Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor cells have been found in autologous hematopoietic cell transplants used after high-dose chemotherapy. To specifically eliminate contaminating mammary tumor cells during ex vivo expansion of CD34+ hematopoietic progenitor cells, we used recombinant immunotoxins (ITs) directed against cell-surface antigens expressed on mammary carcinoma cells. ITs were expressed from fusion cDNAs combining a single-chain antibody fragment (scFv) directed against the Erb-B2 or epidermal growth factor (EGF) receptors with a truncated Pseudomonas exotoxin A fragment devoid of its cell-binding domain. CD34+ hematopoietic progenitor cells did not express Erb-B2 and EGF receptors as detected by Western blotting. Ex vivo expansion of total hematopoietic cells or of colony-forming cells from CD34+ progenitors in the presence of stem-cell factor (SCF), interleukin-1 (IL-1), IL-3, IL-6, and erythropoietin (Epo) was not affected when ITs were added to the cultures. In contrast, MDA-MB 453 and MCF-7 mammary carcinoma cells were depleted in a dose- and time-dependent manner by more than 3 log in coculture with CD34+ cells over a period of 7 days in the presence of 100 to 1,000 ng/mL of anti-Erb-B2 IT. This included elimination of the subpopulations with regrowth potential. Similarly, addition of either anti-Erb-B2 or anti-EGF receptor ITs to primary breast cancer cells isolated from patients with metastatic disease resulted in elimination of cytokeratin-positive cells in seven of seven samples. ITs are highly efficient and convenient to use for the depletion of mammary tumor cells during ex vivo expansion of hematopoietic progenitor-cell autografts.
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PMID:Purging of mammary carcinoma cells during ex vivo culture of CD34+ hematopoietic progenitor cells with recombinant immunotoxins. 947 51

In the post-embryonic life, physiological angiogenesis is tightly controlled. Angiogenesis also occurs in pathological circumstances such as tumor vessel proliferation, retinal neovascularization and ischemia. The development of collateral circulation is not only not deleterious, but life saving. Other cases such as neoplastic neovascularization are the basis of the continuous growth of tumors and metastases, and therefore constitute a target of therapeutical efforts. Among a list of molecules able to control angiogenesis, we emphasize the pivotal role of vascular endothelial growth factor (VEGF). VEGF is a potent mitogen for endothelial cells, but is devoid of mitogenic activity for other cell types. VEGF is a polypeptide with four main different isoforms that are remarkably different in terms of solubility and affinity for matrix proteins. VEGF interacts with two endothelial cell-specific tyrosine kinase receptors. The main interest of its study lies in VEGF's role in pathological angiogenic processes, where an increase in the VEGF mRNA expression has been consistently observed. An interesting example is the up-regulation of VEGF's and VEGF receptors' mRNA in a considerable number of human tumors and retina, where they have a critical role in the development of neovascularization. In recent work in our laboratory, we have found further potential interactions of VEGF with pathophysiological mechanisms, namely, the increase in VEGF gene expression under exposure to reactive oxygen species and the positive interaction between VEGF and erythropoietin. VEGF has outstanding possibilities for therapeutic applications aimed at inhibiting or favoring the development of new vessels.
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PMID:Role of vascular endothelial growth factor in the response to vessel injury. 983 75

We have come to understand apoptosis as not merely a single form of cell death, but as a fundamental theme in cell biology that has far-reaching implications in the fields of physiology and pathology. At the present time, however, the mechanism of apoptosis is not clearly understood, as research into apoptosis is still at the initial stages. Nevertheless, the links between apoptosis and a variety of pathological conditions are gradually becoming clearer. In this article, we will provide a simple explanation of apoptosis and its mechanism as a novel concept of cell death and discuss the way in which apoptosis has been linked to a variety of pathological conditions. WHAT IS APOPTOSIS?: In normal tissue, cells that are no longer needed are rapidly eliminated without affecting the overall function of the tissue. In this process cells undergo an active and spontaneous suicide called programmed cell death. In fact, the majority of physiological cell deaths take the form of apoptosis. The word apoptosis is used, in contrast to necrosis, to describe the situation in which a cell actively pursues a course toward death upon receiving certain stimuli [1]. The morphological changes of apoptosis found in most cell types first involve contraction in cell volume and condensation of the nucleus. When this happens the intracellular organelles such as the mitochondria retain their normal morphology. As apoptosis proceeds, blebbing of the plasma membrane occurs, and the nucleus becomes fragmented. Finally, the cell itself fragments to form apoptotic bodies that are engulfed by nearby phagocytes. With respect to biochemical changes, it is known that the chromosomes become fragmented into nucleosome units, and DNA forms characteristic ladder patterns when subjected to agarose gel electrophoresis. MECHANISM OF APOPTOSIS: It has been reported that apoptosis is induced in various cells by many kinds of irritations, but the precise mechanism is still unclear. Cell injuries that induce apoptosis include those that cause DNA damage such as radiation and anticancer drugs, those that are mediated by the TNF receptor and Fas receptor (the so-called "death signal receptors"), and the deprivation of cytokines that supply survival signals such as IL-3 and erythropoietin. The tumor suppressor gene p53 plays a very important role in apoptosis induced by damage to DNA. This has been demonstrated by studying resistance to apoptosis of cells derived from p53 knockout mice [2]. Other than the irritations that induce apoptosis, molecules that have been strongly implicated as major players in the drama of apoptosis include the Bcl-2 family proteins and the IL-1 converting enzyme (ICE) and its homolog proteases (caspase family). Both groups of proteins show homology with proteins that affect cell death in nematodes. It is believed that molecules that contribute to cell death have been well conserved in multicellular organisms all the way from the relatively primitive nematodes to mammals including humans. It was discovered that Bcl-2 suppressed apoptosis induced in IL-3 dependent cells by deprivation of IL-3 [3]. It has since become the gene around which apoptosis research revolves. Recently, it has become clear that cell death involving the Bcl-2 protein is under the control of similar proteins from the same family [4]. It is interesting that the phenomenon of cell death may be regulated by the balance of the molecules involved in it. APOPTOSIS ABNORMALITIES AND DISEASE: Physiological cell death plays a major role in the growth and permanent maintenance of the human body [5]. In the process of forming the nervous system, neurons that do not form proper connections die. Physiological cell death also accompanies the removal of virus-infected cells by cytotoxic T cells, the elimination of autoreactive immune cells, the formation of the gut, the reconstitution of cartilage and bone, etc. When physiological cell death that normally should occur is inhibited, inappropriate physiological cell death may occur that is harmful to the body and forms the basis of disease. For example, in patients with neural degenerative disorders such as Alzheimer's disease and Parkinson's disease, we can find premature cell death in a particular subset of neurons. The death of T cells in AIDS patients is also a form of physiological cell death. Inhibition of cell death in the immune system enables the survival of autoreactive B cells and T cells, and is therefore a cause of autoimmune disorders. Apoptosis has been particularly linked to cancer. Normal cells are programmed for death if they are subjected to many types of non-physiological stress such as anticancer drugs or radiation, if they become isolated from surrounding cells and are unable to receive their tissue-specific survival signals [6], or if oncogenes are expressed haphazardly [7]. On the other hand, it is believed that the ability to survive is enhanced in transformed cancer cells because they are more resistant to apoptosis, they exhibit resistance to anticancer drugs, they are no longer dependent on survival signals, and they can metastasize. Therefore, the cancer progresses as the cancer cells maintain the proliferative superiority they acquire from their oncogenes. In other words, when cancer cells become resistant to apoptosis, they become resistant to treatment, metastasize, and proliferate destructively. The concept that the malignancy of cancer is due to its resistance to apoptosis is a relatively new one and is worthy of further study.
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PMID:Physician Education: Apoptosis. 1038 21

Mediastinal paragangliomas are rare neoplasms in children. Anemia, as a paraneoplastic syndrome, has been described in adults with metastatic paraganglioma. The management of paraneoplastic anemia from metastatic paraganglioma has been problematic, with no reports in the literature describing successful treatment. This article describes a 17-year-old Jehovah's Witness with a mediastinal paraganglioma, hepatic metastases, and severe anemia. The patient and his family refused blood products and the anemia was refractory to erythropoietin and elemental iron therapy. Serial chemoembolization of the hepatic lesions resulted in resolution of the anemia, allowing subsequent debulking of the mediastinal paraganglioma.
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PMID:Metastatic paraganglioma and paraneoplastic-induced anemia in an adolescent: treatment with hepatic arterial chemoembolization. 1059 70

Hypoxia-inducible factor 1 (HIF-1) is a basic-helix-loop-helix transcription factor that plays essential roles in mammalian development and physiology. HIF-1 is a heterodimer composed of HIF-1alpha and HIF-1beta subunits. The expression and activity of the HIF-1alpha subunit are tightly regulated by cellular O2 concentration. Under hypoxic conditions, HIF-1 activates the transcription of genes encoding erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, and other genes whose protein products increase O2 delivery or facilitate metabolic adaptation to hypoxia. HIF-1 is essential for embryonic vascularization and survival, neovascularization in ischemic myocardium, hypoxia-induced pulmonary vascular remodeling, and tumor vascularization. HIF-1alpha is overexpressed in the majority of common human cancers and their metastases, due to the presence of intratumoral hypoxia and as a result of mutations in genes encoding oncoproteins and tumor suppressors. Pharmacologic manipulation of HIF-1 levels may provide a novel therapeutic approach to diseases that represent the most common causes of mortality in Western society, including cancer, chronic lung disease, and myocardial ischemia.
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PMID:Expression of hypoxia-inducible factor 1: mechanisms and consequences. 1060 34

In the last ten years recombinant 'protein drugs' such as erythropoietin or tissue plasminogen activator have become widely used in the clinic. After some early setbacks antibodies look well placed to join them. A decade of antibody engineering is finally beginning to pay off with a string of chimeric and humanized antibodies gaining the Food and Drug Administration approval in the last two years. Here we will report on recent developments in the clinical application of antibodies, in particular, in the treatment of malignant lymphoma. We will also discuss some of the current strategies for the engineering of both whole antibodies (IgG) and recombinant antibody fragments for the next generation of antibody therapeutics.
Cancer Metastasis Rev 1999
PMID:Engineering antibodies for the clinic. 1085 84

Erythrocytosis is a well-known paraneoplastic syndrome occurring in 1% of cancer cases. Herein, we report a patient with a history of renal cell carcinoma (RCC) who developed a paraneoplastic erythrocytosis 3 months after curative nephrectomy. Concomitantly we documented the presence of a deltoid mass, highly suggestive for a muscle metastasis. The most important features found in this patient were: 1) the absence of erythrocytosis at the time of diagnosis, 2) the high concentration of haemoglobin and hematocrit, with no increase in serum erythropoietin (Epo) level at the time of RCC relapse. Metastasectomy was performed and hemoglobin and hematocrit returned to normal range after the operation. Even in the absence of immunohistochemical and biomolecular evidence of Epo production in the neoplastic tissue, we think the hypothesis of paraneoplastic syndrome may be the most likely, both for the strict temporal relationship between the observation of the neoplastic lesion and the appearance of polycythemia and for the absence of all other known causes of erythrocytosis. An objection to this hypothesis was the ectopic production of an Epo-like factor. The English language literature about muscle metastases and paraneoplastic erythrocytosis was reviewed.
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PMID:A man with a deltoid swelling and paraneoplastic erythrocytosis: case report. 1498 86

The authors report 5 cases of polycythaemia associated with renal cancer. This paraneoplastic syndrome is present in less than 5% of all renal cancers. It is considered to be a factor of poor prognosis, as it is often associated with metastatic and/or high-grade cancer Polycythaemia, secondary to secretion of erythropoietin (EPO) by the tumour, is reversible after nephrectomy. The persistence or recurrence of polycythaemia after nephrectomy may indicate incomplete local resection or the presence of EPO-secreting metastases.
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PMID:[Polycythaemia and renal cancer. Report of 5 cases]. 1537 86

Originally characterized as a growth factor for erythrocytes, erythropoietin (EPO) is used to treat anemia and fatigue in cancer patients receiving radiation therapy and chemotherapy. EPO and the EPO receptor (EPOR) are expressed in nonhematopoietic cells and cancers. However, the role of EPO and EPOR within nonhematopoietic cancer cells remains incompletely understood. Although a recent clinical trial demonstrated worse tumor control and survival in head and neck cancer patients treated with EPO, the role of EPO and EPOR in head and neck squamous cell carcinoma (HNSCC) has not been examined. In the present study, we demonstrate the previously unrecognized EPO-mediated invasion by HNSCC cells through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. Furthermore, we confirmed the expression of EPO and EPOR in a panel of human HNSCC cell lines and tissue specimens. Pharmacological doses of EPO also had a limited proliferation effect in these cell lines. These results define a novel role for EPO in mediating tumor cell invasion. Increased levels of EPO and EPOR in lymph node metastases as compared to primary tumors from HNSCC patients further support the role of EPO/EPOR in HNSCC disease progression and metastasis.
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PMID:Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma. 1585 28

Alveolar rhabdomyosarcoma (RMS) accounts for 20% to 30% of childhood RMS and is associated with a prognosis worse than embryonal RMS. Disseminated RMS can present with extensive bone marrow involvement. Assessing the extent of the tumor is critical, because therapy and prognosis depend on the degree to which the mass has spread beyond the primary site. The value of F-18 FDG PET in patients with RMS has been reported in some series but none specifically involving bone marrow. Children have a highly cellular hematopoietic bone marrow and differentiation of a highly cellular marrow from neoplastic infiltration may be difficult. Various other conditions associated with diffuse FDG uptake in the bone marrow include marrow hyperplasia resulting from hemolytic/iron-deficiency/blood-loss anemia, after chemotherapy with granulocyte/macrophage colony-stimulating factor and recombinant erythropoietin treatment, leukemia, non-Hodgkin lymphoma, and myelodysplasia. It is therefore important to consider the above differential diagnoses in mind when evaluating cases of unexpected marrow uptake in F-18 FDG PET studies. We report here a case of RMS with diffuse bone marrow involvement detected on F-18 FDG PET wherein FDG PET was useful in determining the true extent (primary and metastases) of RMS before definitive therapy and the valuable adjunct role it has with structural imaging in management.
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PMID:Rhabdomyosarcoma with widespread bone marrow infiltration: beneficial management role of F-18 FDG PET. 1788 59


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