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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor progression to the invasive and metastatic states dramatically enhances the morbidity and mortality of cancer. Rational therapeutic interventions will only be possible when we understand the molecular mechanisms governing the cell behavior underlying this transformation. For invasion, a subpopulation of tumor cells must recognize the extracellular matrix barrier, modify the barrier, migrate through the barrier, and then proliferate in the adjacent but ectopic locale. Prevention of any one of these steps would prevent invasion, but determining the most sensitively dysregulated step should provide the most promising therapeutic index. In many invasive tumors, upregulation of active motility is stimulated by growth factor receptor signaling, the EGF receptor being the most frequently implicated. Two key downstream molecular switches, PLCgamma and m-calpain, are required for growth factor-induced motility but not basal, matrix-stimulated motility. Inhibition of either of these enzymes blocks in vitro and in vivo invasion of prostate, breast, and bladder carcinomas and glioblastomas. These represent novel and potentially selective targets for drug development. Future advances in the imaging of tumors in animals and ex vivo organ culture systems should provide additional new targets.
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PMID:Growth factor-induced cell motility in tumor invasion. 1210 55

Previous studies have shown that EGF can induce the tyrosine phosphorylation of caveolin-1 in murine fibroblasts following ErbB1 (EGF receptor) mutation or overexpression, but the cell signaling events linking EGF action with caveolin phosphorylation are not fully established. In this regard, we examined multiple human carcinoma cell lines that express various ErbB family members, including A431 epidermoid carcinoma cells and several squamous carcinoma cell lines. In all cases, EGF treatment induced the tyrosine phosphorylation of caveolin-1 in a time- and EGF dose-dependent manner, and immunoblotting analysis revealed that this phosphorylation occurred at tyrosine-14. The EGF-dependent phosphorylation of caveolin-1 was observed at low temperatures (4 degrees C) and was enhanced by caveolae-disrupting agents (cyclodextrin), suggesting that this EGF-dependent system is in a low temperature-stable arrangement that allows for their interaction under conditions where mobility in the membrane is altered. To further assess the events linking EGF action with caveolin phosphorylation, we evaluated the ligand specificity of these responses and their dependence on known effectors of EGF receptor function. We observed that EGF and HB-EGF, but not heregulin, promoted caveolin-1 phosphorylation in A431 cells, suggesting that these responses are linked to EGF receptor activation and not solely occurring via the activation of other endogenous ErbB family members. In addition, the EGF-induced phosphorylation of caveolin-1 in A431 cells was blocked by the Src kinase antagonists PP1 and PP2, but not by the MEK inhibitor PD98059, the phosphoinositide 3-kinase inhibitors LY294002 and wortmannin, or cytoskeleton-disrupting agents, such as cytochalasin D, colchicine, and nocadazole. Altogether, these data indicate that multiple human carcinoma cells exhibit an EGF receptor-dependent tyrosine phosphorylation of caveolin-1 and that this process is sensitive to Src family kinase inhibitors. These observations support a role for caveolin tyrosine phosphorylation in the profile of cellular responses by which Src potentiates cancer progression following EGF receptor overexpression.
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PMID:Caveolin-1 phosphorylation in human squamous and epidermoid carcinoma cells: dependence on ErbB1 expression and Src activation. 1237 46

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 receptor TK activity is a way to effectively block the tumorigenic effects that arise from these pathways. The HER family of TK receptors is overexpressed or dysregulated in many types of human cancer. As a result these receptors were identified as targets for cancer therapy. Several agents have been developed that reversibly, or irreversibly, inhibit one, two or all of the HER receptors. Tarceva and Iressa are HER1-TK inhibitors that are advanced in development. Clinical data show that these agents as monotherapy have antitumor activity in patients with various types of solid tumor and are well tolerated; encouraging data are also produced when Tarceva or Iressa are combined with chemotherapeutic agents. 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 antitumor activity. HER-TK inhibitors are exciting agents that are likely to have a substantial impact on the way we treat patients with cancer.
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PMID:HER-targeted tyrosine-kinase inhibitors. 1242 50

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

Smad7 and Smad6 are inhibitory Smads that block transforming growth factor-beta (TGF-beta) superfamily signal transduction. Smad7 is overexpressed in chemically induced mouse epidermal tumors, where oncogenic activation of c-ras is a frequent event. To test the role of Smad7 overexpression in tumor progression, we used retroviruses to transduce Smad7 or Smad6 and v-ras(Ha) into primary mouse keratinocytes. By itself, Smad7 transiently enhanced keratinocyte proliferation, blocked normal differentiation, and induced keratin 8, a marker of malignant conversion, but did not cause tumor formation. Smad7 extended the in vitro life span, suppressed senescence, and increased transformation frequency 3-fold of primary keratinocytes coexpressing v-ras(Ha). Smad7/v-ras(Ha) coinfected keratinocytes rapidly progressed to squamous cell carcinomas in vivo, whereas pBabe/v-ras(Ha)- or Smad6/v-ras(Ha)-transduced keratinocytes formed only benign papillomas. Smad7/v-ras(Ha) tumors had elevated proliferation and defective nuclear localizaton of Smad2, Smad3, and Smad5, whereas only Smad5 was altered in Smad6/v-ras(Ha) tumors. Smad7 overexpression in vitro induced epidermal growth factor (EGF)-like growth factors TGF-alpha, heparin binding-EGF, amphiregulin, and EGF receptor tyrosine phosphorylation as well as the EGF-CFC growth factor cripto-1. TGF-alpha and cripto-1 were also overexpressed in Smad7/v-ras(Ha) tumors. These results suggest that Smad7 overexpression accelerates tumor progression through inhibition of TGF-beta superfamily signaling and up-regulation of the EGF-like superfamily of growth factors. This is the first demonstration that Smad7 overexpression can cause malignant conversion in a multistage cancer model and suggests that it may have an important role in the pathogenesis of human cancer.
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PMID:Smad7 but not Smad6 cooperates with oncogenic ras to cause malignant conversion in a mouse model for squamous cell carcinoma. 1463 1

Growth factors and estrogen receptor (ER) signaling cooperate to play essential roles in cell proliferation, differentiation and tumor progression in mouse reproductive organs. Treatment of neonatal mice with diethylstilbestrol (DES) induces an estrogen-independent persistent proliferation and cornification of the vaginal epithelium, which results in cancerous lesions later in life. However, the mechanisms of the estrogen-dependent and -independent pathways essentially remain unknown. We characterized the expression of epidermal growth factor (EGF)-like growth factors (EGF, transforming growth factor alpha (TGF-alpha), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), amphiregulin (APR), epiregulin (EPR) and neuregulin (NRG) 1) and erbB receptors (EGF receptor (EGFR), erbB2/neu, erbB3 and erbB4) in the vaginae of mice treated either neonatally (0-4 day) or as adults (55-59 day) with estrogens. EGFR and erbB2 were activated in the vaginal epithelium of mice by estrogen treatment. This activation was also encountered in vaginae from neonatally DES-exposed mice, along with the expression of EGF, TGF-alpha, HB-EGF, BTC, APR, EPR and NRG1. Immunohistochemical analysis indicated that erbB2 was primarily expressed in vaginal epithelium. Finally, we found that serine 118 and 167 located in the AF-1 domain of ERalpha were phosphorylated in these vaginae. AG825, AG1478 or ICI 182,780 administration blocked proliferation of vaginal epithelium induced by neonatal DES exposure. Thus, signal transduction via EGFR and erbB2 could be related to the estrogen-induced vaginal changes and persistent erbBs phosphorylation and sustained expression of EGF-like growth factors, leading to ERalpha activation that may result in cancerous lesions in vaginae from neonatally DES-exposed mice later in life.
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PMID:Estrogen-independent activation of erbBs signaling and estrogen receptor alpha in the mouse vagina exposed neonatally to diethylstilbestrol. 1464 53

The term "targeted cancer therapies" refers to treatment strategies designed to inhibit the product of an oncogene involved in the process of neoplastic transformation. Different categories of targeted therapies can be identified: 1) Therapies directed at oncogenes that are directly involved in the initiation of neoplastic transformation: the use of imatinib for the treatment of CML or GIST is the classical model in this subgroup. Single agent targeted therapies generally produce high response rates in this situation. 2) Therapies directed at oncogenes involved at a later stage of neoplastic transformation. These oncogenes contribute to tumor progression but not necessarily to the onset of malignant transformation. The use of trastuzumab for HER2-amplified breast adenocarcinoma is the classical model in this subgroup. These treatments are associated with low response rates when used as single agent therapy, whereas generally displaying a synergistic or additive effect with classical chemotherapy in models currently available. In contrast, when these targeted therapies are applied to tumor models where the targeted gene is present but not directly involved in the process of malignant transformation, no antitumor efficacy is generally observed. Recently, the identification of HER1 mutations in subsets of lung carcinoma as a predictive factor for response to gefitinib and erlotinib provided an example of how the empiric use of a targeted treatment may enable to identify new nosological entities. The present paper reviews examples of targeted cancer therapies and their results.
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PMID:Targeted cancer therapies. 1574 38

Invasion and metastasis are critical determinants of cancer morbidity. Genes and molecules participating in these steps must be regarded as potential prognostic factors. Growth factors and their receptors, cell-cycle regulators, cell-adhesion molecules and matrix-degrading enzymes are those to be used as prognostic factors, including epidermal growth factor (EGF), EGF receptor, K-sam, HER-2, interleukin (IL)-8, vascular endothelial growth factor (VEGF), cyclin E, p27, E-cadherin, CD44v6, matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1). Alterations in epigenetics, such as aberrant DNA methylation and histone modification that are, in part, associated with the tumor progression of gastric cancer, can be candidate prognostic factors. The number of methylated genes may serve as a marker of tumor progression. Genetic polymorphism not only affects cancer susceptibility but also influences malignant phenotype; examples include single-nucleotide polymorphism in the HER-2 and MMP-9 genes. Comprehensive gene expression analyses are useful to search for novel genes related to invasion and metastasis and potential prognostic factors. Serial analysis of gene expression (SAGE) has identified several these genes, such as CDH17, APOE, FUS, COL1A1, COL1A2, GW112, and MIA. Overexpression of MIA is found to be associated with poor prognosis. Microarray analysis has great potential for identifying the characteristics of individual cancers, from the view point of gene expression profiles. A combination of these examinations can not only foretell a patient's prognosis but can also give information directly connected with personalized cancer medicine and prevention.
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PMID:Molecular-pathological prognostic factors of gastric cancer: a review. 1586 15

Ovarian cancer (OC) is the leading cause of death in gynecologic diseases in which there is evidence for a complex chemokine network. Chemokines are a family of proteins that play an important role in tumor progression influencing cell proliferation, angiogenic/angiostatic processes, cell migration and metastasis, and, finally, regulating the immune cells recruitment into the tumor mass. We previously demonstrated that astrocytes and glioblastoma cells express both the chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1), and that SDF-1alpha treatment induced cell proliferation, supporting the hypothesis that chemokines may play an important role in tumor cells' growth in vitro. In the present study, we report that CXCR4 and SDF-1 are expressed in OC cell lines. We demonstrate that SDF-1alpha induces a dose-dependent proliferation in OC cells, by the specific interaction with CXCR4 and a biphasic activation of ERK1/2 and Akt kinases. Our results further indicate that CXCR4 activation induces EGF receptor (EGFR) phosphorylation that in turn was linked to the downstream intracellular kinases activation, ERK1/2 and Akt. In addition, we provide evidence for cytoplasmic tyrosine kinase (c-Src) involvement in the SDF-1/CXCR4-EGFR transactivation. These results suggest a possible important "cross-talk" between SDF-1/CXCR4 and EGFR intracellular pathways that may link signals of cell proliferation in ovarian cancer.
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PMID:Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation. 1592 80

Prostaglandin E(2) (PGE(2)), a proinflammatory bioactive lipid, promotes cancer progression by modulating proliferation, apoptosis, and angiogenesis. PGE(2) is a downstream product of cyclooxygenase (COX) and is biochemically inactivated by prostaglandin dehydrogenase (PGDH). In the present study, we investigated the mechanisms by which PGDH is down-regulated in cancer. We show that epidermal growth factor (EGF) represses PGDH expression in colorectal cancer cells. EGF receptor (EGFR) signaling induces Snail, which binds conserved E-box elements in the PGDH promoter to repress transcription. Induction of PGE(2) catabolism through inhibition of EGFR signaling blocks cancer growth in vivo. In human colon cancers, elevated Snail expression correlates well with down-regulation of PGDH. These data indicate that PGDH may serve a tumor suppressor function in colorectal cancer and provide a possible COX-2-independent way to target PGE(2) to inhibit cancer progression.
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PMID:Repression of prostaglandin dehydrogenase by epidermal growth factor and snail increases prostaglandin E2 and promotes cancer progression. 1681 38


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