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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Basic fibroblast growth factor (FGF-2) is nearly ubiquitous in its distribution, leading numerous investigators to propose that there must exist highly specific mechanisms to regulate its bioavailability. Moreover, in each of the tissues where it can be localized, numerous cells are its potential target. The identification of these mechanisms could serve as an important step in developing novel strategies to inhibit FGF action. It could be possible to block such FGF-dependent activities as angiogenesis, tumor growth, reproduction, and selected diseases of cell proliferation. Over the course of the past several years, we have attempted to describe some of the processes that might regulate a target cell's ability to activate FGF-2 in its local milieu.
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PMID:Potential mechanisms regulating the extracellular activities of basic fibroblast growth factor (FGF-2). 752 26

It has previously been shown that administration of basic fibroblast growth factor (FGF-2) to mice bearing xenografted human DLD-2 carcinomas produces significant increases in tumor growth rates and decreased intratumor hypoxia, effects which appear to be secondary to changes in the vasculature. In this study, we treated DLD-2 tumors with FGF-2 (ip, 0.25 mg/kg, q.i.d. x 7) beginning on day 15 after implantation, when average tumor volumes were 238 mm3. One day after cessation of administration of FGF-2 (day 22 after implantation, average tumor volume 1748.1 mm3), clamped tumors were given hyperthermia (42.5 degrees C, 60 min) by water bath heating. The slower-growing tumors in the control mice (sham-injected with Hanks' basic salt solution) were clamped and subjected to hyperthermia treatment at equivalent average tumor volumes (1882.7 mm3), which occurred on day 26 after implantation. Tumors in control groups were clamped but not heated. The time needed for neoplasms to grow to twice their volumes at the time of hyperthermia treatment was 68 days for the FGF-2-treated neoplasms and 47 days for the controls, while 26 and 31 days were needed for the control groups which were not treated with heat. The relative growth delay induced by hyperthermia is therefore 16 (47-31) days for control neoplasms and 42 (68-26) days for FGF-2-treated tumors. Therefore, tumors in the mice injected with FGF-2 were significantly more sensitive to the hyperthermia than controls, by a factor of about 2.6 (42/16). This result indicates that administration of growth factors such as FGF-2 to mice bearing tumors may produce an increased sensitivity of the tumors to hyperthermia.
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PMID:Enhancement of thermal sensitivity of xenografted human DLD-2 tumors by administration of basic fibroblast growth factor. 814 94

A fusion protein containing the full-length sequences of the mitogen, basic fibroblast growth factor (FGF-2), and the ribosome-inactivating protein, saporin (SAP), has been expressed in E. coli. As expected, it binds with high affinity to heparin-Sepharose like FGF-2 and can displace the binding of radiolabeled FGF-2 to its high affinity receptor. In contrast, the fusion protein only has much lower ribosome-inactivating activity than free saporin, although full ribosome-inactivating protein activity can be generated by proteolytic removal of the FGF-2 moiety. Cytotoxicity experiments with B16-F10 mouse melanoma cells establish that the fusion protein is active as a chemical conjugate against these intact cells. Presumably these cells have the ability to activate the SAP component of the fusion protein through an intra-cellular metabolism of the fusion protein. Because we also show the fusion protein has tumor growth inhibition properties and antimetastatic activity in in vivo models of melanoma, the findings support the hypothesis that FGF-based ligand-mediated cytotoxicity can serve to target cytotoxic agents in vivo.
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PMID:Expression and activities of a recombinant basic fibroblast growth factor-saporin fusion protein. 817 64

To clarify the role of basic fibroblast growth factor (FGF-2) in the malignant progression of renal cell carcinoma, we transfected the FGF-2 gene, which lacks the typical signal sequence, into RenCa, a mouse renal cell carcinoma cell line that does not express FGF-2 mRNA. In an in vitro tumor cell invasion assay, the FGF-2-transfected cell lines (RenCa/F) exhibited 3- to 4-fold higher invasive potential than either the parental RenCa (RenCa/P) or the vector-only transfected cell line (RenCa/C). Zymography showed a marked increase in matrix metalloproteinase 2 (MMP-2) production in the culture supernatants of RenCa/F. Furthermore, when injected i.v. or into the renal subcapsule in syngeneic mice, RenCa/F formed more than 10 times as many metastatic nodules in the lung as did RenCa/P and RenCa/C. Metastases to the liver and mesenteric lymph nodes were observed only after the injection of RenCa/F into the renal subcapsule. In contrast, there was no significant difference in either cell proliferation in vitro or tumor growth in vivo among RenCa sublines. These results suggest that if it is overexpressed, endogenous native FGF-2 plays an important role in the invasion and metastasis of renal cell carcinoma, probably through the production of MMP-2.
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PMID:Introduction of basic fibroblast growth factor gene into mouse renal cell carcinoma cell line enhances its metastatic potential. 862 25

The comparative biological properties of NBT-II cells, a rat bladder carcinoma cell line constitutively expressing FGF-1 and FGF-2 were analysed in nude mice. FGF-1 is not secreted by the transfected cells unless the cDNA contains a signal sequence; conversely, NBT-II cells transfected with FGF-2 coding sequence produce and secrete the factor in a biologically active form. Bovine brain capillary endothelial cells are stimulated to proliferate upon addition of medium conditioned by the FGF-2-producing cells and this activity can be abrogated by the addition of anti-FGF-2 blocking antibodies. In addition, the FGF-2-containing medium, which cannot stimulate NBT-II cells due to absence of appropriate receptors, is able to induce scattering of NBT-II cells expressing the FGFR1. It has been reported previously that FGF-1-producing cells are highly tumorigenic in nude mice and induce carcinoma with a period of latency reduced from 6 to 5 weeks when compared to parental NBT-II cells. In contrast, NBT-II cells producing FGF-2 are no more tumorigenic than parental cells, indicating that FGF-1 and FGF-2 have different oncogenic properties in carcinoma. FGF-1 and FGF-2 are potent antiogenic factors that trigger the host endothelial cells. VEGF, another potent angiogen was found to be expressed in small amounts by NBT-II cells and to be expressed in reduced amount in the FGF-producing cells. In the NBT-II system in vivo FGF-1 and FGF-2 are highly and comparatively angiogenic in the resultant carcinoma and this occurs in the absence of production of significant amounts of VEGF by the carcinoma cells. Taken together, our results indicate that activated angiogenesis is not sufficient for rapid tumor expansion. FGF-1 behaves as a tumorigenic factor in the NBT-II bladder carcinoma cell model, whereas expression and secretion of large amounts of FGF-2 are not sufficient for increasing tumor growth.
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PMID:FGF-2 and FGF-1 expressed in rat bladder carcinoma cells have similar angiogenic potential but different tumorigenic properties in vivo. 903 74

Progressive loss of the differentiated phenotype and communication with stroma accompanies the transition of nonmalignant rat prostate epithelial cells to anaplastic, malignant tumors. Here we show that cell surface expression of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase is reduced in malignant tumor cell populations (type II) and undetectable at the mRNA level in 30% of cells. This is in addition to the irreversible loss by splice switching of the FGFR2 ectodomain that abrogates response to FGF-7 and homologues from the stroma. One hundred % of type II malignant cells express FGFR1, which is normally expressed in the stroma. Expression of the FGFR1 kinase in premalignant type I tumor epithelial cells by transfection accelerated progression to the malignant phenotype. In contrast to the FGFR2 kinase fused to the ectodomain of FGFR1, the FGFR1 kinase failed initially to support a mitogenic response to FGF-2 in type I tumor cells. However, the FGFR1-transfected cells acquired a mitogenic response after extensive proliferation of the cell population. Resident FGFR2 and ectopic FGFR1 appeared to be partitioned in the type I cells, because neither full-length nor truncated isoforms of FGFR1 affected the mitogenic response of the other. Restoration of the FGFR2IIIb kinase to malignant cells expressing FGFR1 depressed tumor growth rates, restored responsiveness to stromal cells, and restored epithelial cell differentiation. These observations reveal that homologous FGFR1 and FGFR2 kinases play very different roles in cell growth and differentiation and in development and support of the malignant phenotype.
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PMID:Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells. 939 62

To clarify the role of basic fibroblast growth factor (FGF-2) in the drug resistance of bladder cancer, we transfected the FGF-2 gene into HT1376, an FGF-2 negative human bladder cancer cell line. The FGF-2-transfected cell lines exhibited three- to four-fold higher resistant potential to cisplatin than the vector-only transfected control cell lines in vitro. When cisplatin was injected intraperitoneally after s.c. implantation of HT1376 sublines into nude mice, FGF-2 transfectants formed tumors about twice as large as did controls. In contrast, there was no significant difference in either cell proliferation in vitro or tumor growth in vivo among these cell lines without cisplatin treatment. Furthermore, DNA degradation following cisplatin treatment was markedly suppressed in FGF-2 transfectants compared to control cells. These results suggest that the expression of the FGF-2 gene plays an important role in the acquisition of the cisplatin-resistant phenotype of bladder cancer, probably through the protection against cisplatin-induced apoptosis.
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PMID:Expression of basic fibroblast growth factor is associated with resistance to cisplatin in a human bladder cancer cell line. 948 77

Perlecan, a ubiquitous heparan sulfate proteoglycan, possesses angiogenic and growth-promoting attributes primarily by acting as a coreceptor for basic fibroblast growth factor (FGF-2). In this report we blocked perlecan expression by using either constitutive CMV-driven or doxycycline- inducible antisense constructs. Growth of colon carcinoma cells was markedly attenuated upon obliteration of perlecan gene expression and these effects correlated with reduced responsiveness to and affinity for mitogenic keratinocyte growth factor (FGF-7). Exogenous perlecan effectively reconstituted the activity of FGF-7 in the perlecan-deficient cells. Moreover, soluble FGF-7 specifically bound immobilized perlecan in a heparan sulfate-independent manner. In both tumor xenografts induced by human colon carcinoma cells and tumor allografts induced by highly invasive mouse melanoma cells, perlecan suppression caused substantial inhibition of tumor growth and neovascularization. Thus, perlecan is a potent inducer of tumor growth and angiogenesis in vivo and therapeutic interventions targeting this key modulator of tumor progression may improve cancer treatment.
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PMID:Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo. 978 74

The role of FGF-2 in tumor progression and tumor cell invasiveness was investigated using the rat bladder carcinoma cells NBT-II, which do not constitutively express FGF-2 or its membrane-spanning receptor. The NBT-II cells were transfected using expression vectors encoding either the 18 kD or the 24 kD isoform of FGF-2. The 24 kD isoform contains a nuclear localization signal. The transfected NBT-II cells that expressed 18 kD FGF-2 produced and secreted this factor as the biologically active form and retained an epithelial morphology. When injected to nude mice, the tumorigenic potential of these cells was not increased over that of non-transfected NBT-II cells; however, although the time to tumor development was long, the tumors were highly vascularized, indicating secretion of the angiogenic factor FGF-2. The transfected NBT-II cells that expressed 24 kD FGF-2 varied in their morphological appearance and did not secrete FGF-2; immunofluorescence and Western-blot studies showed that the FGF-2 was mainly intranuclear. When injected to nude mice, these cells produced tumors and migrated not only to the lymph nodes but also to the lungs where they produced metastases. In aggregate, these data indicate that stimulation of angiogenesis is not sufficient to increase tumor growth and that nuclear FGF-2 acts as a tumorigenic and metastasis-promoting factor in the NBT-II carcinoma model.
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PMID:[Impact on tumor angiogenesis and tumor progression of expression of the 18 kd and 24 kd isoforms of FGF-2]. 1037 8

Basic fibroblast growth factor (FGF-2) interacts with high-affinity tyrosine-kinase fibroblast growth factor receptors (FGFRs) and low-affinity heparan sulfate proteoglycans (HSPGs) in target cells. Both interactions are required for FGF-2-mediated biological responses. Here we report the FGF-2 antagonist activity of novel synthetic sulfonic acid polymers with distinct chemical structures and molecular masses (MMs). PAMPS [poly(2-acrylamido-2-methyl-1-propanesulfonic acid)], (MM approximately 7,000-10,000), PAS [poly(anetholesulfonic acid)], (MM approximately 9,000-11,000), PSS [poly(4-styrenesulfonic acid)], (MM = 70,000), and poly(vinylsulfonic acid) (MM = 2,000), inhibited FGF-2 binding to HSPGs and FGFRs in fetal bovine aortic endothelial GM 7373 cells. They also abrogated the formation of the HSPG/FGF-2/FGFR ternary complex, as evidenced by their capacity to prevent FGF-2-mediated cell-cell attachment of FGFR-1-overexpressing, HSPG-deficient Chinese hamster ovary cells to wild-type HSPG-bearing cells. Direct interaction of the polysulfonates with FGF-2 was demonstrated by their ability to protect the growth factor from proteolytic cleavage. Accordingly, molecular modeling, based on the crystal structure of the interaction of FGF-2 with a heparin hexamer, showed the feasibility of docking PAMPS into the heparin-binding domain of FGF-2. In agreement with their FGF-2-binding capacity, PSS, PAS, and PAMPS inhibited FGF-2-induced cell proliferation in GM 7373 cells and murine brain microvascular endothelial cells. The antiproliferative activity of these compounds was associated with the abrogation of FGF-2-induced tyrosine phosphorylation of FGFR-1. Moreover, the polysulfonates PSS and PAS inhibited FGF-2-induced activation of mitogen-activated protein kinase-1/2, involved in FGF-2 signal transduction. In conclusion, sulfonic acid polymers bind FGF-2 by mimicking heparin interaction. These compounds may provide a tool to inhibit FGF-2-induced endothelial cell proliferation in angiogenesis and tumor growth.
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PMID:Modulation of fibroblast growth factor-2 receptor binding, signaling, and mitogenic activity by heparin-mimicking polysulfonated compounds. 1038 2


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