung cancer. 933 46

Macrophages (M phi) are important for angiogenesis during inflammation, wound repair, and tumor growth. However, well-characterized M phi subsets such as IFN-gamma-induced, classically activated (ca) M phi or IL-4/glucocorticoid-induced, alternatively activated (aa) M phi have not been thoroughly examined for a positive or negative association with angiogenesis. While caM phi populate early inflammatory reactions and high-turnover granulomas, aaM phi occur in healing wounds and chronic inflammation. In contrast to caM phi-dominated lesions, aaM phi-rich lesions are highly vascularized. In order to determine their angiogenic potential in vitro, these M phi subsets as well as unstimulated control macrophages (coM phi) were analyzed by RT-PCR for mRNA expression of 10 angiogenic factors after 3 and 6 days of culture. Early during activation, caM phi and coM phi expressed equal levels of 8 of 10 angiogenic factors (PDGF-A, MK, TNF-alpha, TGF-beta 1, PDGF-B, HGF, TGF-alpha, IGF-1), while aaM phi showed expression of only 4 of these factors (TGF-beta 1, PDGF-B, HGF, GF-1). After maturation, TGF-alpha and IGF-1 showed a shift in mRNA expression from caM phi to aaM phi resulting in a considerably enhanced expression of these factors in day-6 aaM phi as compared to day-6 caM phi and coM phi while PDGF-A, MK, and TNF-alpha remained suppressed in day 6 aaM phi. In all M phi subsets including controls, mRNA expression of aFGF and bFGF was minimal or absent while TGFG-beta 1, HGF, and ODGF-B were constitutively expressed. In order to functionally integrate angiogenic factor mRNA expression profiles, mitogenic activity of M phi subsets towards microvascular endothelium was assessed by cocultivation. Coculture experiments revealed that endothelial proliferation induced by aaM phi was 3.0-3.5x higher than induced by caM phi. In conclusion, mature aaM phi are well equipped to play an important role in protracted M phi-associated angiogenic processes. Presumably due to expression of predominantly angio-inhibitory cytokines such as TNF-alpha by caM phi but much less by aaM phi, caM phi exhibit only a low angiogenic potential in vitro and in vivo despite considerable expression of angiogenic factor mRNA.
 ...
PMID:Differences in angiogenic potential of classically vs alternatively activated macrophages. 941 47


1 2 3 4 5 6 7 8 9 10 Next >>