Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated the differential expression in tumor-associated blood vessels of two vascular endothelial growth factor receptors (VEGFRs), VEGFR1 and VEGFR2, during initiation and progression of prostate cancer in the genetically engineered transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model. In our "progression switch" model, expression of VEGFR1 is associated with early and more differentiated disease, whereas expression of VEGFR2 is associated with advanced and more poorly differentiated disease. To test the hypothesis that stage-specific inhibition of vascular endothelial growth factor signaling could be used as therapy for autochthonous prostate cancer, we initiated a preclinical trial with SU5416, a potent antiangiogenic small molecule inhibitor of VEGFR associated tyrosine kinase activity. In our early intervention trial, administration of SU5416 to TRAMP mice did not appear to influence angiogenesis or tumor progression between 10 and 16 weeks of age, a time corresponding to high levels of VEGFR1 expression. In our late intervention trial, however, we observed a significant decrease in tumor-associated mean vessel density, increased apoptotic index, and pronounced regions of cell death when SU5416 was administered to TRAMP mice between 16 and 22 weeks of age, a time corresponding to high levels of VEGFR2 expression. These results clearly demonstrate that therapy directed specifically against the VEGFR signaling axis can dramatically impair angiogenesis and induce apoptosis of autochthonous spontaneous and progressive prostate cancer.
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PMID:SU5416 selectively impairs angiogenesis to induce prostate cancer-specific apoptosis. 1288 33

Studies on signal transduction pathways have generated various promising molecular targets for therapeutic inhibition in cancer therapy. Receptor tyrosine kinases represent an important class of such therapeutic targets. c-Met is a receptor tyrosine kinase that has been shown to be overexpressed and/or mutated in a variety of malignancies. A number of c-Met activating mutations, many of which are located in the tyrosine kinase domain, have been detected in various solid tumors and have been implicated in invasion and metastasis of tumor cells. It is known that stimulation of c-Met via its natural ligand, hepatocyte growth factor (also known as scatter factor, HGF/SF) results in a plethora of biological and biochemical effects in the cell. Activation of c-Met signaling can lead to scattering, angiogenesis, proliferation, enhanced cell motility, invasion, and eventual metastasis. In this review, the role of c-Met dysregulation in tumor progression and metastasis is discussed in detail with particular emphasis on c-Met mutations. Moreover, we summarize current knowledge on various pathways of c-Met signal transduction, highlighting the central role in the cytoskeletal functions. In this summary is included recent data in our laboratory indicating that phosphorylation of focal adhesion proteins, such as paxillin, p125FAK, and PYK2, occurs in response to c-Met stimulation in lung cancer cells. Most importantly, current data on c-Met suggest that when mutated or overexpressed in malignant cells, c-Met would serve as an important therapeutic target.
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PMID:c-Met: structure, functions and potential for therapeutic inhibition. 1288 8

Endothelin-1 (ET-1) is overexpressed in ovarian carcinoma and acts as an autocrine factor selectively through the ETA receptor (ETAR) to promote tumor cell proliferation, survival, neovascularization, and invasiveness. Loss of gap junctional intercellular communication (GJIC) is critical for tumor progression by allowing the cells to escape growth control. Exposure of HEY and OVCA 433 ovarian carcinoma cell lines to ET-1 led to a 50-75% inhibition in intercellular communication and to a decrease in the connexin 43 (Cx43)-based gap junction plaques. To investigate the phosphorylation state of Cx43, ovarian carcinoma cell lysates were immunoprecipitated and transient tyrosine phosphorylation of Cx43 was detected in ET-1-treated cells. BQ 123, a selective ETAR antagonist, blocked the ET-1-induced Cx43 phosphorylation and cellular uncoupling. Gap junction closure was prevented by tyrphostin 25 and by the selective c-Src inhibitor, PP2. Furthermore, the increased Cx43 tyrosine phosphorylation was correlated with ET-1-induced increase of c-Src activity, and PP2 suppressed the ET-1-induced Cx43 tyrosine phosphorylation, indicating that inhibition of Cx43-based GJIC is mainly mediated by the Src tyrosine kinase pathway. In vivo, the inhibition of human ovarian tumor growth in nude mice induced by the potent ETAR antagonist, ABT-627, was associated with a reduction of Cx43 phosphorylation. These findings indicate that the signaling mechanisms involved in GJIC disruption on ovarian carcinoma cells depend on ETAR activation, which leads to the Cx43 tyrosine phosphorylation mediated by c-Src, suggesting that ETAR blockade may contribute to the control of ovarian carcinoma growth and progression also by preventing the loss of GJIC.
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PMID:Endothelin-1 decreases gap junctional intercellular communication by inducing phosphorylation of connexin 43 in human ovarian carcinoma cells. 1290 86

The interaction of osteopontin (OPN) with CD44 and alphavbeta3-integrin has been implicated in numerous signal transduction pathways that may promote cancer metastasis. CD44v6 is a splice variant of CD44 which has been identified as a marker of cancer progression. In this study, immortalized liver carcinoma cells (HepG2) were used to examine the effect of OPN on two isoforms of CD44: CD44 standard (CD44 s) and CD44v6. Western blots demonstrated that OPN up-regulated plasma membrane CD44v6 protein expression in a concentration- and time-dependent fashion. CD44v6 levels returned to control levels when OPN-alphavbeta3-integrin binding was blocked by an RGD peptide or tyrosine kinase activity was inhibited. OPN significantly increased CD44v6 protein synthesis, while simultaneously decreasing protein degradation. Steady-state mRNA levels of both CD44s and CD44v6 were unaltered in the presence of OPN stimulation. OPN increased HepG2 in vitro adhesion to hyaluronate (HA); excess soluble HA extinguished OPN-mediated HepG2 adhesion, indicating CD44 dependence. In conclusion, OPN binds to the alphavbeta3-integrin to increase plasma membrane CD44v6 expression and augment in vitro adhesion to HA. This may contribute to the mechanism by which OPN enhances metastatic behavior in hepatocellular cancer cells.
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PMID:Osteopontin-dependent CD44v6 expression and cell adhesion in HepG2 cells. 1294 55

Improved understanding of tumor biology has led to the identification of numerous growth factors that are involved in malignant transformation and tumor progression. Many of these factors induce cellular responses through receptors with intrinsic tyrosine kinase (TK) activity. Therefore, inhibiting the activity of TK receptors is one of the ways to effectively block the disordered proliferation of cancer that arises from these pathways. The human epidermal growth factor receptor (HER) family is overexpressed or dysfunctional in many human malignancies. Therefore, these receptors have been identified as targets for cancer therapy. Several agents have been developed that reversibly or irreversibly inhibit one, two, or all of the HER receptors. Iressa and Tarceva are HER1-specific TK inhibitors that are in advanced development. The large phase II study of Iressa (IDEAL1) in patients with non-small-cell lung cancer (NSCLC) in whom previous platinum-based therapy has failed, found that the median survival time (MST) was 7.6 months, which was no less than that with Docetaxel treatment. Other dual or pan-HER, reversible or irreversible, TK inhibitors are being investigated in phase I trials. Early data show that they are generally well tolerated and have provided evidence of against activity tumors. HER-TK inhibitors are likely to have a substantial impact on the treatment of cancer patients.
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PMID:Molecular target-based cancer therapy: tyrosine kinase inhibitors. 1295 75

Aberrant cell survival and resistance to apoptosis are hallmarks of tumor invasion and progression to metastatic disease, but the mechanisms involved are poorly understood. The epithelial-mesenchymal transition (EMT), a process that facilitates progression to invasive cancer, provides a superb model for studying such survival mechanisms. Here, we used a unique spheroid culture system that recapitulates the structure of the colonic epithelium and undergoes an EMT in response to cytokine stimulation to study this problem. Our data reveal that the EMT results in the increased expression of both VEGF and Flt-1, a tyrosine kinase VEGF receptor, and that the survival of these cells depends on a VEGF/Flt-1 autocrine pathway. Perturbation of Flt-1 function by either a blocking antibody or adenoviral expression of soluble Flt-1, which acts in a dominant-negative fashion, caused massive apoptosis only in cells that underwent EMT. This pathway was critical for the survival of other invasive colon carcinoma cell lines, and we observed a correlative upregulation of Flt-1 expression linked to in vivo human cancer progression. A role for Flt-1 in cell survival is unprecedented and has significant implications for Flt-1 function in tumor progression, as well as in other biological processes, including angiogenesis and development.
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PMID:Flt-1-dependent survival characterizes the epithelial-mesenchymal transition of colonic organoids. 1452 39

We have previously reported that Fms-like tyrosine kinase-3 ligand (flt3-L) induced tumor stabilization and regression of palpable ectopic prostate tumors (TRAMP-C1). Although some mice remained "tumor free" for several months following termination of therapy, tumors invariably reappeared and grew progressively in all animals. The lack of a curative response suggests that TRAMP-C1 tumors may inhibit the development of a flt3-L-induced anti-tumor immune response. Consistent with this view, we demonstrate herein that TRAMP-C1 tumors isolated from flt3-L treated animals contained a marked dendritic cell (DC) infiltrate that was temporally correlated with tumor regression. However, tumor-associated DCs, especially in a flt3-L setting, progressively lost MHC class II antigen expression during tumor growth. Treatment with the DC maturation factor trimeric CD40 ligand (CD40-L) either alone or in combination with fl3-L neither prevented loss of DC class II antigens nor disease relapse. Because loss of class II antigens would prevent CD4+ helper T (Th) cell development, we treated tumor-bearing mice with agonistic anti-4-1BB antibody (Ab), which can promote cytotoxic T lymphocyte (CTL) development independent of Th cell function. However, anti-4-1BB Ab alone did not alter TRAMP-C1 growth kinetics, and, when used in combination, was no more effective than flt3-L alone. The inability of the 4-1BB co-stimulatory signal to promote tumor regression may have been related to two additional features of TRAMP-C1 tumors. First, tumor-associated T cells, but not splenic T cells from tumor-bearing animals, were profoundly deficient in expression of CD3-epsilon (CD3epsilon) and T cell receptor-beta chain (TCRbeta). Second, CTLs required 24 h to efficiently kill TRAMP-C1 target cells even after up-regulation of MHC class I antigens by interferon-gamma. This rate of tumor cell destruction by CTLs may not be sufficient to prevent tumor progression. Taken together, these data reveal several important immunosuppressive characteristics of the prostate tumor microenvironment (TME) that immunotherapeutic interventions must first overcome to achieve longterm cures. These data also highlight the importance of utilizing treatment versus vaccination models in the evaluation of immunotherapeutic modalities.
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PMID:Impact of the tumor microenvironment on host infiltrating cells and the efficacy of flt3-ligand combination immunotherapy evaluated in a treatment model of mouse prostate cancer. 1462 25

The epidermal growth factor receptor (EGFR) has emerged in recent years as a key target of molecular therapy for solid tumors. The postembryonic role of EGFR is normally limited. In cancer, however, abnormal EGFR-tyrosine kinase (TK) activity plays a central role in many of the processes involved in tumor progression, such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Several different approaches have been taken to inhibit EGFR-mediated activity in tumor cells, including monoclonal antibodies directed at the ligand-binding portion of the EGFR and small-molecule agents that directly inhibit the intracellular TK domain of EGFR. Two of these TK inhibitors, gefitinib and erlotinib (OSI-774, Tarceva ), have shown antitumor activity and good tolerability across several tumor types in early dose-finding clinical trials, particularly for non-small-cell lung cancer (NSCLC). In heavily pretreated patients with advanced NSCLC, gefitinib showed clinically significant tumor responses and symptom relief with good tolerability. Based on these results, gefitinib has now been approved for the third-line treatment of advanced NSCLC. The use of gefitinib in standard treatment programs or combined with other molecular targeted agents may substantially improve the outlook for patients with NSCLC or other types of solid tumors
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PMID:Biologically targeted treatment of non-small-cell lung cancer: focus on epidermal growth factor receptor. 1464 89

The epidermal growth factor receptor (EGFR) signaling pathway plays an important role in a number of processes that are key to tumor progression, including cell proliferation, angiogenesis, metastatic spread, and inhibition of apoptosis. EGFR is expressed or overexpressed in non-small-cell lung cancer (NSCLC), and EGFR-mediated growth has been associated with advanced disease and poor prognosis in NSCLC patients. ZD1839 (Iressa) is an orally active, selective EGFR-tyrosine kinase inhibitor that blocks EGFR signal transduction. In preclinical studies using NSCLC cell lines, ZD1839 has been shown to inhibit tumor cell growth. In addition, ZD1839, as monotherapy and in combination with commonly used cytotoxic agents, has produced growth delay in NSCLC human xenografts. Preliminary results from phase I trials in patients with advanced disease have shown that ZD1839 has excellent bioavailability, an acceptable tolerability profile, and promising clinical activity in patients with a variety of tumor types, particularly in NSCLC. ZD1839 is currently in phase III clinical development for the treatment of advanced NSCLC.
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PMID:ZD1839 (Iressa) in non-small-cell lung cancer. 1465 86

Progression of human colon cancer is often associated with elevated expression and activity of the Src family tyrosine kinase (SFK). SFK is ordinarily in equilibrium between inactive and primed states by a balance of negative regulatory kinase Csk and its counteracting tyrosine phosphatase(s), both of which act on the regulatory C-terminal tyrosine of SFK. To evaluate the contribution of the regulatory system of SFK in cancer progression, we here modulated the equilibrium status of SFK by introducing wild-type or dominant-negative Csk in human epithelial colon cancer cells, HCT15 and HT29. Overexpression of wild-type Csk induced decreased SFK activation, increased cell-cell contacts mediated by E-cadherin, decreased the number of focal contacts and decreased cell adhesion/migration and in vitro invasiveness. Conversely, expression of a dominant-negative Csk resulted in elevated SFK activation, enhanced phosphorylation of FAK and paxilllin, enhanced cell scattering, an increased number of focal contacts, dramatic rearrangement of actin cytoskeleton and increased cell adhesion/migration and in vitro invasiveness. In these scattered cells, however, localization, expression and phosphorylation of either E-cadherin or beta-catenin were not significantly affected, suggesting that the E-cadherin-mediated cell-cell contact is indirectly regulated by SFK. Furthermore, all these events occurred absolutely dependent on integrin-mediated cell adhesion. These findings demonstrate that Csk defines the ability of integrin-SFK-mediated cell adhesion signaling that influences the metastatic potential of cancer cells.
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PMID:Csk defines the ability of integrin-mediated cell adhesion and migration in human colon cancer cells: implication for a potential role in cancer metastasis. 1471 34


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