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

Interleukin 6 (IL-6) is a multifunctional cytokine important in the inflammatory response. Its potential role as an antitumor agent has been suggested by its demonstrated activity in a variety of tumor models. The mechanism of antitumor activity has been proposed to be its enhancement of cytotoxic T-cell function. In the current work we demonstrate clear antitumor activity for this cytokine in a nonimmunogenic tumor system. B16 melanoma cells transfected with the human IL-6 complementary DNA demonstrated slower tumor growth in vivo. Tumors that developed from these cells had a prominent stromal matrix, an easily recognized infiltration of inflammatory cells, fewer mitotic figures, and fewer blood vessels. These in vivo findings corresponded with a greater adhesion of the IL-6-transfected B16 cells to stromal matrix proteins (laminin, fibronectin, and vitronectin) and a less prominent vascular response in an intradermal angiogenesis assay. Therefore, we propose that with weakly antigenic tumors, such as B16 melanoma, IL-6 may mediate important antitumor responses by nonspecific proinflammatory mechanisms.
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PMID:In vivo and in vitro characteristics of interleukin 6-transfected B16 melanoma cells. 139 47

The extracellular matrix protein vitronectin is recognized as an adhesive substrate by cells expressing at least one of four known vitronectin receptors: integrins alpha v beta 1, alpha v beta 3, alpha v beta 5 or alpha IIb beta 3. Cell interaction with vitronectin may induce spreading and migration and have an effect on cell growth and differentiation in specific processes, such as tumor growth and metastasis, wound healing, bone resorption and viral infection.
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PMID:Vitronectin and its receptors. 769 4

Despite rapid advances in our understanding of the biology of cell adhesion, the data available in the literature make it is difficult to propose one simple scheme in which cell adhesion molecules can be related to tumor growth and metastasis. This difficulty can be related to a number of factors. Some of the apparently conflicting experimental results that demonstrate both enhanced or diminished tumor cell adhesion during tumor progression may be attributed to the experimental systems used. Those studies that have injected tumor cells intravenously have, in general, shown that enhanced tumor cell adhesiveness correlates with metastatic ability. It should be recognized that this experimental approach bypasses many of the early stages of the metastatic cascade and is biased towards tumor cells with an enhanced ability to form aggregates with cells in the circulation and to adhere to distant vascular sites. On the other hand, studies that have implanted tumors into animals and allowed them to grow and metastasize (spontaneous metastasis) have generally demonstrated an inverse relationship between adhesive ability and the ability to metastasize. Another major obstacle in understanding the role of CAMs in metastasis is the well known problem of tumor heterogeneity and the phenotypic instability of metastatic cells over relatively short periods of time (141). The cells that make up a metastatic focus may thus be quite different from the tumor cells that originally formed the lesion. It is quite possible that the selective pressures that initially enable a cancer cell to form a metastatic lesion may be quite different than those that later favor rapid tissue growth. The major obstacle in making any sweeping generalizations about cell adhesion molecules and tumor progression, however, is that the process of successful metastasis is inherently complex, requiring tumor cells to possess decreased adhesive interactions with surrounding cells and extracellular matrix at some points in the cascade and increased adhesive interactions at other times. Based on the information available, the following scenario can be proposed. Using the schema shown in Figure 1, successful metastasis initially requires that normal cell-cell and cell-substratum adhesion be disrupted, causing release of neoplastic cells from the primary tumor (step 1). For epithelial tumors, down-regulation of cadherins and perhaps, integrins, appear to be involved. This loss of cell adhesion must be followed by migration of tumor cells into the vascular system (step 2), a step requiring efficient cell-substratum interactions. In melanomas, this step seems to require expression of the vitronectin receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of integrins and other cell adhesion molecules in tumor progression and metastasis. 842 75

Integrins are heterodimeric transmembrane molecules that mediate cell-cell and cell-substratum adhesion. Because alterations in the adhesive properties of tumor cells influence tumor growth and progression, the distribution of different alpha and beta integrin subunits was studied in both the parenchyma and the connective tissue in 6 normal and 25 adenomatous human anterior pituitaries. All normal parenchymal cells expressed the alpha3beta1 and alpha6beta4 integrins. By contrast, in adenomatous parenchymal cells the expression of alpha3beta1 was down-regulated and that of alpha6beta4 abrogated. Neoexpression of alphavbeta3 Occurred in the parenchyma of a subset of adenomas. All normal connective tissue cells expressed the alpha1 and beta1 subunits, a third subunit (alpha5) being present in the normal endothelium. By comparison, all adenomatous stromal cells expressed many more integrin subunits (alpha1, alpha3, alpha5, alphav, beta1 and beta3), adenomatous endothelial cells bearing additional subunits (alpha6, beta4 and beta5). Vitronectin, absent from the normal connective tissue, was constantly observed in the adenomatous stroma. To conclude, compared with cells of the normal gland, adenomatous anterior pituitary cells display a decreased expression of integrins whereas the adenomatous stroma expresses a rich repertoire of integrins. These changes are not related to the secretory type, grade or invasiveness of the adenoma. The resulting alterations in the adhesive properties of adenomatous cells could facilitate their dissemination. Enrichment of the integrin repertoire expressed by the adenomatous vasculature is indicative of its dual nature, systemic and tumoral.
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PMID:Adenomatous transformation of the human anterior pituitary is associated with alterations in integrin expression. 869 May 24

Osteopontin (OPN) is a secreted adhesive glycoprotein with a gly-arg-gly-asp-ser (GRGDS) cell binding domain. Several independent studies have suggested that OPN functions in tumor growth and metastasis, and one likely possibility is that OPN facilitates tumor invasion by promoting tumor cell migration. Consistent with this hypothesis, immobilized OPN promoted concentration-dependent tumor cell migration (i.e., haptotaxis) in modified Boyden chambers. In particular, cleavage of OPN by thrombin, which likely occurs in the tumor microenvironment, resulted in enhancement of OPNs haptotactic activity; and assays performed with purified preparations of the two individual OPN thrombin-cleavage fragments demonstrated that all detectable activity was associated with the GRGDS-containing fragment. In contrast to the activity of both OPN and its GRGDS-containing fragment in promoting haptotaxis, neither of these proteins in solution promoted chemotaxis, indicating that each must be immobilized to promote cell migration. In haptotaxis assays, antibody LM609 to integrin alpha v beta 3 blocked > 80% cell migration towards the GRGDS-containing OPN fragment, implicating alpha v beta 3 as its principal functional receptor. In comparison with equimolar quantities of other adhesive proteins, the GRGDS-containing OPN thrombin-cleavage fragment was not only > 2-fold more effective than intact OPN at promoting haptotaxis, but also > 8-fold and > 6-fold more effective than fibrinogen and vitronectin, respectively, indicating that this OPN fragment is highly active relative to other alpha v beta 3 ligands.
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PMID:Cell migration promoted by a potent GRGDS-containing thrombin-cleavage fragment of osteopontin. 897 13

Integrins are a superfamily of cell surface receptors involved in cell-cell and cell-matrix adhesion. Integrin-mediated interactions are involved in the regulation of numerous cellular functions such as fertilization, implantation, cell differentiation and migration during embryonic development, maintaining tissue architecture, blood clot formation and retraction programmed cell death, tumor growth and metastasis formation, lymphocyte homing and response of cells to mechanical stresses. This broad spectrum of activity is achieved by combining the ability to create mechanically functional junctions (cell-matrix and cell-cell) and signal-transducing capabilities. Osteoblasts and osteoclasts express specific integrin receptors and the pattern of expression varies depending on the stage of cell differentiation. Interactions of integrins with bone-matrix adhesive proteins are thought to be important for regulating the tissue integrity and may provide a local, responsive regulatory system of osteoblastic differentiation as well. Osteoclasts most likely attach to osteopontin exposed on the bone surface via the classic vitronectin receptor alpha v beta 3 and this binding may be crucial to their bone resorption activity.
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PMID:Integrins and bone--cell adhesion and beyond. 952

The integrin alpha(v)beta3 interacts with the arginine-glycine-aspartic acid (RGD) tripeptide recognition sequence of a variety of extracellular matrix proteins. Recent studies show that alpha(v)beta3 plays an important role in tumor-induced angiogenesis and tumor growth and that antagonists of alpha(v)beta3 inhibit angiogenic processes that include endothelial cell adhesion and migration. Consequently, we reasoned that an RGD-based peptidomimetic antagonist of alpha(v)beta3 might inhibit tumor angiogenesis and tumor growth in vivo. An RGD-peptidomimetic library was screened to identify antagonists of vitronectin binding to alpha(v)beta3, and the compounds chosen were modified to produce selective and potent inhibitors of alpha(v)beta3. One of these compounds, beta-[[2-2-[[[3-[(aminoiminomethyl)amino]-phenyl]carbonyl]amino]ac etyl]amino]-3,5-dichlorobenzenepropanoic acid (SC-68448), inhibited vitronectin binding to both alpha(v)beta3 and the closely related platelet receptor, alpha(IIb)beta3, in a dose-responsive manner. SC-68448 inhibited vitronectin binding to alpha(v)beta3 (IC50, 1 nM) and fibrinogen binding to the platelet receptor alpha(IIb)beta3 (IC50, >100 nM), demonstrating that SC-68448 was 100-fold more potent as an inhibitor of alpha(v)beta3 versus alpha(IIb)beta3. In cell-based studies, SC-68448 inhibited alpha(v)beta3-mediated endothelial cell proliferation in a dose-dependent manner but did not inhibit tumor cell proliferation, suggesting that effects on endothelial cell proliferation were not due to SC-68448-induced cytotoxicity. In accord with these results, SC-68448 inhibited angiogenesis in vivo in a basic fibroblast growth factor-induced rat corneal neovascularization model. A xenogeneic severe combined immune deficiency mouse/rat Leydig cell tumor model was developed for testing SC-68448 as an inhibitor of tumor growth in vivo. Rat Leydig cell tumors grew rapidly in severe combined immune deficiency mice and produced humoral hypercalcemia of malignancy. SC-68448 inhibited the growth of the tumors in mice by up to 80% and completely blocked the development of hypercalcemia. Together, these results demonstrate the feasibility of antitumor therapies based upon the development of nontoxic small molecule pharmacological antagonists of integrin alpha(v)beta3.
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PMID:A peptidomimetic antagonist of the integrin alpha(v)beta3 inhibits Leydig cell tumor growth and the development of hypercalcemia of malignancy. 958 35

Expression of the beta3 subunit of the alphavbeta3 vitronectin receptor on melanoma cells is associated with tumor thickness and the ability to invade and metastasize. To address the role of alphavbeta3 in the complex process of progression from the nontumorigenic radial to the tumorigenic vertical growth phase of primary melanoma, we examined the biological consequences of overexpressing alphavbeta3 in early-stage melanoma cells using an adenoviral vector for gene transfer. Overexpression of functional alphavbeta3 in radial growth phase primary melanoma cells 1) promotes both anchorage-dependent and -independent growth, 2) initiates invasive growth from the epidermis into the dermis in three-dimensional skin reconstructs, 3) prevents apoptosis of invading cells, and 4) increases tumor growth in vivo. Thus, alphavbeta3 serves diverse biological functions during the progression from the nontumorigenic radial growth phase to the tumorigenic and-invasive vertical growth phase primary melanoma.
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PMID:Adenoviral gene transfer of beta3 integrin subunit induces conversion from radial to vertical growth phase in primary human melanoma. 981 23

Urokinase receptor antagonists based on the growth factor domains of both human and murine urokinase which show sub-nanomolar affinities for their homologous receptors have been expressed as recombinant proteins. Further modification of these molecules by preparing fusions with the constant region of human IgG has led to molecules with high affinities and long in vivo half-lives. Smaller peptidic inhibitors have been obtained by a combination of bacteriophage display and peptide analog synthesis. All of these molecules inhibit the binding of the growth factor domain of uPA to the uPA receptor and enhance binding of the uPA receptor to vitronectin. Protein uPA receptor antagonists were tested in an in vivo tumor model using the human breast carcinoma MDAmb231 in immunodeficient mice. Both human and murine receptor antagonists showed significant inhibition of primary tumor growth, demonstrating that in vivo, both tumor and stromal cell uPA receptor dependent plasminogen activation can modulate tumor growth.
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PMID:Urokinase receptor antagonists: discovery and application to in vivo models of tumor growth. 1019 Feb 94

MCF-7 breast cancer cells stably transfected with protein kinase C-alpha (MCF-7-PKC-alpha cells) show anchorage-independent growth and exhibit increased tumorigenicity in nude mice. Since integrins are involved in tumor growth and metastatic spread, we investigated whether integrin expression is differentially regulated in MCF-7-PKC-alpha cells. Fluorescence-activated cell sorting revealed that alphavbeta3 is highly expressed on MCF-7-PKC-alpha cells, but is undetectable on MCF-7V cells (MCF-7 cells transfected with vector only). In contrast, MCF-7-PKC-alpha cells have reduced expression of alphavbeta5. Blocking experiments with antibodies to alphavbeta3 and alphavbeta5 revealed that these receptors are used by MCF-7-PKC-alpha cells to adhere primarily to vitronectin and osteopontin. Consistent with heterodimer expression, MCF-7-PKC-alpha cells express increased beta3 and decreased beta5 on their surface. Surface expression of alphav on MCF-7-PKC-alpha cells is unchanged. Western blotting, Northern analysis, and nuclear run-on assays indicated that post-translational mechanisms increase the surface expression of beta3 on MCF-7-PKC-alpha cells. In contrast, reduced beta5 transcription diminishes beta5 surface expression on MCF-7-PKC-alpha cells. These results indicate that overexpression of PKC-alpha in MCF-7 cells alters beta5 and beta3 expression by transcriptional and post-translational mechanisms, respectively, resulting in altered heterodimer expression. These findings suggest that the increased metastatic capacity of tumor cells with elevated protein kinase C levels may result, in part, from modulation of integrin expression.
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PMID:Overexpression of protein kinase C-alpha in MCF-7 breast cancer cells results in differential regulation and expression of alphavbeta3 and alphavbeta5. 1037 5


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