Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effectors of mucosal and natural immunity (i.e. natural killer, NK, cells and NKT lymphocytes) are known to play an important role in host defence against tumors. Gammadelta T lymphocytes are the most represented cell populations in mucosal associated lymphoid tissue and share several characteristics of T and NK cells. Two main subsets of gammadelta T cells are known: one, expressing the Vdelta2 T cell receptor (TCR), is found in the peripheral blood, while T cells expressing Vdelta1 TCR are resident in epithelial tissues. The former subset is capable of killing myeloma and Burkitt lymphoma cells, while the latter has been implied in the defence against epithelial cancers. Furthermore, there is increasing evidence that alphabeta and gammadelta T lymphocytes make distinct contributions to anticancer surveillance. Indeed, unlike alphabeta T cells, gammadelta T lymphocytes are involved in the recognition of antigens that do not undergo the conventional major histocompatibility complex (MHC)-driven antigen presentation. Down-regulation of expression of MHC alleles as well as tumor-specific antigens is observed frequently during tumor progression, resulting in an impairment of MHC-restricted, alphabeta-T-cell-mediated tumor-specific immunity. Given the unique set of antigens recognized and the lack of requirement for classical antigen-presenting molecules, gammadelta T lymphocytes might, therefore, represent a useful and potent system in anti-cancer surveillance, as proposed for the immune response against pathogens. Evidence that gammadelta and alphabeta cells make distinct contribution to anti-cancer surveillance have been recently provided in mice. Here, we discuss the potential role played by resident Vdelta1+ and circulating Vdelta2+ T lymphocytes in the defense against solid tumors and hematological malignancies.
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PMID:Role of gammadelta T lymphocytes in tumor defense. 1535 83

The presence of hypoxic areas is a common feature of solid tumors and has been associated with decreased sensitivity of the tumors to radiation therapy and oxygen-dependent chemotherapeutic agents, as well as worsened outcomes, including survival. Anemia is also common in cancer patients and is believed to contribute to tumor hypoxia. Thus, the rationale exists for administering recombinant human erythropoietin (rHuEPO, epoetin alfa) in an effort to increase hemoglobin levels, correct anemia, and thereby possibly increase the sensitivity of tumors to standard cancer treatment and improve patient outcomes. The results of several preclinical studies that examined the impact of anemia prevention by rHuEPO on tumor sensitivity to radiation therapy in rodent models of cancer showed that induction of anemia increased hypoxia in tumor cells and that correction of anemia with rHuEPO could improve tumor oxygenation. Further studies in rodent models showed significantly delayed tumor growth in both irradiated mice and irradiated rats treated with rHuEPO. In those studies, the increased radiosensitivity observed was believed to be due to improved tumor oxygenation following the correction of anemia. Similarly, enhancements in chemosensitivity were found in rHuEPO-treated rodent models. In the chemosensitivity studies, as in the radiosensitivity studies, the therapeutic benefit obtained was believed to reflect improved tumor oxygenation subsequent to an rHuEPO-related increase in oxygen availability. One study evaluated the potential biologic effects of epoetin alfa on tumor progression using murine myeloma models (MOPC-315 and 5T33 MM). Treatment of MOPC-315 tumor-bearing mice with epoetin alfa induced complete tumor regression in 30%-60% of mice. Regression was found to be tumor specific, and the effect of epoetin alfa was shown to be T-cell mediated. Additionally, epoetin alfa administration prolonged survival and reduced morbidity and mortality in the 5T33 MM tumor model. Those investigators suggested that epoetin alfa may have antitumor activity in addition to its hematopoietic effects. Overall, these preclinical findings suggest that correction of anemia by rHuEPO can increase tumor sensitivity to both radiation therapy and chemotherapy and that epoetin alfa may exert an immunomodulatory effect in multiple myeloma.
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PMID:rHuEPO and treatment outcomes: the preclinical experience. 1559 22

The proteasome plays a critical role in the degradation of proteins involved in the regulation of cell cycle, apoptosis, and angiogenesis. Bortezomib is the first in a new class of antineoplastic agents known as proteasome inhibitors to become available for clinical use. Bortezomib targets pathways relevant to tumor progression and therapy resistance and can directly modulate expression of cyclins, p27kip1, p53, nuclear factor-kB, Bcl-2, and Bax. In in vitro and in vivo, growth inhibition and apoptosis have been observed in tumor cells following exposure to bortezomib. Currently, bortezomib is approved for the treatment of patients with relapsed and/or refractory multiple myeloma who have received > or =2 therapies and progressed on their most recent therapy. Efforts are now being directed toward exploring the use of bortezomib in the treatment of advanced non-small-cell lung cancer (NSCLC). Clinical trials using bortezomib as monotherapy or in combinations, such as with taxanes, gemcitabine and platinums, and novel agents are under way, and preliminary results have demonstrated activity with bortezomib as a single agent and in combination with chemotherapy in advanced NSCLC. In addition, pharmacogenomics and biomarker analysis are being used in an attempt to identify tumor types likely to respond to treatment with bortezomib.
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PMID:Use of proteasome inhibition in the treatment of lung cancer. 1563 66

Multiple myeloma (MM) is a B-cell neoplasm that is characterized by the clonal expansion of malignant plasma cells and is frequently associated with chromosomal translocations placing an oncogene under the control of the immunoglobulin heavy chain enhancer. Despite these pathogenic translocations, MM cells remain dependent on external cues for survival. We present evidence that brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors, and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), contribute to these survival cues. MM cells express TrkB, and respond to BDNF by activating mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase-a PI3K target (PI3K/Akt) signaling cascades. Addition of BDNF protects human MM cell lines (HMCLs) from apoptosis induced by dexamethasone or bortezomib and prolongs the survival of primary MM cells cultured alone or with human bone marrow (BM) stroma. As BDNF and TrkB are expressed by osteoblasts, stromal cells, and endothelial cells within the BM microenvironment, a BDNF-TrkB axis may be critical to the interactions of MM with bone and stroma that contribute to MM tumor progression. Finally, BDNF is expressed by malignant plasma cells isolated from a subset of patients with MM, as well as by most HMCLs, suggesting a potential role for this neurotrophin axis in autocrine as well as paracrine support of MM.
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PMID:A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival. 1565 81

The 26S proteasome is a large intracellular adenosine 5'-triphosphate-dependent protease that identifies and degrades proteins tagged for destruction by the ubiquitin system. The orderly degradation of cellular proteins is critical for normal cell cycling and function, and inhibition of the proteasome pathway results in cell-cycle arrest and apoptosis. Dysregulation of this enzymatic system may also play a role in tumor progression, drug resistance, and altered immune surveillance, making the proteasome an appropriate and novel therapeutic target in cancer. Bortezomib (formerly known as PS-341) is the first proteasome inhibitor to enter clinical practice. It is a boronic aid dipeptide that binds directly with and inhibits the enzymatic complex. Bortezomib has recently shown significant preclinical and clinical activity in several cancers, confirming the therapeutic value of proteasome inhibition in human malignancy. It was approved in 2003 for the treatment of advanced multiple myeloma (MM), with approximately one third of patients with relapsed and refractory MM showing significant clinical benefit in a large clinical trial. Its mechanism of action is partly mediated through nuclear factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. Several clinical trials are currently ongoing in MM as well as several other malignancies. This article discusses proteasome inhibition as a novel therapeutic target in cancer and focuses on the development, mechanism of action, and current clinical experience with bortezomib.
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PMID:Proteasome inhibition as a novel therapeutic target in human cancer. 1565 9

Angiogenesis is the hallmark of cancer. Growing evidence indicates that an imbalance between pro- and anti-angiogenic molecules triggers the angiogenic switch during tumor progression. Several molecules, able to affect vascular formation and function, are now beginning to be elucidated. Recent data indicate that angiogenesis also occurs in hematological malignancies. In multiple myeloma it has been demonstrated that patients with active disease have an increase in bone marrow angiogenesis correlated with the progression of disease and an adverse prognosis. The pathophysiology of myeloma-induced angiogenesis is complex and involves either the direct production of angiogenic molecules by myeloma cells or their induction in the microenvironment. In this review we have focalized our attention on the main factors involved in the angiogenic switch that occurs in MM patients.
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PMID:Angiogenic switch in multiple myeloma. 1576 77

Fragile sites are chromosomal structures that have been proposed to have a determining role in cancer-associated DNA instability. The human WWOX gene spans the FRA16D chromosomal fragile site, the common minimal region of homozygous deletion found in adenocarcinomas and three out of five translocation breakpoints in multiple myeloma. Transcripts from the alternatively spliced WWOX gene encode proteins with common N-terminal WW domains and variable homology to the oxidoreductase family of proteins. In this study, the Drosophila orthologue of the WWOX gene was identified and subjected to mutagenesis via homologous recombination. The resultant DmWWOX1 mutants were viable but exhibited an increased sensitivity to ionizing radiation. This radiation sensitivity was rescued by reintroduction and expression of either the wild-type Drosophila or human WWOX genes. Thus, the protective function of DmWWOX in response to irradiation in Drosophila is conserved with human WWOX (hWWOX). This is consistent with a protective role for hWWOX where aberrant expression, as a result of breakage at the associated fragile site, could contribute directly to cancer progression.
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PMID:FRA16D common chromosomal fragile site oxido-reductase (FOR/WWOX) protects against the effects of ionizing radiation in Drosophila. 1600 79

ARK5, AMP-activated protein kinase (AMPK)-related protein kinase mediating Akt signals, is closely involved in tumor progression, and its stage-associated expression was observed in colorectal cancer. In this study, we found ARK5 expression in multiple myeloma cell lines expressing c-MAF and MAFB. In addition, gene expression profiling of 351 clinical specimens revealed ARK5 expression in primary myelomas expressing c-MAF and MAFB, suggesting that ARK5 may be a transcriptional target of the Large-MAF family. Sequence analysis of the ARK5 gene promoter revealed that it contains two putative MAF-recognition element (MARE) sequences. In support of this hypothesis, ARK5 was induced when an MAFB or c-MAF expression vector was introduced into non-ARK5-expressing colon cancer cells. Furthermore, ARK5 promoter activity was dramatically decreased by mutation or deletion of MARE sequences. Chromatin immunoprecipitation assays revealed an interaction between the Large-MAF family proteins and MARE sequences in the ARK5 promoter. Moreover, in ARK5 mRNA-expressing multiple myeloma lines, but not in ARK5-negative lines, insulin-like growth factor (IGF)-1 increased invasion activity. IGF-1-induced invasion was reproduced when ARK5 was overexpressed in Burkitt's lymphoma and plasmacytoma lines. Based on results, we conclude that ARK5 is a transcriptional target of the Large-MAF family through MARE sequence and that ARK5 may in part mediate the aggressive phenotype associated with c-MAF- and MAFB-expressing myelomas.
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PMID:ARK5 is transcriptionally regulated by the Large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma. 1604 63

Bone destruction is a hallmark of multiple myeloma, and recent studies demonstrated a strong interdependence between tumor progression and bone resorption. Increased bone resorption as a major characteristic of multiple myeloma is caused by osteoclast activation and osteoblast inhibition (uncoupling). Myeloma cells alter the local regulation of bone metabolism by increasing the receptor activator of NF-kappaB ligand (RANKL) and decreasing osteoprotegerin (OPG) expression within the bone marrow microenvironment, thereby stimulating the central pathway for osteoclast formation and activation. In addition, they produce the chemokines MIP-1alpha, MIP-1beta and SDF-1alpha, which also increase osteoclast activity. Furthermore, myeloma cells suppress osteoblast function by the secretion of osteoblast inhibiting factors, e.g. Dickkopf (DKK)-1. The resulting bone destruction releases several cytokines, which in turn promote myeloma cell growth. Therefore, the inhibition of bone resorption could stop this vicious circle and not only decrease myeloma bone disease, but also the tumor progression. Preclinical studies provided strong evidence that the suppression of the osteoclast activity using bisphosphonates, RANKL blockade or inhibition of MIP-1alpha or MIP-1beta is effective both in reducing myeloma bone disease and tumor growth and therefore may offer an important treatment strategy in multiple myeloma.
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PMID:Myeloma bone disease. 1618 25

Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that is involved in angiogenesis, cell survival and tumor progression. In this study we show that human myeloma cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 protein in human myeloma cells has also been demonstrated. Moreover, using small interfering RNA (siRNA) to silent Runx2 in myeloma cells, we suppressed OPN mRNA and protein expression. OPN production in myeloma cells was stimulated by growth factors as IL-6 and IFG-1 and in turn OPN stimulated myeloma cell proliferation. In an 'in vitro' angiogenesis system we showed that OPN production by myeloma cells is critical for the proangiogenic effect of myeloma cells. The expression of OPN by purified bone marrow (BM) CD138(+) cells has also been investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to controls. Moreover, significantly higher BM angiogenesis has been observed in MM patients positive for OPN as compared to those negative. Our data highlight that human myeloma cells with active Runx2/Cbfa1 protein directly produce OPN that is involved in the pathophysiology of MM-induced angiogenesis.
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PMID:Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients. 1620 9


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