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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The currently accepted models of metastasis are inconsistent with many clinical observations of the natural history of cancer and its response to therapy. Specifically, the authors suggest that it is time for a "paradigm shift." It is time to reject the "local, regional, systemic hypothesis" of cancer and replace it with a hypothesis more consistent with the clinical facts, specifically, that cancer exists in many different forms (i.e. localized disease arising from locally acting carcinogens, which can spread locally and should be treated locally, and cancer that arises as localized disease but evolves to more malignant invasive disease [the current model of metastasis]). The other forms of cancer are systemic disease, which is induced by systemic carcinogens, and cancer arising in multiple cells and multiple sites, giving rise to a picture described as metastatic cancer. The importance of this paradigm shift is that more attention would be focused on identifying systemically acting carcinogens as they relate to etiology and to molecular abnormalities in the neoplastic cells that might be targeted clinically. Recent advances in cancer treatment have demonstrated that molecules that target cancer cell molecular abnormalities (rather than tissue of origin, lymph node, or metastasis) such as bcr-abl or mutations in a cellular receptor such as c-kit or epidermal growth factor possess curative potential. In addition, more attention should be devoted to distinguishing between local tumors and systemic disease, using sophisticated molecular biologic techniques. Perhaps most important, there is a need to devise therapeutic strategies that would treat cancer as a systemic illness and hopefully have a substantial impact on overall cancer mortality.
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PMID:Metastasis--an alternative hypothesis. 1573 96

Raf kinase inhibitory protein (RKIP; also known as phosphatidylethanolamine-binding protein or PEBP) is a modulator of the Raf/MAPK signaling cascade and a suppressor of metastatic cancer. Here, we show that RKIP inhibits MAPK by regulating Raf-1 activation; specifically, RKIP acts subsequent to Raf-1 membrane recruitment, prevents association of Raf-1 and p21-activated kinase (PAK), and blocks phosphorylation of the Raf-1 kinase domain by PAK and Src family kinases. Mutation of the PAK and Src phosphorylation sites on Raf-1 to aspartate, a phosphate mimic, prevented RKIP association with or inhibition of Raf-1 signaling. Interestingly, although RKIP can interact with B-Raf, RKIP depletion had no effect on activation of B-Raf. Because c-Raf-1 and B-Raf are both required for maximal MAPK stimulation by epidermal growth factor in neuronal and epithelial cell lines, we determined whether RKIP significantly affects MAPK signaling. In fact, RKIP depletion increased not only the amplitude but also the sensitivity of MAPK and DNA synthesis to epidermal growth factor stimulation by up to an order of magnitude. These results indicate that selective modulation of c-Raf-1 but not B-Raf activation by RKIP can limit the dynamic range of the MAPK signaling response to growth factors and may play a critical role in growth and development.
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PMID:Raf kinase inhibitory protein regulates Raf-1 but not B-Raf kinase activation. 1588 2

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Understanding the mechanisms regulating VEGF expression in neuroblastoma cells provides additional therapeutic options to control neuroblastoma tumor growth. VEGF mRNA is controlled by growth factors and hypoxia via the transcription factor hypoxia-inducible factor (HIF-1alpha). HIF-1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene, VHL, which targets HIF-1alpha degradation. To determine whether the levels of VEGF in neuroblastomas are due to mutations in VHL, we evaluated genomic DNA from 15 neuroblastoma cell lines using PCR. We found no mutations in exons 1, 2, or 3 of the VHL gene. VEGF mRNA levels in neuroblastoma cells cultured in serum-free medium increased after 8 to 16 hours in serum, insulin-like growth factor-I (IGF-I), epidermal growth factor, or platelet-derived growth factor. Serum/IGF-I induced increases in HIF-1alpha protein that temporally paralleled increases in VEGF mRNA, whereas HIF-1beta levels were unaffected. VEGF and HIF-1alpha levels were blocked by inhibitors of phosphatidylinositol 3-kinase and mammalian target of rapamycin. Furthermore, we confirmed that HIF-1alpha mediates approximately 40% of the growth factor activity stimulating VEGF protein expression. Topotecan blocked the IGF-I-stimulated increase in HIF-1alpha but not HIF-1beta, and this resulted in a decrease in VEGF in four neuroblastoma cell lines tested. These data indicate that growth factors in an autocrine or paracrine manner play a major role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to phosphatidylinositol 3-kinase, mammalian target of rapamycin, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
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PMID:Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells. 1593 Feb 97

Prostate adenocarcinoma metastasizes to the skeleton more frequently than any other organ. An underlying cause of this phenomenon may be the ability of bone-produced factors to specifically select disseminated prostate cancer cells that are susceptible to their trophic effects. Platelet-derived growth factor (PDGF), a potent mitogen for both normal and tumor cells, is produced in several tissues including bone, where it is synthesized by both osteoblasts and osteoclasts. Here, we show that PDGF causes a significantly stronger activation of the Akt/PKB survival pathway in bone-metastatic prostate cancer cells compared to nonmetastatic cells. Normal prostate epithelial cells and DU-145 prostate cells, originally derived from a brain metastasis, are not responsive to PDGF. In contrast, epidermal growth factor stimulates Akt to the same extent in all prostate cells tested. This difference in PDGF responsiveness depends on the higher expression of alpha-PDGFR in bone-metastatic compared to nonmetastatic prostate cells and the lack of alpha-PDGFR expression in normal and metastatic prostate cells derived from tissues other than bone. Thus, alpha-PDGFR expression might identify prostate cancer cells with the highest propensity to metastasize to the skeleton.
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PMID:Bone-metastatic potential of human prostate cancer cells correlates with Akt/PKB activation by alpha platelet-derived growth factor receptor. 1600 72

The human epidermal growth factor (EGF) receptor (HER) family of receptor tyrosine kinases has frequently been implicated in cancer. Apart from overexpression or mutation of these receptors, also the aberrant autocrine or paracrine activation of HERs by EGF-like ligands may be important in cancer progression. Neuregulins constitute a family of EGF-like ligands that bind to HER3 or HER4, preferably forming heterodimers with the orphan receptor HER2. Mesenchymal neuregulin typically serves as a pro-survival and pro-differentiation signal for adjacent epithelia. Disruption of the balance between proliferation and differentiation, because of autocrine production by the epithelial cells, increased sensitivity to paracrine signals or disruption of the spatial organization, may lead to constitutive receptor activation, in the absence of receptor overexpression. Consequently, the analysis of ligand expression and/or activated receptors in tumor samples may broaden the group of patients that can benefit from targeted therapies.
Clin Exp Metastasis 2004
PMID:Roles for neuregulins in human cancer. 1603 12

Renal cell carcinoma (RCC) still represents a therapeutic challenge when patients have advanced or metastatic disease. Treatment using IL-2 and IFN-alpha continues to be the standard of care in patients who are able to tolerate such regimens. Targeted therapy may become the first-line treatment for patients resistant or intolerant to cytokines as new emerging drugs continue to be investigated. Understanding the genetic abnormalities related to the development of RCC (e.g., VHL gene abnormalities) and identifying molecular targets (e.g., epidermal growth factor, vascular endothelial growth factor and carbonic anhydrase IX) are playing a major role in the emergence of these novel agents for the treatment of this malignancy. Overall, these drugs are better tolerated and more acceptable to use by patients than the traditional cytokine-based regimens. The use of oral drugs to treat various malignancies including RCC seems to be the new paradigm of the future. Further understanding of their mechanisms of action and confirmation of their benefits on the clinical outcome is needed.
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PMID:Emerging drugs for renal cell carcinoma. 1626 62

In the past several years, significant advances in the treatment of colorectal cancer (CRC) have been made. With the introduction of irinotecan and oxaliplatin combined with infusional 5-fluororuracil, survival times for patients with metastatic CRC have nearly doubled. With the incorporation of biologic agents that target the vascular endothelial growth factor and epidermal growth factor (EGF) pathways, additional improvements in response, progression-free survival, and overall survival have been seen in patients with advanced, metastatic disease. This article reviews the impact of EGF receptor inhibitors on improving survival in CRC when combined with oxaliplatin-containing regimens.
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PMID:Enhancing oxaliplatin-based regimens in colorectal cancer by inhibiting the epidermal growth factor receptor pathway. 1633 50

Tumor cells traverse the basement membrane zone and gain access to the underlying mesenchyme to eventually form metastases. Laminin 5 is a major component of the basement membrane and connects keratinocytes at the level of hemidesmosomes to the mesenchyme. Underneath invading tumor cells anti-laminin 5 staining is diminished, and laminin 5 degradation products can stimulate cell migration and epidermal growth factor (EGF) receptor signaling. To investigate laminin 5 expression in parental HaCaT and tumorigenic c-Ha-ras-transformed HaCaT II-4rt keratinocytes, the cells were cultivated under monolayer and organotypic culture conditions. In monolayer cultures, HaCaT and c-Ha-ras-transformed HaCaT II-4rt keratinocytes secreted comparable amounts of laminin 5. After 7 days of organotypic cultures, collagen IV, beta4-integrin, nidogen and laminin 5 were detected along the epithelial-mesenchymal interface of parental HaCaT keratinocytes, while staining for these proteins was patchy or absent in the organotypic cultures with c-Ha-ras-transformed HaCaT II-4rt cells. Immunoblotting analysis confirmed absence of laminin 5 deposition in organotypic cultures of c-Ha-ras-transformed HaCaT II-4rt while the protein was detected in organotypic cultures of HaCaT keratinocytes. Surprisingly, however, the alpha3 and gamma2 laminin chain transcripts were strongly induced in c-Ha-ras-transformed HaCaT II-4rt cells by organotypic culture conditions, indicating that invasive epidermal tumor cells retain high mRNA levels for laminin 5 chains and suggesting an autocrine/paracrine induction of the laminin chain mRNAs. Moreover, as laminin 5 was absent in organotypic cultures of c-Ha-ras-transformed HaCaT II-4rt cells, it suggests immediate degradation of the protein. Degradation products may further contribute to the malignant phenotype by enhancing cellular migration and EGF-receptor activation.
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PMID:Expression of laminin 5 by parental and c-Ha-ras-transformed HaCaT keratinocytes in organotypic cultures. 1646 Aug 39

Altered signaling pathways are key regulators of cellular functions in tumor cells. Constitutive activation of signal transducer and activator of transcription (STAT)3 and -5 may be involved in tumor formation and progression. We have investigated the role of STAT5 in cutaneous melanoma metastases using various RNA and protein techniques. In melanoma specimens, Stat5b transcripts were upregulated approximately 3.8-fold. In 13 of 21 (62%) human melanoma metastases, STAT5 was phosphorylated in comparison to normal human melanocytes and benign nevi. The STAT5 target gene Bcl-2 was frequently upregulated. The investigation of the underlying mechanism revealed specific STAT5 activation by recombinant human epidermal growth factor (rEGF). rEGF-induced activation of STAT5 occurred in vitro through the non-receptor tyrosine kinases transforming gene (src) of Rous Sarcoma virus and Janus kinase 1. Inhibition of Stat5b expression by small interfering RNA strongly reduced the expression of Bcl-2 and led to decreased cell viability and increased apoptosis in the melanoma cell lines A375 and BLM. Transfection with dominant-negative Stat5b caused enhanced cell death and G1 arrest in A375 cells. Our study identifies phosphorylated STAT5 in melanoma and shows regulation through rEGF; STAT5 may thus act as a survival factor for growth of human melanoma and may represent a potential target for molecular therapy.
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PMID:STAT5 phosphorylation in malignant melanoma is important for survival and is mediated through SRC and JAK1 kinases. 1674 10

Targeted biologic therapy for cancer has evolved from the laboratory to active clinical protocols and applied clinical practice in selected patients. Major targets include epidermal growth factor, and vascular endothelial growth factor receptors which are commonly expressed in gastro-intestinal cancers head & neck and lung cancers, and to some degree breast and gynecologic malignancy. Down stream signal transduction pathway inhibition of B-raf and N-ras mutations are examined in melanoma. New approaches involving re-packaging of chemotherapeutic agents are being exemplified in the nanoparticle formulation of paclitaxel which provides increased access to endothelial and tumor cells with potential enhanced therapeutic efficacy compared to the conventional version solubilized in a cremophor.
Cancer Metastasis Rev 2006 Jun
PMID:Targeting growth factors and angiogenesis; using small molecules in malignancy. 1677 May 40


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